HK1200098B

HK1200098B - Ph dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same

Info

Publication number: HK1200098B
Application number: HK15100531.9A
Authority: HK
Inventors: U‧马拉蒂; S‧柴尔德里斯; S‧伽马米尔; R‧W‧斯特罗梓尔
Original assignee: PLx 奥普科公司
Priority date: 2011-09-29
Filing date: 2012-09-29
Publication date: 2018-08-31

Description

pH-dependent carrier for targeted release of drugs along the gastrointestinal tract, composition thereof, preparation and use thereof

RELATED APPLICATIONS

This application claims benefit and priority from U.S. provisional patent application serial No. 61/540699, filed 9/29/2011 (09/29/2011) (29.09.2011).

Background

1. Field of the invention

Embodiments of the present invention relate to targeted release and/or pH-dependent release vehicles and compositions comprising the targeted release and/or pH-dependent release vehicles of the present invention and at least one bioactive agent, as well as methods of making and using the same.

More specifically, embodiments of the present invention relate to targeted release and/or pH-dependent release carriers and compositions comprising a targeted release and/or pH-dependent release carrier of the present invention and an effective amount of at least one active agent (active agent or agents), wherein the targeted release and/or pH-dependent release carrier comprises at least one biocompatible pharmaceutical agent (active agent or agents), and wherein the active agent comprises a nutraceutical and/or a pharmaceutical agent, and wherein the targeted release and/or pH-dependent release carrier comprises at least one targeted release and/or pH-dependent release agent for the active agent, such that the bioactive agent can be released in a targeted manner into the tract (tract) of an animal, mammal or human. Embodiments of the invention also relate to methods of making and using the vectors and/or compositions.

2. Description of the related Art

U.S. patent No. 4,666,701 discloses that gamma-linolenic acid or dihomo-gamma-linolenic acid is useful for reducing or preventing gastrointestinal bleeding and other side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs) when administered continuously, including in arthritis and other conditions for replacing the administration with administration of the acid alone without exacerbating the symptoms. This patent does not teach the targeted release of bioactive agents mediated by free fatty acids.

However, free fatty acids are known to be harmful to the upper GI tract. See, e.g., Velasquez et al, "oleic-induced mucosally in cervical ridges intestinesine (oleic acid-induced mucosal lesions in developing small pig intestines)," am.J. Physiol64G576-81, 1993; velasquez et al, "fat acid-induced input in collapsing pig interest: effect of the severity of injury and carbon chain length (fatty acid-induced damage in the developing intestine of small pigs)' Pediatr.33543-7, 1993; and this membrane damaging effect has been exploited therapeutically (see Croffie et al, "Sclerosing agents for use in GI endoscopies," gastroenterological Endoscopy661-6, 2007 (ethanolamine oleate, a drug used to induce endothelial cell membrane damage for the treatment of esophageal varices). Thus, the formulation of the invention contains a large number of two components known to be harmful to the upper GI tract, NSAIDs and free fatty acids (Davenport, "damage to the Gastric mucosa by fatty acids and acetylsalicylic acid)," Gastroenterology,46245-253, 1964, however the formulation of the invention shows comparable protection if there is no excellent protection against NSAID gastrointestinal toxicity.

U.S. patent application serial No. 10/433454, filed 11/6/2003, discloses a composition comprising a biocompatible oil carrier for non-steroidal anti-inflammatory drugs (NSAIDs), said carrier having a relatively high phospholipid content, exhibiting reduced Gastrointestinal (GI) NSAID toxicity. Preferred neutral lipids in these carriers are uncharged lipids: triglycerides which are still uncharged at all relevant phs (pH 1-9).

In U.S. patent nos. 4,950,656, 5,043,329, 5,763,422 and 5,955,451, saturated zwitterionic phospholipids are used in combination with saturated triglycerides to reduce GI toxicity, to increase cyclohexane solubility of NSAIDs, and to improve NSAID efficacy. U.S. Pat. nos. 5,763,422 and 5,955,451 specifically demonstrate the increase in aspirin (ASA) by the addition of triglycerides, tripalmitoyl glyceride: solubility of dipalmitoyl lecithin (DPPC) in cyclohexane. Increased cyclohexane solubility is believed to be associated with increased NSAID efficacy and/or reduced ASA GI toxicity.

In the publications and patents of Lichtenberger and its co-workers, a composition comprising a phospholipid and an NSAID is formed by: dissolving the components in an organic solvent such as methanol, ethanol or chloroform, and removing the solvent by distillation or evaporation; or the NSAID is dissolved in an aqueous solution at or above the pKa of the NSAID and added to the phospholipid membrane, followed by lyophilization if a solid product is desired. These methods allow the two components to chemically interact to form an associated complex. These methods most commonly use Phosphatidylcholine (PC) as the phospholipid, either synthetically prepared, such as Dipalmitoylphosphatidylcholine (DPPC), or as a purified or semi-purified PC compound.

More recently, in U.S. patent No. 6,451,339, Patel et al disclosed compositions for enhanced delivery of hydrophobic agents, wherein the compositions are substantially free of triglycerides and comprise a combination of hydrophilic and hydrophobic surfactants.

Although these patents and applications disclose compositions and methods for making the compositions, wherein the compositions are effective in reducing NThe GI toxicity of SAID, but the patents and applications do not disclose any information for preparing a carrier with the ability to target the release of NSAIDs to different parts of the gastrointestinal tract. The use of different pH-sensitive polymers as coatings for acid-labile drugs and drugs with upper gastrointestinal toxicity to take advantage of the differential pH profile of the gastrointestinal tract for targeted release of bioactive agents has been disclosed. However, this approach is limited by random pharmacokinetics and significant food effects (Leonards, j.r. and g. Levy, JAMA)193: 99-104, 1965, Bogenoft, C., I.Carlsson, et al, European Journal of Clinical pharmacy,14(5)，351-355，1978)。

thus, there is a need in the art for new and novel carriers and compositions comprising the same that are capable of targeted release of an active agent to different regions of the gastrointestinal tract and other tracts such as the urinary or reproductive tract. There is also a need in the art for a carrier and a composition comprising said carrier that is capable of targeted and/or pH-dependent release of an active ingredient, wherein the targeting and/or pH dependency corresponds to a targeting profile and/or pH profile of the tract in the body of an animal, mammal or human, such that the biologically active agent, such as an NSAID, is selectively released in the tract, such as into the duodenum or small intestine, and not into the stomach of the GI tract, that is, the carrier slowly and inefficiently releases the bioactive agent in a low pH environment such as gastric fluid, but rapidly and efficiently releases the bioactive agent in the presence of bile in small intestinal fluids in higher pH environments (e.g., pH values of 4-5), such as the upper duodenum, and even higher pH environments (e.g., pH values of 7-8).

Disclosure of Invention

SUMMARY

The carriers of the invention and compositions comprising the carriers of the invention have the ability to target the release of the bioactive agent to a selected region of the tissue, organ or tract being targeted, such as to a region of the Gastrointestinal (GI) tract, urinary tract, reproductive tract or other tract having a mucosal gel. Carrier-mediated targeted release is particularly useful for the following active ingredients: (a) is harmful to the upper GI tract (esophagus, stomach, and duodenum), (b) is acid labile, (c) is impermeable/insoluble in GI fluids, (d) is sensitive to first pass metabolism, and/or (e) causes gastric irritation, discomfort, or dyspepsia. In certain embodiments, targeted release is a pH dependent release such that the bioactive agent(s) are minimally released at the low pH of the stomach (e.g., pH less than about 3- < pH3) and effectively released at higher pH of the upper duodenum (e.g., at pH greater than or equal to 4- > pH 4). In certain embodiments, targeted release is a pH-dependent release such that the active agent(s) are minimally released at the low pH of the stomach (e.g., pH less than about 3- < pH3) and upper duodenum (e.g., at a pH greater than or equal to 4-5) and are effectively released at the higher pH of the small intestine in the presence of high concentrations of bile. In certain embodiments, the pH-dependent release of the active agent(s) is due to the inclusion in the carrier of a pH-dependent release agent such as at least one oil-soluble or oil-miscible compound comprising at least one ionizable group such as a carboxylic acid group, a hydroxyl group, an amino group, an amide group, or other similar ionizable group. In other embodiments, the at least one ionizable group comprises at least one carboxylic acid group or the at least one oil-soluble or oil-miscible compound comprises at least one carboxylic acid group. In other embodiments, the compound comprising at least one carboxylic acid group is sometimes referred to herein as the fatty acid of the free fatty acid to fully distinguish these acids from the ester groups of mono-, di-, and triglycerides. Fatty acids are particularly useful for customizable release of bioactive agents along the gastrointestinal tract and other tracts having pH profiles, as most fatty acids are non-ionized or neutral at low pH (e.g., gastric fluid pH) but become ionized at higher pH (e.g., intestinal fluid pH), allowing them to selectively deliver bioactive agent payloads. We present herein partition data, dissolution data, Fourier Transform Infrared (FTIR) spectroscopy data and animal data demonstrating the targeted release of NSAIDS, pH dependent release of NSAIDS and the efficacy of these targeted NSAID release and/or pH dependent release carriers in mammals. These data clearly demonstrate that the vectors of the present invention are ideally suited for targeted delivery of NSAIDS to different regions of the gastrointestinal tract. Partitioning data and animal toxicity data demonstrate that these carriers effectively target aspirin release in a pH-dependent manner, and that selective targeted release to the small intestine effectively reduces aspirin stomach toxicity. The data also indicate that targeted and/or pH-dependent release agents can function even in the presence of other components such as phospholipids, triglycerides, etc. at relatively low and relatively high levels. The data also indicate that the targeted and/or pH dependent release characteristics of the carriers of the invention are effective for different NSAIDs and NSAID types. Because these NSAIDs are weak acids, the efficacy of these compositions demonstrating targeted and/or pH dependent release of different NSAIDs strongly supports the ability of the carriers of the invention to also be useful for targeted and/or pH dependent release of other drugs and/or nutrients. The data also indicate that the release profile of the carrier can be designed such that the bioactive agent(s) are released at low pH, but not at higher pH, so that the active agent can be targeted to tissues in contact with a low pH environment, such as the stomach. Thus, the carriers of the present invention result in novel, novel and easily customizable active agent compositions having unique active agent release characteristics, unique active agent efficacy, and/or unique active agent GI bioavailability and/or toxicity. Since this targeted release of the active agent from the lipid matrix appears to be due to the ionized state of the targeted release agent in the carrier relative to the pH and other physiological internal environments in selected regions of the tract, such as the GI tract, targeted release of any bioactive agent is possible.

Carrier

Embodiments of the present invention provide carriers with the ability to target the release of an active agent and/or pH-dependent release of an active agent. The carrier typically comprises at least one targeted release agent, wherein the targeted release agent is capable of releasing one or more active agents in a targeted manner. In certain embodiments, the targeted release agent is a pH-dependent release agent that releases the active agent in a pH-dependent manner. The carrier may also contain other biocompatible pharmaceutical agents to modulate the desired release and/or dissolution profile or to modify and/or alter other properties of the carrier and/or bioactive agent. In addition to targeting the release, e.g., in a pH-dependent manner, the carrier and/or components thereof may also modify and/or alter the chemical, physical and/or behavior of the active agent in a tissue and/or organ when administered to an animal, mammal or human.

Embodiments of the present invention provide a carrier capable of pH-dependent release of an active agent or agents, wherein the carrier comprises at least one pH-dependent release agent, such as at least one oil-soluble or oil-miscible compound comprising at least one ionizable group, such as a carboxylic acid group, a hydroxyl group, an amino group, an amide group, or other similar ionizable group. In other embodiments, the carrier comprises at least one carboxylic acid group or the at least one oil-soluble compound comprising at least one carboxylic acid group is a free fatty acid.

Composition comprising a metal oxide and a metal oxide

Embodiments of the present invention provide compositions comprising a carrier of the present invention and an effective amount of at least one biologically active agent, wherein the carrier is designed to achieve targeted release of the active agent in a tissue and/or organ and/or to modify and/or alter the chemical, physical and/or behavior of the active agent when administered to an animal, mammal or human.

Embodiments of the present invention provide compositions comprising a carrier of the present invention and an effective amount of at least one pharmaceutical and/or nutraceutical agent, wherein the carrier is designed to achieve targeted release of the pharmaceutical and/or nutraceutical agent and/or modify and/or alter the chemical, physical and/or behavior of the agent in a tissue and/or organ when administered to an animal, mammal or human.

The above compositions may be in the form of a solution of the active agent in the carrier, a suspension of the active agent in the carrier wherein some of the active agent may be dissolved in the carrier, a suspension of the active agent in the carrier wherein none of the active agent is dissolved in the carrier, a paste of the active agent in the carrier, or any other mixture or combination of the active agent in the carrier or surrounded by the carrier. The active agent may be present in the carrier in an amount sufficient to produce a paste-like suspension, a coated solid material such as coated crystals or coated microparticles or nanoparticles, wherein the thickness of the coating may range from a monolayer to millimeters, a matrix of coated solid material, or any other form comprising the carrier of the present invention and one or more biologically active agents.

Preparation method

Embodiments of the present invention provide methods of making the carriers of the present invention by mixing the desired components together under conditions of temperature, pressure, and time sufficient to form a carrier having tailored active agent release properties and/or tailored active agent interaction properties in the presence or absence of a solvent system. If a solvent system is used, the solvent is removed by distillation and/or evaporation.

Embodiments of the present invention provide methods of making compositions of the present invention by contacting a carrier of the present invention with an effective amount of at least one active agent under conditions of temperature, pressure and time sufficient to form a composition having tailored active agent release properties and/or tailored active agent interaction properties in the presence or absence of a solvent system. If a solvent system is used, the solvent is removed by distillation and/or evaporation, and this process is sometimes referred to as a solvent/evaporation process. In the absence of a solvent system, the active agent and carrier are simply mixed under conditions of temperature, pressure and time sufficient to form the designed composition, and this process is sometimes referred to as a mixing process. In certain embodiments, the active agent comprises at least one pharmaceutical agent and/or at least one nutritional agent. One of ordinary skill will recognize that the mixing process reduces steps and eliminates any concern for trace amounts of solvent and may include advantages such as: reduced manufacturing costs, environmental manufacturing issues, etc. Alternatively, certain formulations may benefit from solvation of the ingredients.

Application method

Embodiments of the present invention provide methods of administering a composition of the present invention, wherein the methods comprise administering to a human, mammal, or animal a composition of the present invention comprising a carrier and an effective amount of at least one active agent, wherein the effective amount is sufficient to elicit a desired response. The mode of administration may be oral, sublingual or rectal, or by endoscopic esophageal, gastric, or intestinal instillation. In certain embodiments, administration may be topical, such as to the eye, urinary tract, reproductive tract, or other tract, tissue, or organ for which topical administration represents an effective treatment.

Screening method

Embodiments of the present invention also provide methods for screening for active agents, such as pharmaceutical and/or nutritional agents, wherein the methods comprise forming a composition comprising a test active agent in a vehicle of the present invention. Once the composition is formed, the composition is placed in a differential solubility system. After addition to a differentially soluble system, the method includes determining the partition coefficient of the active agent between the two immiscible solutions or solvents. To determine the relative release, solubility and partitioning across the relatively pure hydrophobic gastric or duodenal mucosal or epithelial cell membranes, a two-phase system consisting of cyclohexane and simulated gastric fluid (e.g., 0.1HCl) or cyclohexane and duodenal upper fluid (e.g., ph4.5 buffer) may be used. To determine the distribution of mixed polarity epithelial, cellular, or intercellular membranes across the stomach or duodenum, a two-phase system consisting of octanol and simulated gastric fluid (e.g., 0.1HCl) or octanol and upper duodenal fluid (e.g., ph4.5 buffer) may be used. To determine the relative release, solubility and partitioning across mucosal surfaces that are relatively more hydrophilic than the stomach, a two-phase system consisting of octanol and simulated intestinal fluid containing digestive enzymes and lipid emulsifiers (e.g., ph7.2 buffer containing 1% pancreatin and 20mM bile acids) can be used. Embodiments of the screening method may further comprise varying the pH of the aqueous medium and determining the partition coefficient at different pH values to test the pH-dependent partition characteristics of the active agent in the carrier. We believe that the differential partition coefficient is an indirect measure of the ability to target delivery of an active agent from a given carrier, such that carrier properties can be tailored for a given active agent delivery mode, such as targeted delivery of an active agent in the gastrointestinal tract.

Method for testing pH-dependent release capacity

Embodiments of the present invention also provide methods of testing the pH-dependent release of active agents, such as pharmaceutical and/or nutritional agents, from a vehicle of the present invention, wherein the method comprises forming a composition comprising the test active agent in a vehicle of the present invention. Once the composition is formed, the composition is filled into hard shell capsules. After filling the composition into the capsules, the capsules are placed in a plurality of dissolution buffers having different pH values and/or different levels of digestive enzymes and/or bile acids, the dissolution rates in the different buffers are measured and the pH-dependent release profile of the test active in the carrier is determined. We believe that the dissolution data allows the preparation of compositions designed to release the active agent at a desired location along the tract of an animal, mammal or human, such as the gastrointestinal tract.

Drawings

The invention may be better understood by reference to the following detailed description taken in conjunction with the accompanying illustrative drawings in which like elements are numbered alike:

pH dependent release of bioactive agents

FIG. 1 depicts a 10:1, 1:1 and 1:10 weight ratio of acetylsalicylic acid (ASA) and free fatty acid of soy origin (FFA) compositions to 1:1 simply prepared by mixing and heating at 35 ℃ for 30 minutesAssignment (LogP) data for 1 weight ratio of ASA triple strength lecithin product (ASA triple strand chain product) (ASA: Phosal35SB) and 100% ASA. The triple strength lecithin product (P35) was Phosal35 SB. In the test of Log P_{Cyclohexane/0.1 NHCl}An equal amount of aspirin was used in each formulation. ASA concentration was measured by HPLC in each solvent. Data are mean ± SD of three replicate assays.

FIG. 2 depicts the assignment (LogP) data for dual ratios of ASA and FFA compared to ASA: Phosal35SB, where ASA and FFA were simply mixed in an aspirin suspension of ASA in soy FFA at two pH values and heated at 35 ℃ for 30 minutes to produce a 1:1 weight ratio of ASA and FFA, ASA: Phosal35SB was a 1:1 weight ratio of aspirin and a triple strength lecithin product (Phosal35 SB). Log P testing of equal amounts of aspirin in various formulation forms_{Cyclohexane/0.1 NHCl}. ASA concentration in each solvent was measured by HPLC at the indicated pH. Data are mean ± SD of three replicate assays.

FIG. 3 depicts the LogP distribution (LogP) data for ASA: FFA carriers comprising 1 wt.%, 5 wt.% and 10% w/w PC compared to ASA: P35, aspirin alone, ASA: P35 is a 1:1 weight ratio, with P35(Phosal35 SB). Equal amounts of each formulation were tested for Log P_{Cyclohexane/0.1 NHCl}. Data are mean and SD of three replicates. The formulation was prepared by mixing aspirin with the carrier in a 1:1 weight ratio.

Figure 4 depicts the dissolution profile of an immediate release aspirin tablet at different pH levels. Data are mean ± Standard Deviation (SD) of duplicate determinations.

Figure 5 depicts the dissolution profile of a triple strength lecithin carrier-ASA composition filled capsules at different pH levels. Data are mean ± Standard Deviation (SD) of duplicate determinations.

Free fatty acid in lecithin oil mediates pH dependent release of bioactive agents

Figure 6 depicts the dissolution of aspirin (ASA) compared to carriers with and without Free Fatty Acid (FFA). Data are mean ± Standard Deviation (SD) of duplicate determinations.

Targeted release of bioactive agents along the gastrointestinal tract

FIG. 7 depicts the dissolution profile at 150rpm in "simulated gastric fluid" (0.1N HCl) pH 1. Data are mean ± Standard Deviation (SD) of duplicate determinations.

FIG. 8 depicts the dissolution profile at 150rpm in "simulated duodenal fluid" pH 4.5. Data are mean ± Standard Deviation (SD) of duplicate determinations.

Figure 9 depicts the dissolution profile at 150rpm in "simulated intestinal fluid" pH7. The intestinal juice was phosphate buffered saline at pH7 supplemented with 1% pancreatin and 20mM bile acid. Data are mean ± Standard Deviation (SD) of duplicate determinations.

Fig. 10A & B depict side-by-side comparisons of the average dissolution profiles of 0 wt.% PC and 2.5 wt.% PC formulations in the following different media, simulated gastric, duodenal, and intestinal fluids, and phosphate buffer at ph 6.8. Data are mean ± Standard Deviation (SD) of duplicate determinations.

pH Spectrum and general composition of the Chamber fluid of the Upper GI tract

Fig. 11 depicts a diagram of the upper GI tract of a human, including the stomach and small intestine (duodenum, jejunum, and ileum), indicating the pH range of different regions of the upper GI tract. Typically, gastric pH is acidic. Progressively to the far side of the stomach, the small intestine becomes more alkaline, mainly due to pancreatic secretion. The alkaline pH and high concentration of bile acids in the jejunum and ileum, especially after meals, enable emulsification/digestion of lipids.

Targeted release of bioactive agents along the gastrointestinal tract to improve gastrointestinal safety

Fig. 12 depicts gastric lesions in rats treated with 40mg/kg aspirin once a day from the AC1, P1, P2, and AC2 formulations or negative control (NAC) below.

Fig. 13 depicts intraluminal gastric and intestinal hemoglobin after 3 days of treatment with NAC, AC1, P1, P2 and AC 2.

Use of a carrier to increase bioavailability of poorly permeable bioactive agents

Fig. 14 depicts FTIR spectra of aspirin in various carriers.

FIG. 15 depicts ASA partitioning in an octanol/0.1N HCl system using carriers with different FFA: TG ratios ranging from 100: 0 to 0: 100, increments of 20.

Commonality of carrier-targeted release to all weakly acidic bioactive agents

Salicylic Acid (SA)

Fig. 16 depicts the partitioning of Salicylic Acid (SA) and SA formulations A, C, E and G at low pH and at neutral pH.

Figure 17 depicts the two-stage dissolution profile of salicylic acid in different carriers at 75RPM in pH1 "simulated gastric fluid" and then in pH7.2 "simulated intestinal fluid".

Naproxen (NAP)

Figure 18 depicts unmodified Naproxen (NAP) and partitioning at pH1 and at pH7 in NAP formulations A, C, E and G.

Indometacin (INDO)

Fig. 19 depicts unmodified indomethacin (indoo) and partitioning at pH1 and at pH7 in indoo formulations A, C, E and G.

Mefenamic acid (MFA)

Fig. 20 depicts mefenamic acid (MFA) and partitioning at pH1 and at pH7 in MFA formulations A, C, E and G.

Definition of terms

The following terms have the meanings given below, which may or may not correspond to their generally accepted meanings:

general terms

The term "mixture" means a blend of one or more ingredients wherein the ingredients may interact at the molecular level, e.g., a homogeneous mixture is a mixture wherein the ingredients are uniformly and homogeneously distributed, and a heterogeneous mixture is a mixture wherein the ingredients are non-uniformly and homogeneously distributed.

The term "combination" means one or more of the ingredients combined but not admixed.

The term "substantially" means that the attribute, condition, or value is within about 10% of the indicated value. In other embodiments, the term is within about 5% of the indicated value. In other embodiments, the term is within about 2% of the indicated value. In other embodiments, the term is within about 1% of the indicated value.

The term "substantially free" or "substantially free" means a composition that contains less than or equal to about 5 wt.% of the specified ingredients. In certain embodiments, the term means less than or equal to about 2 wt.%. In other embodiments, the term means less than or equal to about 1 wt.%. In other embodiments, the term means less than or equal to about 0.5 wt.%. In other embodiments, the term means less than or equal to about 0.1 wt.%. In other embodiments, the term means less than or equal to about 0.05 wt.%. In other embodiments, the term means less than or equal to about 0.01 wt.%. In other embodiments, the term means less than or equal to about 0.005 wt.%. In other embodiments, the term means less than or equal to about 0.001 wt.%. In other embodiments, the term means less than or equal to about 0.0005 wt.%. In other embodiments, the term means less than or equal to about 0.0001 wt.%. Such ingredients may include, without limitation, water, solvents, or any other ingredient substantially excluded from the desired composition.

The term "relatively high concentration" means that the drug or nutritional agent constitutes greater than or equal to about 50 wt.% of the final composition. In certain embodiments, the term means that the pharmaceutical or nutraceutical constitutes greater than or equal to about 55 wt.% of the final composition. In certain embodiments, the term means that the pharmaceutical or nutraceutical constitutes greater than or equal to about 60 wt.% of the final composition. In certain embodiments, the term means that the pharmaceutical or nutraceutical constitutes greater than or equal to about 65 wt.% of the final composition. In certain embodiments, the term means that the drug or nutritional agent constitutes greater than or equal to about 70 wt.% of the final composition. In certain embodiments, the term means that the pharmaceutical or nutraceutical constitutes greater than or equal to about 75 wt.% of the final composition. In certain embodiments, the term means that the pharmaceutical or nutraceutical constitutes greater than or equal to about 80 wt.% of the final composition. In certain embodiments, the term means that the drug or nutritional agent constitutes greater than or equal to about 85 wt.% of the final composition.

The term "major component" means a component that is present in the composition in an amount of at least 33 wt.% based on 100 wt.% of the formulation.

The term "association complex" or "associated complex" means a non-covalent association between two or more compounds, wherein the compounds are held together by non-covalent chemical and/or physical interactions, including hydrogen bonding, ionic bonding, dipolar interactions, hyperpolarizable interactions, van der waals interactions, electrostatic interactions, non-polar bonding or interactions, or any other chemically and/or physically attractive interaction. For example, NSAIDs and zwitterionic phospholipids form associated complexes.

The term "non-covalent interaction" means a chemical and/or physical interaction, including hydrogen bonding, ionic bonding, dipolar interaction, hyperpolarizable interaction, van der waals interaction, electrostatic interaction, non-polar bonding or interaction, or any other chemically and/or physically attractive interaction.

The term "hydrophilic" means having a strong affinity for water; compounds that tend to dissolve in, mix with or be wetted by water.

The term "hydrophobic" means lacking affinity for water; tend to repel and not absorb water; compounds that tend not to dissolve in or mix with water or become wetted by water.

The term "zwitterion" means a molecule having a positively and negatively charged functional group at biological pH.

The term "anion" means a molecule having an overall negative charge at biological pH.

The term "cation" means a molecule having an overall positive charge at biological pH.

The term "relatively hydrophobic barrier" means any external, internal, cellular, or subcellular barrier having hydrophobic properties that generally resists or reduces transport and/or partitioning of hydrophilic agents across the barrier. Such barriers include, without limitation, mucosal gel layers (e.g., gastric, duodenal, or colonic mucosal gel layers, vaginal mucosal gel layers, esophageal mucosal gel layers, nasal mucosal gel layers, pulmonary mucosal gel layers, etc.), plasma membranes (cell membranes), blood brain barriers, placental barriers, testicular barriers, or any other barrier of a human, mammal, or animal through which the distribution and/or transport of hydrophobic materials occurs more readily than hydrophilic materials.

The term "residual water" means water remaining in the components used to prepare the compositions of the present invention. Typically, the residual water constitutes a small impurity in the components of the composition of the present invention.

The term "minimal residual water" means that the compositions of the present invention comprise less than about 5 wt.% residual water. In certain embodiments, the compositions of the present invention comprise less than about 4 wt.% residual water. In certain embodiments, the compositions of the present invention comprise less than about 3 wt.% residual water. In certain embodiments, the compositions of the present invention comprise less than about 2 wt.% residual water. In certain embodiments, the compositions of the present invention comprise less than about 1 wt.% residual water.

The term "low moisture" means that the composition contains only residual water found in the components used to prepare the composition of the present invention.

The term "modify, alter and/or enhance chemical and/or physical properties and/or behavior" means that the carriers of the present invention are designed to form a hydrophobic matrix in which the active agent is mixed as a solid or liquid (depending on the nature of the active agent). The role of these hydrophobic matrices is to modify, alter or enhance the chemical and/or physical properties of the active agent by providing an immiscible/distinct environment as compared to aqueous biological fluids such as blood, gastric fluid, duodenal fluid, intestinal fluid, large intestinal fluid, vaginal fluid, rectal solid/fluid or any other biological fluid, creating a condition in which the active agent freely partitions between the two immiscible environments. In addition, properties of the carriers of the present invention such as viscosity, lipophilicity, hydrophobicity, dispersibility, dispensability, softening temperature, melting temperature, and the like also function to modify, alter, or increase the rate of dispensing of the active agent by sequestering the active agent in the immiscible carrier until the carrier matrix is dispersed into particles small enough to facilitate mass transfer from the immiscible carrier to the biological fluid. For a solid active agent to be sequestered in the carrier matrix of the present invention, an additional reduction in the rate of partitioning ensues, since the active agent must be dissolved out of the matrix when the particle size of the matrix is reduced in the biological fluid due to mechanical action of the tissue and/or organ and/or due to biochemical processes occurring in the tissue and/or organ.

The term "targeted manner" means that the active agent is targeted for release into the desired biological environment.

The term "pH-dependent manner" means how pH affects how the carrier of the present invention functions to modify, alter or enhance the chemical and/or physical properties of an active agent by providing an immiscible/distinct environment compared to aqueous biological fluids such as blood, gastric fluid, duodenal fluid, intestinal fluid, large intestinal fluid, vaginal fluid, rectal solid/fluid or any other biological fluid, creating a condition in which the active agent freely partitions between the two immiscible environments. In addition, the vectors of the present inventionSuch as viscosity, lipophilicity, hydrophobicity, dispersibility, dispensability, softening temperature, melting temperature, etc., also function to modify, alter or increase the dispensing rate of the active agent by sequestering the active agent in the immiscible carrier until the carrier matrix is dispersed into particles small enough to facilitate mass transfer from the immiscible carrier to the biological fluid. For a solid active agent to be sequestered in the carrier matrix of the present invention, an additional reduction in the rate of partitioning ensues, as the solid must dissolve out of the matrix as the particle size of the matrix is reduced in the biological fluid due to mechanical action of the tissue and/or organ and/or due to biochemical processes occurring in the tissue and/or organ. Thus, the pH of the biological fluid changes the rate at which the immiscible carrier matrix disperses in the biological fluid and the mass transfer rate of the active agent from the carrier matrix. For weak acid and weak base active agents, the carrier may be designed to reduce the release of the active agent until the pH of the biological fluid is at or near (within about 1 pH unit or less) the pK of the active agent_aOr pK_b. For weak acid actives, the carrier reduces the release of the active in a low pH environment, such as gastric fluid, which is shown at or near (within about 1 pH unit or less) the pK of the weak acid active_aIncreased release in a pH environment.

The terms "one or more," "at least one," "one," or "a plurality" each mean a single item or more than one item.

Pharmaceutical agents and compounds

The term "active agent" or "bioactive agent" or "active ingredient" or "biologically active ingredient" means any pharmaceutical agent or any nutraceutical agent as defined by the U.S. Food and Drug Administration (FDA).

The term "pharmaceutical agent" means any compound or composition, typically a drug approved, for example, by the FDA, that has been or will be approved for administration to humans, mammals, and/or animals for the treatment of certain conditions, diseases, syndromes, dysfunctions, and the like.

The term "nutraceutical" means any compound or composition for administration to humans, mammals, and/or animals for nutritional supplementation or other use.

The terms "weak acid active" and "weak base active" are actives that are only partially ionized in an aqueous solution and the degree of ionization depends on the pH of the aqueous solution.

The term "anti-inflammatory agent" means any of a variety of agents that reduce or inhibit inflammation in tissues, organs, and the like. Anti-inflammatory agents include non-steroidal anti-inflammatory drugs (COX1 and/or COX2 inhibitors), drugs used to treat irritable bowel disorder or disease (IBD), a family of ulcerative diseases including ulcerative colitis and crohn's disease that involve the colon and distal small intestine, and other drugs that have anti-inflammatory activity in humans, mammals, and/or animals. The targeted delivery systems of the present invention may also find utility in the treatment of pH imbalances in the gastrointestinal, urinary and reproductive tracts of animals, mammals and humans.

The term "NSAID" means any of a variety of drugs commonly classified as non-steroidal anti-inflammatory drugs including, without limitation, ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin, diclofenac, COX2 inhibitors, or any mixture thereof.

The term "oil" means any of a wide variety of minerals, plant and synthetic materials, and animal and vegetable fats and oils, which are generally smooth, flammable, viscous, liquid-like, or liquefiable at room temperature, soluble in a variety of organic solvents such as ethers, but insoluble in water.

The term "lipid" means any of a group of organic compounds comprising: fats, oils, waxes, sterols, monoglycerides, diglycerides and triglycerides, which are insoluble in water but soluble in non-polar organic solvents and greasy to the touch.

The term "neutral lipid" (NL) means an uncharged, non-phosphoglyceride lipid, including mono-, di-, tri-or mixtures thereof. In some embodiments, the term neutral lipid refers exclusively to Triglycerides (TG).

The term "phospholipid" (PL) means any biocompatible phospholipid.

The term "zwitterionic phospholipid" means any phospholipid that has a positive and negative charge at biological pH, including, but not limited to, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingomyelin and other ceramides, as well as various other zwitterionic phospholipids.

The term "biocompatible" means biocompatible with living cells, tissues, organs or systems and without, with minimal or with acceptable risk of injury, toxicity or rejection by the human, mammal or animal immune system.

The term "biocompatible agent" means any compound that is biocompatible with living cells, tissues, organs or systems, and does not risk damage, toxicity or rejection by the human, mammal or animal immune system. There are many types of biocompatible agents suitable for use in the present invention, including hydrophobic biocompatible agents, biocompatible oils, pH-dependent biocompatible release agents such as biocompatible fatty acids or biocompatible fatty polyacids, and lecithin oils.

The term "biocompatible oil" means any oil that is biocompatible with living cells, tissues, organs, or systems, and that does not risk damage, toxicity, or rejection by the human, mammal, or animal immune system. In certain embodiments, the biocompatible oil is any oil that has been approved by the FDA or other governmental agency for human consumption or for human, mammalian or animal consumption, wherein the compound can be a solid or a liquid at room temperature or at biological temperatures. In certain embodiments, the term means any oil that is fluid at biological temperatures. In other embodiments, the term means any oil that is fluid at room temperature.

The term "biocompatible fatty acid or biocompatible free fatty acid" means any fatty acid or Free Fatty Acid (FFA) that is biocompatible with living cells, tissues, organs or systems, and that does not risk damage, toxicity or rejection by the human, mammal or animal immune system. In certain embodiments, the biocompatible fatty acid is a monocarboxylic acid. In certain embodiments, the biocompatible fatty acid has at least 8 carbon atoms. In other embodiments, the biocompatible fatty acid has at least 10 carbon atoms. In other embodiments, the biocompatible fatty acid has at least 12 carbon atoms. In other embodiments, the biocompatible fatty acid has at least 14 carbon atoms. In other embodiments, the biocompatible fatty acid has at least 16 carbon atoms. In other embodiments, the biocompatible fatty acid has at least 18 carbon atoms. In certain embodiments, the biocompatible fatty acid can be an unsaturated fatty acid. In certain embodiments, the biocompatible fatty acid can be a saturated fatty acid. In certain embodiments, the biocompatible fatty acid can be a mixture of saturated fatty acids and unsaturated fatty acids. The term "free fatty acids" is sometimes used as a term to completely distinguish fatty acids from fatty acid esters of mono-, di-and triglycerides.

The term "biocompatible fatty acid ester" means any fatty acid ester that is biocompatible with living cells, tissues, organs or systems, and does not risk damage, toxicity or rejection by the human, mammal or animal immune system. In certain embodiments, the biocompatible carboxylic acid ester is an ester of a mono-or polyhydric alcohol.

The term "biocompatible fatty acid salt" means any salt of a biocompatible carboxylic acid. In certain embodiments, the salt is a salt of a monocarboxylic acid.

The term "biocompatible fatty polyacid" means any biocompatible compound having more than one carboxylic acid moiety per compound that is biocompatible with living cells, tissues, organs, or systems and does not risk damage, toxicity, or rejection by the human, mammal, or animal immune system. In certain embodiments, the biocompatible polyacid has at least 8 carbon atoms. In other embodiments, the biocompatible polyacid has at least 10 carbon atoms. In other embodiments, the biocompatible polyacid has at least 12 carbon atoms. In other embodiments, the biocompatible polyacid has at least 14 carbon atoms. In other embodiments, the biocompatible polyacid has at least 16 carbon atoms. In other embodiments, the biocompatible polyacid has at least 18 carbon atoms. In certain embodiments, the biocompatible fatty acid can be an unsaturated fatty acid. In certain embodiments, the biocompatible fatty acid can be an unsaturated fatty acid. In certain embodiments, the biocompatible fatty acid can be a saturated fatty acid. In certain embodiments, the biocompatible fatty acid can be a mixture of saturated fatty acids and unsaturated fatty acids.

The term "lecithin" means a tan fatty substance derived from plants or animals and defined as a complex mixture of phospholipids that are insoluble in acetone, consisting primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol, combined with various amounts of other substances such as triglycerides, fatty acids and carbohydrates, as isolated from crude vegetable oil sources. It contains NLT 50.0% of acetone insoluble material. In certain embodiments, lecithin may be composed of lipids emulsified with unsaturated fatty acid side chains. In other embodiments, the lecithin may be composed of lipids with saturated lipids. In other embodiments, the lecithin may be composed of lipids with a mixture of lipids.

The term "crude lecithin" means lecithin containing about 10-15 wt.% phosphatidylcholine.

The term "semi-crude or triple strength lecithin" means lecithin in which the phosphatidylcholine content has increased to 35 wt.% to about 50 wt.%.

The term "lecithin oil" means liquid lecithin, wherein the lecithin is dissolved in the oil and/or free fatty acids. In certain embodiments, the lecithin oil is a semi-crude or triple strength lecithin dissolved in triglycerides and/or free fatty acids.

The term "purified phospholipid" means a naturally extracted or synthetic phospholipid having a phospholipid purity of greater than at least 90 wt.%, a single compound or a class of closely related phospholipids such as phosphatidylcholine, phosphatidylethanolamine, Dipalmitoylphosphatidylcholine (DPPC), or other similar phospholipids. The purified phospholipid is not lecithin, but can be derived from lecithin by extraction and purification.

The term "targeted biocompatible release agent" or "targeted release agent" means an agent that controls the release of one or more active agents in a targeted manner, i.e., releases an active agent into a particular tissue or organ depending on the physiological environment of the tissue or organ.

The term "pH-dependent biocompatible release agent" or "pH-dependent release agent" means a targeted release agent that controls the release of one or more active agents in a pH-dependent manner. For example, when a composition comprising a fatty acid or fatty polyacid is administered orally such that the fatty acid or fatty polyacid retains the active agent in the carrier at a low pH, but when the composition leaves the stomach and is released at a pH elevated in the upper intestine to about pH7, a fatty acid having from about 8 to about 50 carbon atoms or a fatty polyacid having from about 12 to about 50 carbon atoms will release the active agent or agents in a pH dependent manner. pH-dependent biocompatible release agents are a subclass of the broad class of biocompatible agents, and in particular, hydrophobic biocompatible agents.

The term "carrier" means a component that is a matrix (base) for an active agent, such as a drug and/or nutritional agent.

The term "hydrophobic carrier" means a component that is a matrix for an active agent, such as a drug and/or a nutritional agent, wherein the carrier comprises one or more or at least one hydrophobic biocompatible pharmaceutical agent and wherein the carrier is immiscible in water.

The term "oil-based carrier" means an oil-based component that is a matrix for active agents such as pharmaceuticals and/or nutraceuticals. The oil-based carrier comprises one or more biocompatible oils and/or biocompatible hydrophobic agents, and is water-immiscible.

Method of administration

The terms "internal administration," "internally administered," or "parenteral administration" mean administration by any technique that delivers the composition directly into the bloodstream, tissue site, organ, etc., without first passing through the digestive tract.

The term "oral administration" or "orally administered" means oral administration.

The term "topical administration" or "topically administered" means administration to a surface such as the skin, a mucosal gel layer (e.g., vaginal, rectal, ocular, etc.), tissues and/or organs exposed during a surgical procedure, or any other exposed body tissue.

Detailed Description

The present inventors have discovered that unique carriers for biologically active agents, such as pharmaceutical and/or nutritional agents, can be prepared wherein the carrier comprises one or more biocompatible targeted release agents such that the carrier targets the release of the active agent to one or more specific portions of the animal, mammal or human tract, such as the Gastrointestinal (GI) tract, urinary tract, reproductive tract, or tissue, such as ocular tissue. The inventors have also found that the carrier can be designed to comprise a sufficient amount of at least one biocompatible pH sensitive or dependent release agent such that the carrier releases the active agent such as a drug and/or nutritional agent in a pH dependent manner. The present inventors have also found that the pharmaceutical and/or nutraceutical compositions may be formulated to comprise a carrier of the present invention and an effective amount of at least one pharmaceutical agent and/or at least one nutraceutical agent, wherein the agents may be released in a targeted or tailored manner in the body's tract, such as the gastrointestinal tract. The present inventors have found that the carrier of the present invention may comprise a pH-dependent release system which releases the pharmaceutical and/or nutritional agent in a pH-dependent manner, targets different parts of the body's tract, such as the gastrointestinal tract, and due to the hydrophobic nature of the carrier and/or carrier components, improves the ability of the agent to partition across a hydrophobic mucosal barrier or mucosa in a pH-dependent manner. The compositions of the present invention are also well suited for the delivery of bioactive ingredients in a pH-dependent manner due to pH changes that occur in tissues, organs or tracts in response to certain pre-disease or disease states.

With the increasing number of people in the world and especially the elderly population in the us and people with a body heavier than the previous generation, there is an increasing need for new delivery systems for bioactive agents known to have certain adverse effects such as adverse gastrointestinal reactions, especially for non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are widely used drugs for managing pain, for reducing or managing cardiovascular disease, for reducing platelet aggregation, for reducing fever, for reducing or preventing cancer, and for many other uses. However, a major disadvantage of NSAIDs is that they can to some extent cause irritation, erosion and/or ulceration of the stomach and upper GI tract. In recent years, Lichtenberger and co-workers have demonstrated that associating NSAIDs with phospholipids can greatly reduce GI toxicity of certain NSAIDs such as aspirin and ibuprofen. However, compositions containing large amounts of NSAID and large amounts of phospholipid are susceptible to degradation over time due to hydrolysis of the acetyl side chains for aspirin and fatty acid side chains for phospholipids. In an ongoing effort to construct improved delivery systems for NSAIDs and any other pharmaceutical and/or nutraceutical agents that require targeted release or delivery of the NSAID or agent into the desired part of the gastrointestinal tract, we have developed carrier systems that are water immiscible and comprise at least one targeted release agent. We demonstrate herein that a carrier comprising at least one targeted-release agent can be used to deliver one or more active agents to different parts of the gastrointestinal tract. For example, if a given active agent has a known adverse interaction with the stomach or other low pH biological environment, the carrier may be designed such that the active agent is not effectively released until the pH rises to a pH greater than about pH3. In these carriers, the active agent is released at a rate of less than about 20% in 30 minutes at a pH less than pH2, and greater than 80% in 30 minutes at a pH above about pH3. These same targeted release carriers are also well suited for acid sensitive active agents where the release is designed for pH values greater than pH 5. We also demonstrate herein that water-immiscible carriers can be formulated to release rapidly into low pH environments rather than into higher pH environments. Thus, the carriers of the present invention can be designed to release the active agent to any pH environment and potentially to any given biological environment.

We have found that the targeted release agent is any compound comprising at least one ionizable group such as a carboxylic acid group, a hydroxyl group, an amino group, an amide group, or other similar ionizable group, that is immiscible in water or soluble in oil, and has a pKa value greater than or equal to about ph3.5 for weak acids. These targeted release agents are neutral at pH values below their pKa values, particularly at pH values less than pH2, and become ionized at pH values above their pKa values. Thus at low pH (< pH2), the targeted release agent simply behaves as an oil that remains immiscible in aqueous fluids, and achieves minimal release of the active agent in the low pH fluid environment. But as the pH rises, the release agent becomes ionized and now acts as an active surfactant, resulting in rapid dissolution of the carrier containing the active agent in a higher pH environment. Because the pH profile of the gastrointestinal tract begins in the stomach and proceeds to the large intestine, the pH rises from a pH value in the stomach of about pH1 to about pH3 to a pH value in the duodenum of about pH3 to pH5, to a pH value in the large intestine as high as pH8, using release agents with different pKa values, we can design carriers that will release the active agent efficiently and rapidly only when the pH of the environment is at or above the pKa of the release agent. We have also found that the carrier of the invention may contain just a sufficient amount of release agent to 100% of the release agent. We have also found that other components such as neutral lipids, zwitterionic surfactants, excipients and/or adjuvants can be added to the carrier without significantly or negatively affecting the release properties of the carrier. Thus, carriers comprising 100% release agent achieve similar distribution profiles, dissolution profiles, and in vivo efficacy compared to carriers with small or large amounts of other components including neutral lipids and phospholipids.

We have found that fatty acids represent a class of targeted release agents that are immiscible in water and have a pKa value generally greater than about pH3 and are converted to surfactants by ionization at pH values at or above their pKa values. We have also found that vehicles can be tested to determine their potential use as targeted release vehicles using partitioning studies of vehicle/active agent compositions in a biphasic system, where one phase represents a low pH or aqueous environment and the other phase represents a hydrophobic environment. Partitioning data provides predictive information about the ability of a given carrier to release a given active agent at a given pH. We have also found that by studying the release profile of a composition comprising a targeted release carrier of the invention and a given active agent in various dissolution media, in particular dissolution media having different pH values, it is possible to determine the dissolution of the active agent from pH1 to above pH7, thereby testing the pH dependent release profile of the composition. Dissolution profiles provide in vitro data to predict the release profile of a given system.

Embodiments of the present invention relate to compositions comprising: (1) a carrier comprising a sufficient amount of a pH-dependent release system, and (2) at least one bioactive agent, wherein the carrier releases the bioactive agent in a pH-sensitive manner, characterized in that less than 20% of the bioactive agent is released into gastric fluid and more than 50% of the bioactive agent is released into intestinal fluid having a pH greater than pH3.

Embodiments of the present invention relate to compositions comprising: (1) a carrier comprising a sufficient amount of a pH-dependent release system, and (2) at least one bioactive agent, wherein the carrier releases the bioactive agent in a pH-sensitive manner, characterized in that the bioactive agent is minimally released into the stomach and is efficiently released into the intestinal region.

Embodiments of the present invention relate to compositions comprising: (1) a carrier comprising a sufficient amount of a pH-dependent release system, and (2) at least one biologically active agent, wherein the carrier releases the biologically active agent in a pH-sensitive manner, characterized in that the biologically active agent is minimally released at a first pH and is effectively released at a second pH.

Embodiments of the present invention relate to compositions comprising: (1) a carrier comprising a sufficient amount of a pH-dependent release system, and (2) at least one bioactive agent, wherein the carrier releases the bioactive agent in a pH-sensitive manner, characterized in that the bioactive agent is minimally released into the stomach and is efficiently released into regions of the intestine having different concentrations and/or types of bile acids and/or digestive enzymes.

In certain embodiments, the pH sensitive mode is characterized by differential release of the active agent into gastric and intestinal fluids. In other embodiments, the bioactive agent is substantially non-ionized at gastric fluid pH and becomes ionized as pH increases. In other embodiments, the pH-dependent release system comprises one or more fatty acids having at least 8 carbon atoms. In other embodiments, the bioactive agent is selected from the group consisting of weakly acidic bioactive agents, weakly basic bioactive agents, and mixtures or combinations thereof. In other embodiments, the weakly acidic bioactive agent is selected from a weakly acidic non-steroidal anti-inflammatory drug (NSAID) and a mixture of NSAIDs.

Embodiments of the present invention relate to pharmaceutical compositions comprising: a carrier comprising a sufficient amount of a pH-dependent release system, and at least one weakly acidic non-steroidal anti-inflammatory drug (NSAID), wherein the carrier releases the NSAID in a pH-sensitive manner, characterized in that less than 20% of the bioactive agent is released into the gastric fluid and more than 50% of the bioactive agent is released in intestinal fluid at a pH greater than pH3, and wherein the bioactive agent is substantially non-ionized at the pH of the gastric fluid and becomes ionized when the pH increases. In other embodiments, the pH-dependent release system comprises one or more fatty acids having at least 8 carbon atoms.

Embodiments of the present invention relate to a pharmaceutical composition comprising a suspension of a weakly acidic non-steroidal anti-inflammatory drug (NSAID) agent or a mixture of NSAIDs in a carrier comprising a sufficient amount of a pH dependent release system.

An embodiment of the present invention is directed to a pharmaceutical composition comprising a suspension of a weakly acidic non-steroidal anti-inflammatory drug (NSAID) agent or a mixture of NSAIDs in a carrier comprising a sufficient amount of at least one fatty acid having at least 8 carbon atoms.

Embodiments of the present invention relate to a method of targeting a bioactive agent along the Gastrointestinal (GI) tract, the method comprising the step of orally administering a composition comprising a carrier comprising a sufficient amount of a pH-dependent release system and at least one bioactive agent, wherein the carrier releases the bioactive agent in a pH-sensitive manner, characterized in that less than 20% of the bioactive agent is released into the gastric fluid and more than 50% of the bioactive agent is released in intestinal fluid at a pH greater than pH3, and wherein the bioactive agent is uncharged at the pH of the gastric fluid and charged at a pH greater than pH3 or unstable in fluids at a pH less than pH3.

Embodiments of the present invention relate to carrier compositions comprising at least one biocompatible targeted release agent, wherein the carrier composition and/or components thereof are capable of controllably releasing at least one active agent into certain portions of the Gastrointestinal (GI) tract. In other embodiments, the biocompatible targeted release agent comprises a pH-dependent release agent capable of controllably releasing the active agent in a pH-dependent manner. In other embodiments, the biocompatible targeted release agent comprises a pH-dependent release agent capable of controllably releasing the active agent into certain portions of the gastrointestinal tract based on the pH of said portions. In other embodiments, the pH-dependent release agent comprises a biocompatible fatty acid having at least 8 carbon atoms. In other embodiments, the carrier further comprises at least one neutral lipid, wherein the neutral lipid is immiscible with water. In other embodiments, the neutral lipid comprises a monoglyceride, diglyceride, triglyceride, or mixtures and combinations thereof, wherein the ester side chain has at least 6 carbon atoms. In other embodiments, the carrier further comprises less than 10 wt.% of one or more phospholipids.

Embodiments of the present invention relate to a carrier composition comprising 100 wt.% of at least one biocompatible fatty acid having at least 8 carbon atoms and 0 wt.% to 100 wt.% of at least one neutral lipid, wherein the carrier composition and/or components thereof are capable of controllably releasing at least one active agent into certain parts of the Gastrointestinal (GI) tract and wherein the wt.% may add up to a value of more than 100. In other embodiments, the carrier composition further comprises less than 10 wt.% phospholipids. In other embodiments, the carrier composition further comprises less than 5 wt.% phospholipids. In other embodiments, the carrier composition further comprises less than 2.5 wt.% phospholipids.

Embodiments of the present invention relate to compositions comprising a carrier comprising at least one biocompatible targeted release agent and an effective amount of at least one biologically active agent, wherein the carrier composition and/or components thereof are capable of controllably releasing the at least one active agent into certain portions of the Gastrointestinal (GI) tract. In other embodiments, the carrier and/or component thereof modifies and/or alters the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ, reduces and/or alters tissue and/or organ toxicity, increases and/or alters bioavailability, and/or increases and/or alters efficacy. In other embodiments, the carrier is capable of releasing the at least one active agent in a pH-dependent manner. In other embodiments, the biocompatible targeted release agent comprises at least one biocompatible fatty acid having at least 8 carbon atoms.

Embodiments of the present invention relate to a composition containing a carrier comprising 100 wt.% of at least one biocompatible fatty acid having at least 8 carbon atoms and 0 wt.% to 100 wt.% of at least one neutral lipid, wherein the neutral lipids are immiscible in water, wherein the wt.% may add up to a value of greater than 100, and an effective amount of at least one bioactive agent, wherein the carrier composition and/or components thereof are capable of controllably releasing the at least one active agent into certain portions of the Gastrointestinal (GI) tract. In other embodiments, the carrier and/or component thereof modifies and/or alters the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ, reduces and/or alters tissue and/or organ toxicity, increases and/or alters bioavailability, and/or increases and/or alters efficacy. In other embodiments, the carrier further comprises less than 10 wt.% phospholipids. In other embodiments, the carrier further comprises less than 5 wt.% phospholipids. In other embodiments, the carrier further comprises less than 2.5 wt.% phospholipids.

Embodiments of the present invention relate to a composition containing a carrier comprising less than 8 wt.% of at least one biocompatible fatty acid having at least 8 carbon atoms or greater than 14 wt.% of at least one biocompatible fatty acid having at least 8 carbon atoms and 0 wt.% to 100 wt.% of at least one neutral lipid, wherein the neutral lipid is immiscible in water, and 0 wt.% to 100 wt.% of at least one phospholipid, wherein the wt.% may add up to a value of greater than 100, and an effective amount of at least one bioactive agent, wherein the carrier composition and/or components thereof is capable of controllably releasing the at least one active agent into certain portions of the Gastrointestinal (GI) tract. In other embodiments, the carrier and/or component thereof modifies and/or alters the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ, reduces and/or alters tissue and/or organ toxicity, increases and/or alters bioavailability, and/or increases and/or alters efficacy.

Carrier

Embodiments of the present invention broadly relate to carrier compositions comprising at least one biocompatible targeted release agent. The carrier and/or components thereof modifies and/or alters the chemical and/or physical properties and/or behavior of at least one active agent in the tissue and/or organ to reduce and/or alter tissue and/or organ toxicity, increase and/or alter bioavailability, and/or increase and/or alter efficacy. In certain embodiments, the carriers and/or their components modify and/or alter the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ in a pH-dependent manner to reduce and/or alter tissue and/or organ toxicity, increase and/or alter bioavailability, and/or increase and/or alter efficacy. In certain embodiments, the biocompatible agent is hydrophobic.

The present invention broadly relates to a carrier for an active agent comprising: (1) one or more biocompatible fatty acids, (2) optionally one or more biocompatible fatty acid esters, (3) optionally one or more biocompatible oils, (4) optionally one or more biocompatible fatty acid salts, (5) optionally a second complexing agent, and (6) optionally a protective system comprising an agent for reducing and/or eliminating toxicity, irritation, or side effects. The carrier is typically a viscous fluid capable of being administered orally, directly, internally and/or topically.

In certain embodiments, the vectors of the present invention may also comprise other components, such as: (1) an excipient, (2) an adjuvant, (3) a desiccant, (4) an antioxidant, (5) a preservative, (6) a chelating agent, (7) a viscosity modifier, (8) an osmolality modifier, (9) a flavoring and taste masking agent, (10) a coloring agent, (11) an odorant, (12) a sunscreen agent, (13) a suspending agent, (14) a binder, and (15) a mixture thereof.

The carrier is typically a viscous fluid and the compositions prepared therefrom are typically solutions, pastes, semisolids, dispersions, suspensions, colloidal suspensions, or mixtures thereof and can be administered orally, parenterally, or topically.

Fatty acid targeted release agent

We also believe that the carrier and/or components thereof interact with certain types of active agents to affect the particle size, morphology, other physical characteristics, physical/chemical properties and/or behavior of the active agent in the carrier, and the physical/chemical properties of the crystal. In certain embodiments, the active agent is added to the carrier at an elevated temperature, wherein the temperature may be up to the melting temperature of the active ingredient, but below the decomposition temperature of either the carrier component or the active ingredient. The inventors believe that the pK of the release agent and/or active agent is at or near the pK of the pH-dependent release agent and/or active agent once the pH of the environment is at or near_aOr pK_bThe enhanced properties result in increased bioavailability of the active agent.

A second complexing agent

Embodiments of the carrier composition may further comprise at least one second agent capable of interacting with the active agent added to the carrier. Embodiments of the carrier composition may also include a second anti-toxicity system designed to reduce the toxic side effects of the active agent. Embodiments of these carrier compositions are typically free of water or substantially or essentially free of water and/or free of solvent or substantially or essentially free of solvent. As an oil, the carrier is water-immiscible. We have found that therapeutic compositions can be prepared by adding at least one therapeutically active agent, including pharmaceutical and/or nutritional agents, to the carriers of the invention having tailored properties. We have also found that pharmaceutical compositions can be prepared by adding at least one pharmaceutical agent to the carrier of the present invention under conditions to form a pharmaceutical composition having tailored properties. The present inventors have also found that nutritional compositions can be prepared by adding at least one nutritional agent to the carrier of the present invention, resulting in a nutritional composition with tailored properties. Embodiments of these compositions are non-aqueous or substantially non-aqueous and/or solvent-free or substantially solvent-free, i.e., the compositions are not miscible in a pH-dependent manner in biological fluids.

For pharmaceutical agents with GI toxicity, the carriers of the invention may also comprise neutral lipids and/or phospholipids, e.g. non-steroidal anti-inflammatory drugs (NSAIDs) as pharmaceutical agents, wherein the neutral lipids and/or phospholipids are known to reduce the pathogenic effects of NSAIDs, such as GI ulcers, bleeding, liver damage, kidney damage and/or cardiovascular diseases and/or side effects such as: hypertension, atherosclerosis, thrombosis, angina pectoris, stroke and myocardial infarction. In certain embodiments, the carriers of the present invention include a Free Fatty Acid (FFA) carrier in the absence or presence of a phospholipid, wherein the phospholipid reduces and/or eliminates the drug and/or nutritional toxicity, irritation, or side effects of certain drugs and/or nutrients such as NSAIDs, while the carrier without the phospholipid provides for direct targeted release of the NSAIDs resulting in released GI toxic side effects.

Composition comprising a metal oxide and a metal oxide

Embodiments of the present invention broadly relate to compositions comprising a carrier of the present invention and an effective amount of at least one active agent, with or without at least one second agent for the active agent or a protective agent for the active agent. In certain embodiments, the carriers of the present invention are non-aqueous, contain only residual water and are immiscible in water or aqueous solutions, but are capable of dispersing in aqueous solutions to release the active agent in a pH-dependent manner. In other embodiments, the vehicle of the present invention is oil-based, contains only residual water and is immiscible in water or aqueous solutions, but is capable of dispersing in aqueous solutions to release the active agent.

In certain embodiments, the carriers of the present invention can be tailored to have good targeted active agent release characteristics, to have reduced active agent toxicity or irritation, to have increased active agent bioavailability, and to have increased active agent migration across relatively hydrophobic barriers in humans, mammals, or animals.

In other embodiments, the carriers of the present invention may be tailored to have good targeted active agent release characteristics, to have reduced active agent GI toxicity or irritation, to have increased active agent bioavailability, and to have increased active agent migration across relatively hydrophobic barriers in humans, mammals, or animals.

Pharmaceutical and nutritional compositions

Embodiments of the present invention broadly relate to pharmaceutical compositions comprising a carrier of the present invention and an effective amount of a pharmaceutical agent or a mixture of pharmaceutical agents to form a solution and/or suspension of the pharmaceutical agent or mixture of pharmaceutical agents in the carrier. In certain embodiments, the pharmaceutical compositions can be tailored to have good targeted drug release characteristics, to have reduced drug toxicity or irritation, to have increased drug bioavailability, and to have increased drug migration across relatively hydrophobic barriers in humans, mammals, or animals. In other embodiments, the pharmaceutical composition may be tailored to have good targeted drug release characteristics, to have reduced drug GI toxicity or irritation, to have increased drug bioavailability, and to have increased drug migration across relatively hydrophobic barriers in humans, mammals, or animals.

Embodiments of the present invention broadly relate to nutritional compositions comprising a carrier of the present invention and an effective amount of a nutritional agent or mixture of nutritional agents to form a solution and/or suspension of the nutritional agent or mixture of nutritional agents in the carrier. In certain embodiments, the nutritional compositions may be tailored to have good targeted nutrient release characteristics, to have reduced nutrient toxicity or irritation, to have increased nutrient bioavailability, and to have increased nutrient migration across relatively hydrophobic barriers in humans, mammals, or animals. In other embodiments, the nutritional compositions may be tailored to have good targeted nutrient release characteristics, to have reduced nutrient GI toxicity or irritation, to have increased nutrient bioavailability, and to have increased nutrient migration across relatively hydrophobic barriers in humans, mammals, or animals.

In other embodiments, the pharmaceutical agent is an NSAID. In other embodiments, the NSAID compositions of the invention may further comprise: (1) a pharmaceutically acceptable amount of an antioxidant selected from vitamin a, vitamin C, vitamin E or other antioxidants approved by the FDA for human, mammalian or animal consumption; (2) a pharmaceutically acceptable amount of a multivalent cation selected from the group consisting of copper, zinc, gold, aluminum, and calcium; (3) a pharmaceutically acceptable amount of an agent that promotes fluidity, increases viscosity, promotes spreadability, promotes dispersibility, and/or promotes permeability selected from the group consisting of dimethyl sulfoxide (DMSO), propylene glycol (PPG), and medium chain triglycerides/MCT, and mixtures or combinations thereof; (4) a pharmaceutically acceptable amount of a food coloring or non-toxic dye; (5) a pharmaceutically acceptable amount of a flavor enhancer; (6) an excipient; and/or (7) adjuvants.

In other embodiments, the drug and/or nutritional agent is acid labile. The carrier may be tailored to selectively minimize release of the acid-labile active agent in the stomach and selectively target release of the acid-labile active agent to the small or large intestine. This embodiment may be particularly useful for patients at risk for Cardiovascular (CV) disease and acid reflux (acidreflux) disease or at increased risk for gastrointestinal bleeding who require the use of proton pump inhibitors, including but not limited to omeprazole (omeprazole) or lansoprazole (lansoprazole).

Compositions for use in therapy

Embodiments of the present invention broadly relate to methods comprising administering a composition of the present invention to a human, mammal, or animal. The carrier may be tailored such that the composition has good drug and/or nutrient release characteristics, has reduced drug and/or nutrient toxicity or irritation, has increased drug and/or nutrient bioavailability, and has increased drug or nutrient bioavailability across relatively hydrophobic barriers in humans, mammals, or animals. For example, a drug and/or nutrient having GI toxicity and/or GI irritation, the carrier of the present invention may be tailored to ameliorate, reduce or eliminate GI toxicity and/or GI irritation of the drug and/or nutrient. In certain embodiments, the drug and/or nutritional agent reduces, ameliorates, or treats inflammation. In other embodiments, the pharmaceutical and/or nutraceutical reduces, ameliorates, or treats platelet aggregation. In other embodiments, the pharmaceutical and/or nutraceutical reduces, ameliorates, or treats febrile activity. In other embodiments, the pharmaceutical and/or nutritional agent reduces, ameliorates, or treats the ulcerated regions of the tissue. Of course, the drug and/or nutritional agent also reduces, ameliorates, or treats a combination of these symptoms.

Process for preparing carriers and compositions

Embodiments of the present invention broadly relate to methods for making the carriers of the present invention by mixing (1) one or more biocompatible fatty acids, (2) optionally one or more biocompatible fatty acid esters, (3) optionally one or more biocompatible oils, (4) optionally one or more biocompatible fatty acid salts, (5) optionally a second complexing agent, and (6) a protection system optionally comprising an agent that reduces and/or eliminates toxicity, irritation, or side effects, under conditions of temperature, pressure, and time sufficient to form a carrier with tailored properties. The advantage of the mixing process is that no solvent is required in the preparation and therefore no solvent removal is required.

Embodiments of the present invention also broadly relate to methods for preparing a carrier of the present invention by mixing (1) one or more biocompatible fatty acids, (2) optionally one or more biocompatible fatty acid esters, (3) optionally one or more biocompatible oils, (4) optionally one or more biocompatible fatty acid salts, (5) optionally a second complexing agent, and (6) optionally a protection system comprising an agent that reduces and/or eliminates toxicity, irritation, or side effects, in the presence of a solvent system under conditions of temperature, pressure, and time sufficient to form a carrier with tailored properties, followed by removal of the solvent system. We have demonstrated that the behaviour of the compositions is not affected by the preparation with or without the use of solvents.

In certain embodiments, the support is typically prepared at room temperature, under atmospheric pressure, and mixed for a time sufficient for the support to be uniform and/or homogeneous or substantially uniform and/or substantially homogeneous. However, the support may be prepared at higher or lower pressures. In other embodiments, the mixing may be conducted at an elevated temperature up to the melting point of the component with the highest melting point, but below the decomposition temperature of either carrier component. In other embodiments, the temperature is raised to a temperature of up to about 130 ℃. In other embodiments, the temperature is raised to a temperature of up to 80 ℃. In other embodiments, the temperature is raised to a temperature of up to 60 ℃. In other embodiments, the temperature is raised to a temperature of up to 40 ℃.

In certain embodiments, the pressure is at or near atmospheric pressure. In other embodiments, the pressure is above atmospheric pressure. In other embodiments, the pressure is below atmospheric pressure.

In certain embodiments, the time is for a period of about 5 minutes to about 12 hours. In other embodiments, the time is for a period of from about 10 minutes to about 8 hours. In other embodiments, the time is for a period of about 20 minutes to about 4 hours. In other embodiments, the time is for a period of about 30 minutes to about 2 hours. In other embodiments, the time is for a period of about 30 minutes to about 1 hour.

In certain embodiments, the mixing is performed by low shear mixing, such as a paddle mixer. In other embodiments, the mixing is performed by high shear mixing such as an extruder, a closed mixer, or the like. In certain embodiments, the mixing is performed by a combination of low shear mixing and high shear mixing. In certain embodiments, the mixing is performed by sonication with or without low shear and/or high shear mixing. In certain embodiments, the mixing is performed by vortex mixing in the presence or absence of sonication.

Embodiments of the present invention broadly relate to methods for preparing compositions of the present invention by mixing a carrier of the present invention and an effective amount of at least one active agent under conditions of temperature, pressure and time sufficient to form a composition having tailored properties. In certain embodiments, the composition may further comprise a second complexing agent for the active agent, with or without a solvent system, under conditions of temperature, pressure, and time sufficient to form a composition having tailored properties. If a solvent system is used, the system is typically removed prior to use. In certain embodiments, the composition may further comprise a protective agent for the active agent. In certain embodiments, the active agent comprises a pharmaceutical agent, a nutraceutical agent, or mixtures and combinations thereof. In certain embodiments, the composition is prepared at room temperature and atmospheric pressure until the carrier is homogeneous and/or homogeneous. In other embodiments, the mixing may be conducted at an elevated temperature up to the melting point of the component with the highest melting point, but below the decomposition temperature of either carrier component. In other embodiments, the temperature is raised to a temperature of up to about 130 ℃. In other embodiments, the temperature is raised to a temperature of up to 80 ℃. In other embodiments, the temperature is raised to a temperature of up to 60 ℃. In other embodiments, the temperature is raised to a temperature of up to 40 ℃. In certain embodiments, the pressure is at or near atmospheric pressure. In other embodiments, the pressure is above atmospheric pressure. In other embodiments, the pressure is below atmospheric pressure. In certain embodiments, the time is for a period of about 5 minutes to about 12 hours. In other embodiments, the time is for a period of from about 10 minutes to about 8 hours. In other embodiments, the time is for a period of about 20 minutes to about 4 hours. In other embodiments, the time is for a period of about 30 minutes to about 2 hours. In other embodiments, the time is for a period of about 30 minutes to about 1 hour. In certain embodiments, the mixing is performed by low shear mixing, such as a paddle mixer. In other embodiments, the mixing is performed by high shear mixing such as an extruder, a closed mixer, or the like. In certain embodiments, the mixing is performed by a combination of low shear mixing and high shear mixing. In certain embodiments, the mixing is performed by sonication with or without low shear and/or high shear mixing. In certain embodiments, the mixing is performed by vortex mixing in the presence or absence of sonication. Of course, the compositions may be prepared by mixing the active agent and carrier components in any order, and thus, the carrier need not be preformed prior to addition of the active agent. In addition, the order of addition is not critical and can vary depending on the components, the mixer, the desired final properties, or operator selection.

Methods of using vectors and compositions

Embodiments of the present invention broadly relate to methods of using the compositions of the present invention by administering the compositions of the present invention to a human, mammal, or animal in a dose sufficient to cause at least one therapeutic effect, such as the treatment and/or prevention of pain, fever, inflammation, cancer, inflammatory bowel syndrome, crohn's disease, cardiovascular disease, infection, brain and spinal cord injury, alzheimer's disease, other neurological diseases, diabetes, and/or any other disease or condition treatable by the administration of an active agent, such as a drug and/or nutrient. In other embodiments, the composition treats, prevents, and/or ameliorates the symptoms of a disease and/or disorder.

Embodiments of the present invention broadly relate to methods comprising orally or internally administering a composition comprising a carrier of the present invention and a therapeutically effective amount of a composition of the present invention to increase transport of a drug or nutritional agent across the blood-brain barrier or into the Central Nervous System (CNS) or Peripheral Nervous System (PNS), allow more of the drug or nutritional agent to reach the site of trauma and reduce inflammation, platelet aggregation, pain (nociception), cell death and/or apoptosis due to inflammation and/or induce competitive cell death of cancer cells in the prevention or treatment of cancer.

Embodiments of the present invention broadly relate to methods comprising orally or internally administering a composition comprising a carrier of the present invention and a therapeutically effective amount of a composition of the present invention to prevent, treat and/or ameliorate symptoms associated with alzheimer's disease.

Composition range used in the present invention

Carrier

Universal carrier

The vector of the present invention may comprise:

(1)100 wt.% of at least one biocompatible pharmaceutical agent,

(2) from about 0 wt.% to 100 wt.% of a second complexing agent or a mixture of second complexing agents, wherein the second complexing agent is dependent on the nature of the active agent carried by the carrier,

(3) from about 0 wt.% to about 50 wt.% of a second anti-toxic agent or a mixture of second anti-toxic agents, wherein the second anti-toxic agent depends on the nature of the active agent carried by the carrier, and

(4) from about 0 wt.% to about 50 wt.% of (a) an excipient or mixture of excipients, (b) an adjuvant or mixture of adjuvants, (c) a desiccant or mixture of desiccants, (d) an antioxidant or mixture of antioxidants, (e) a preservative or mixture of preservatives, (f) or a mixture of chelating agents, (g) a viscosity modifier or mixture of viscosity modifiers, (h) an osmolality modifier or mixture of osmolality modifiers, (I) a flavoring or mixture of flavors, (j) a coloring or mixture of coloring agents, (k) an odorant or mixture of odorants, (l) an opacifier or mixture of opacifiers, (m) a suspending agent or mixture of suspending agents, and (n) a mixture thereof.

The vector of the present invention may comprise:

(1)100 wt.% of at least two biocompatible pharmaceutical agents,

The above compositions are not formulated as a mixture having a total of 100 wt.% of the specified components.

pH-dependent carrier

The vector of the present invention may comprise:

(1)100 wt.% of at least one pH-dependent biocompatible release agent,

The vector of the present invention may comprise:

(1)100 wt.% of at least one pH-dependent biocompatible release agent,

(2) about 0 wt.% to 100 wt.% of at least one other biocompatible pharmaceutical agent,

(3) from about 0 wt.% to 100 wt.% of a second complexing agent or a mixture of second complexing agents, wherein the second complexing agent is dependent on the nature of the active agent carried by the carrier,

(4) from about 0 wt.% to about 50 wt.% of a second anti-toxic agent or a mixture of second anti-toxic agents, wherein the second anti-toxic agent depends on the nature of the active agent carried by the carrier, and

(5) from about 0 wt.% to about 50 wt.% of (a) an excipient or mixture of excipients, (b) an adjuvant or mixture of adjuvants, (c) a desiccant or mixture of desiccants, (d) an antioxidant or mixture of antioxidants, (e) a preservative or mixture of preservatives, (f) or a mixture of chelating agents, (g) a viscosity modifier or mixture of viscosity modifiers, (h) an osmolality modifier or mixture of osmolality modifiers, (I) a flavoring or mixture of flavors, (j) a coloring or mixture of coloring agents, (k) an odorant or mixture of odorants, (l) an opacifier or mixture of opacifiers, (m) a suspending agent or mixture of suspending agents, and (n) a mixture thereof.

Fatty acid pH-dependent carrier

The vector of the present invention may comprise:

(1) about 0 wt.% to 100 wt.% of a biocompatible fatty acid or a mixture of biocompatible fatty acids (sometimes referred to herein as free fatty acids),

(2) about 0 wt.% to 100 wt.% of a biocompatible fatty acid ester or a mixture of biocompatible fatty acid esters,

(3) about 0 wt.% to 100 wt.% of a biocompatible fatty acid salt or a mixture of biocompatible fatty acid salts,

(4) about 0 wt.% to 100 wt.% of a biocompatible oil or a mixture of biocompatible oils,

(5) from about 0 wt.% to 100 wt.% of a second complexing agent or a mixture of second complexing agents, wherein the second complexing agent is dependent on the nature of the active agent carried by the carrier,

(6) from about 0 wt.% to about 50 wt.% of a second anti-toxic agent or a mixture of second anti-toxic agents, wherein the second anti-toxic agent depends on the nature of the active agent carried by the carrier, and

(7) from about 0 wt.% to about 50 wt.% of (a) an excipient or mixture of excipients, (b) an adjuvant or mixture of adjuvants, (c) a desiccant or mixture of desiccants, (d) an antioxidant or mixture of antioxidants, (e) a preservative or mixture of preservatives, (f) or a mixture of chelating agents, (g) a viscosity modifier or mixture of viscosity modifiers, (h) an osmolality modifier or mixture of osmolality modifiers, (I) a flavoring or mixture of flavors, (j) a coloring or mixture of coloring agents, (k) an odorant or mixture of odorants, (l) an opacifier or mixture of opacifiers, (m) a suspending agent or mixture of suspending agents, and (n) a mixture thereof.

In other embodiments, the vector comprises:

(1) about 5 wt.% to 100 wt.% of a biocompatible fatty acid or a mixture of biocompatible fatty acids (sometimes referred to herein as free fatty acids),

(2) about 5 wt.% to 100 wt.% of a biocompatible fatty acid ester or a mixture of biocompatible fatty acid esters,

(3) about 5 wt.% to 100 wt.% of a biocompatible fatty acid salt or a mixture of biocompatible fatty acid salts,

(6) from about 0 wt.% to about 25 wt.% of a second anti-toxic agent or a mixture of second anti-toxic agents, wherein the second anti-toxic agent depends on the nature of the active agent carried by the carrier, and

(7) from about 0 wt.% to about 25 wt.% of (a) an excipient or mixture of excipients, (b) an adjuvant or mixture of adjuvants, (c) a desiccant or mixture of desiccants, (d) an antioxidant or mixture of antioxidants, (e) a preservative or mixture of preservatives, (f) or a mixture of chelating agents, (g) a viscosity modifier or mixture of viscosity modifiers, (h) an osmolality modifier or mixture of osmolality modifiers, (I) a flavoring or mixture of flavors, (j) a coloring or mixture of coloring agents, (k) an odorant or mixture of odorants, (l) an opacifier or mixture of opacifiers, (m) a suspending agent or mixture of suspending agents, and (n) a mixture thereof.

In other embodiments, the vector comprises:

(1) from about 10 wt.% to 100 wt.% of a biocompatible fatty acid or a mixture of biocompatible fatty acids, sometimes referred to herein as free fatty acids,

(2) about 10 wt.% to 100 wt.% of a biocompatible fatty acid ester or a mixture of biocompatible fatty acid esters,

(3) about 10 wt.% to 100 wt.% of a biocompatible fatty acid salt or a mixture of biocompatible fatty acid salts,

The above compositions are formulated as a mixture having a total of 100 wt.% of the specified components.

Another way of expressing the carrier is by weight ratio of the components. In certain embodiments, the ratio of component species is from 1 to 3: 4: 5: 6: 7, from 1: 0 to 0: 1: 0 to 1: 0:1, and from 0: 1. In other embodiments, the ratio of component species is from 1-3: 4: 5: 6: 7 to 10: 1: 0 to 1: 10: 0 to 10:1 to 1: 10: 1. In other embodiments, the ratio of component species is from 1-3: 4: 5: 6: 7, from 5: 1: 0 to 1: 5: 0 to 5: 1 to 1: 5: 1. In other embodiments, the ratio of component species is from 1-3: 4: 5: 6: 7, from 4: 1: 0 to 4: 0 to 4: 1 to 1: 4: 1. In other embodiments, the ratio of component species is from 1-3: 4: 5: 6: 7, from 3: 1: 0 to 1: 3: 0 to 3: 1 to 1: 3: 1. In other embodiments, the ratio of component species is from 1-3: 4: 5: 6: 7, from 2: 1: 0 to 1: 2: 0 to 2: 1 to 1: 2: 1. In other embodiments, the ratio of component species is from 1: 0 to 1: 7 to 1-3: 4: 5: 6: 7. Of course, the actual value of each level may vary over the entire range within the respective range.

The carrier and/or carrier component is designed to modify and/or alter the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ to reduce and/or alter tissue and/or organ toxicity, increase and/or alter bioavailability, and/or increase and/or alter efficacy. In certain embodiments, the carrier and/or biocompatible hydrophobic agent modifies and/or alters the chemical and/or physical properties and/or behavior of at least one active agent in a tissue and/or organ in a pH-dependent manner to reduce and/or alter tissue and/or organ toxicity, increase and/or alter bioavailability, and/or increase and/or alter efficacy.

In certain embodiments, the carrier comprises about 100 wt.% to 50 wt.% of a biocompatible oil and about 0 wt.% to 50 wt.% of a biocompatible fatty acid. In other embodiments, about 0 wt.% to 50 wt.% of the biocompatible oil and about 100 wt.% to 50 wt.% of the biocompatible fatty acid.

Low phospholipid carriers

In certain embodiments, the carrier comprises about 100 wt.% to 99 wt.% of the biocompatible oil and about 0 wt.% to 1 wt.% of the phospholipid. In other embodiments, about 100 wt.% to 98 wt.% of the biocompatible oil and about 0 wt.% to 2 wt.% of the phospholipid. In other embodiments, about 100 wt.% to 95 wt.% of the biocompatible oil and about 0 wt.% to 5 wt.% of the phospholipid. In other embodiments, the bio-compatible oil is about 100 wt.% to about 90 wt.% and the phospholipid is about 0 wt.% to about 10 wt.%.

In other embodiments, the carrier comprises about 100 wt.% to 80 wt.% of a biocompatible oil, about 0 wt.% to about 10 wt.% of a biocompatible fatty acid, and about 0 wt.% to 10 wt.% of a phospholipid. In other embodiments, the carrier comprises about 100 wt.% to 40 wt.% of a biocompatible oil, about 0 wt.% to about 40 wt.% of a biocompatible fatty acid, and about 0 wt.% to 10 wt.% of a phospholipid.

In certain embodiments, the carrier comprises about 100 wt.% to 80 wt.% of a biocompatible fatty acid, about 0 wt.% to about 10 wt.% of a biocompatible oil, and about 0 wt.% to 10 wt.% of a phospholipid. In other embodiments, about 100 wt.% to 40 wt.% of the biocompatible fatty acid, about 0 wt.% to about 40 wt.% of the biocompatible oil, and about 0 wt.% to 10 wt.% of the phospholipid.

In certain embodiments, the carrier may further comprise about 0.5 wt.% to about 2 wt.% sterol, about 5 wt.% to about 10 wt.% glycolipid, and about 0.5 wt.% to 2 wt.% water, less than 2 wt.%. The phospholipid comprises about 75 wt.% to about 100 wt.% phosphatidylcholine, about 0 wt.% to about 10 wt.% phosphatidylethanolamine, about 0 wt.% to about 10 wt.% lyso-phosphatidylcholine, and about 0 wt.% to about 2 wt.% phosphatidylinositol. The biocompatible oil comprises about 50 wt.% to 80 wt.% triglycerides, about 0 wt.% to 5 wt.% mono-and diglycerides, and about 5 wt.% to about 20 wt.% free fatty acids.

High phospholipid carriers

In certain embodiments, the carrier comprises about 30 wt.% to 50 wt.% phospholipid, about 30 wt.% to 50 wt.% bio-compatible oil, about 0.5 wt.% to about 2 wt.% sterol, about 5 wt.% to about 10 wt.% glycolipid, about 0.5 wt.% to 2 wt.% water. The phospholipid comprises about 75 wt.% to about 100 wt.% phosphatidylcholine, about 0 wt.% to about 10 wt.% phosphatidylethanolamine, about 0 wt.% to about 10 wt.% lyso-phosphatidylcholine, and about 0 wt.% to about 2 wt.% phosphatidylinositol. The biocompatible oil comprises about 50 wt.% to 80 wt.% triglycerides, about 0 wt.% to 5 wt.% mono-and diglycerides, and about 5 wt.% to about 20 wt.% free fatty acids.

In certain embodiments, the carrier comprises about 30 wt.% to 50 wt.% phospholipid, about 30 wt.% to 50 wt.% bio-compatible oil, about 0.5 wt.% to about 2 wt.% sterol, about 5 wt.% to about 10 wt.% glycolipid, about 0.5 wt.% to 2 wt.% water. The phospholipid comprises about 75 wt.% to about 100 wt.% phosphatidylcholine, about 0.1 wt.% to about 10 wt.% phosphatidylethanolamine, about 0.1 wt.% to about 10 wt.% lyso-phosphatidylcholine, and about 0.5 wt.% to about 2 wt.% phosphatidylinositol. The biocompatible oil comprises about 50 wt.% to 80 wt.% triglycerides, about 0.5 wt.% to 5 wt.% mono-and diglycerides, and about 5 wt.% to about 20 wt.% free fatty acids.

Free fatty acid, biocompatible oil and phospholipid composition

In certain embodiments, the carrier comprises Free Fatty Acids (FFA), bio-compatible oils (BCO), and Phospholipids (PL) in a weight ratio of a: b: c (FFA: BCO: PL), wherein a ranges from 1 to 10, b ranges from 0 to 10, and c ranges from 0 to 10. In certain embodiments, a ranges from 0 to 10, b ranges from 1 to 10, and c ranges from 0 to 10. In certain embodiments, a ranges from 1 to 10, b ranges from 1 to 10, and c ranges from 0 to 10. The FFA in the carrier may be a single free fatty acid or a mixture of free fatty acids as defined herein. The BCO in the carrier can be a single biocompatible oil or a mixture of biocompatible oils. The PL in the carrier may be a single phospholipid or a mixture of phospholipids.

In certain embodiments, the carrier comprises Free Fatty Acids (FFA), Neutral Lipids (NL), and Phospholipids (PL) in a weight ratio of a: b: c (FFA: NL: PL), wherein a ranges from 1 to 10, b ranges from 0 to 10, and c ranges from 0 to 10. In certain embodiments, a ranges from 0 to 10, b ranges from 1 to 10, and c ranges from 0 to 10. In certain embodiments, a ranges from 1 to 10, b ranges from 1 to 10, and c ranges from 0 to 10. The FFA in the carrier may be a single free fatty acid or a mixture of free fatty acids as defined herein. The NL in the vector can be a single neutral lipid or a mixture of neutral lipids. The PL in the carrier may be a single phospholipid or a mixture of phospholipids.

Second complexing agent and/or antitoxic agent

NSAID

In certain NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 7.5 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 5 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 2.5 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises from about 0.1 wt.% to about 10 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises from about 0.5 wt.% to about 10 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises from about 1 wt.% to about 10 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant. In other NSAID compositions, the second anti-toxic agent comprises from about 2 wt.% to about 10 wt.% of at least one zwitterionic agent such as a zwitterionic surfactant.

In certain NSAID compositions, the second anti-toxic agent comprises from about 0 wt.% to about 50 wt.% of at least one triglyceride neutral lipid. In other NSAID compositions, the second anti-toxic agent comprises from about 0.1 wt.% to about 10 wt.% of at least one Proton Pump Inhibitor (PPI).

In certain NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent and from about 0 wt.% to about 50 wt.% of at least one neutral lipid. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent and from about 1 wt.% to about 50 wt.% of at least one neutral lipid.

In certain NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent and from about 0 wt.% to about 10 wt.% of at least one PPI. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent and from about 0.5 wt.% to about 10 wt.% of at least one PPI. In other NSAID compositions, the second anti-toxic agent comprises less than or equal to about 10 wt.% of at least one zwitterionic agent, from about 0.5 wt.% to about 50 wt.% of at least one neutral lipid, and from about 0.5 wt.% to about 10 wt.% of at least one PPI.

Composition comprising a metal oxide and a metal oxide

The compositions of the present invention are generally formulated with at least one bioactive agent as the major component.

The compositions of the present invention may have a weight ratio of active agent to carrier, wherein the carrier is present in an amount to form at least a monolayer coating on the active agent. In certain embodiments, the weight ratio of active agent to carrier is from about 100: 1 to about 1: 100. In other embodiments, the ratio is from about 100: 1 to about 1: 10. In other embodiments, the ratio is from about 50: 1 to about 1: 5. In other embodiments, the ratio is from about 25: 1 to about 1: 5. In other embodiments, the ratio is from about 10:1 to about 1: 1. In other embodiments, the ratio is from about 5: 1 to about 1: 1. In other embodiments, the ratio is from about 5: 1 to about 1:1, with the term about meaning ± 5%.

Dosage of medicine or nutrient

In pharmaceutical compositions, the composition will generally contain from about 1mg to about 5000mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 10mg to about 2500mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 250mg to about 2500mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 500mg to about 2500mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 500mg to about 2000mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 1mg to about 2000mg per dose, depending on the pharmaceutical agent(s). In other pharmaceutical compositions, the composition will contain from about 1mg to about 1000mg per dose, depending on the pharmaceutical agent(s). The exact dosage of each composition will, of course, depend on the pharmaceutical agent(s) used and the potency of the pharmaceutical agent(s).

In a nutritional composition, the composition will typically contain from about 1mg to about 5000mg per dose, depending on the nutritional agent(s). In other nutrient compositions, the composition will contain from about 10mg to about 2500mg per dose, depending on the nutrient(s). In other nutrient compositions, the composition will contain from about 250mg to about 2500mg per dose, depending on the nutrient(s). In other nutrient compositions, the composition will contain from about 500mg to about 2500mg per dose, depending on the nutrient(s). In other nutrient compositions, the composition will contain from about 500mg to about 2000mg per dose, depending on the nutrient(s). In other nutrient compositions, the composition will contain from about 1mg to about 2000mg per dose, depending on the nutrient(s). In other nutrient compositions, the composition will contain from about 1mg to about 1000mg per dose, depending on the nutrient(s). The exact dosage of each composition will, of course, depend on the pharmaceutical agent(s) used and the potency of the pharmaceutical agent(s).

Reagents suitable for use in the invention

pH-dependent release agent

Fatty acids

Suitable biocompatible fatty acids for use in the present invention include, without limitation, any saturated or unsaturated fatty acid or mixtures or combinations thereof suitable for human, mammalian or animal consumption. Exemplary fatty acids include Short Chain Free Fatty Acids (SCFFA), Medium Chain Free Fatty Acids (MCFFA), Long Chain Free Fatty Acids (LCFFA), Very Long Chain Free Fatty Acids (VLCFFA), and mixtures or combinations thereof. SCFFA includes compounds having a C content of less than 4 to less than 8 carbon atoms₄-C₈) Free fatty acids of the carbyl tail group of (a). MCFFA comprises a polymer having a carbon number of 8 to less than 14 (C)₈-C₁₄) Free fatty acids based on carbon (ii). LCFFA comprises a polymer having a C containing 14-24 carbon atoms₁₄-C₂₄) Free fatty acids based on carbon (ii). VLCFFA include those having a carbon number greater than 24 (> C)₂₄) Free fatty acids based on carbon (ii). Exemplary unsaturated fatty acids include, without limitation, myristoleic acid [ CH₃(CH₂)₃CH＝CH(CH₂)₇COOH，cis-Δ⁹，C∶D14∶1，n-5]Palmitoleic acid [ CH ]₃(CH₂)₅CH＝CH(CH₂)₇COOH，cis-Δ⁹，C∶D16∶1，n-7]Sapienic acid [ CH ]₃(CH₂)₈CH＝CH(CH₂)₄COOH，cis-Δ⁶，C∶D16∶1，n-10]Oleic acid [ CH ]₃(CH₂)₇CH＝CH(CH₂)₇COOH，cis-Δ⁹，C∶D18∶1，n-9]Linoleic acid [ CH ]₃(CH₂)₄CH＝CHCH₂CH＝CH(CH₂)₇COOH，cis，cis-Δ⁹，Δ¹²，C∶D18∶2，n-6]α -linolenic acid [ CH₃CH₂CH＝CHCH₂CH＝CHCH₂CH＝CH(CH₂)₇COOH，cis，cis，cis-Δ⁹，Δ¹²，Δ¹⁵，C∶D18∶3，n-3]Arachidonic acid [ CH ]₃(CH₂)₄CH＝CHCH₂CH＝CHCH₂CH＝CHCH₂CH＝CH(CH₂)₃COOH，cis，cis，cis，cis-Δ⁵Δ⁸，Δ¹¹，Δ¹⁴，C∶D20∶4，n-6]Eicosapentaenoic acid [ CH ]₃CH₂CH＝CHCH₂CH＝CHCH₂CH＝CHCH₂CH＝CHCH₂CH＝CH(CH₂)₃COOH]，cis，cis，cis，cis，cis-Δ⁵，Δ⁸，Δ¹¹，Δ¹⁴，Δ¹⁷，20∶5，n-3]Erucic acid [ CH ]₃(CH₂)₇CH＝CH(CH₂)₁₁COOH，cis-Δ¹³，C∶D22∶1，n-9]Docosatetraenoic acid [ CH ]₃CH₂CH＝CHCH₂CH＝CHCH₂CH＝CHCH₂CH＝CH CH₂CH＝CHCH₂CH＝CH(CH₂)₂COOH，cis，cis，cis，cis，cis，cis-Δ⁴，Δ⁷，Δ¹⁰，Δ¹³，Δ¹⁶，Δ¹⁹，C∶D22∶6，n-3]Or mixtures and combinations thereof.

Exemplary saturated fatty acids include, without limitation, lauric acid [ CH₃(CH₂)₁₀COOH，C∶D12∶0]Myristic acid [ CH ]₃(CH₂)₁₂COOH，C∶D14∶0]Palmitic acid [ CH ]₃(CH₂)₁₄COOH，C∶D16∶0]Stearic acid [ CH ]₃(CH₂)₁₆COOH，C∶D18∶0]Eicosanoic acid [ CH ]₃(CH₂)₁₈COOH，C∶D20∶0]Behenic acid [ CH ]₃(CH₂)₂₀COOH，C∶D22∶0]Tetracosanoic acid [ H ]₃(CH₂)₂₂COOH，C∶D24∶0]Cerotic acid [ CH ]₃(CH₂)₂₄COOH，C∶D26∶0]Or mixtures and combinations thereof.

Exemplary saturated fatty acids include, without limitation, butyric acid (C)₄) Valeric acid (C)₅) Hexanoic acid (C)₆) Heptanoic acid (C)₇) Octanoic acid (C)₈) Pelargonic acid (C)₉) Decanoic acid (C)₁₀) Undecanoic acid (C)₁₁) Lauric acid (C)₁₂) Tridecanoic acid (C)₁₃) Myristic acid (C)₁₄) Pentadecanoic acid (C)₁₅) Palmitic acid (C)₁₆) Heptadecanoic acid (C)₁₇) Stearic acid (C)₁₈) Nonadecanoic acid (C)₁₉) Arachidic acid (C)₂₀) Heneicosanoic acid (C)₂₁) Behenic acid (C)₂₂) Tricosanoic acid (C)₂₃) Tetracosanoic acid (C)₂₄) And eicosapentaenoic acid (C)₂₅) Wax acid (C)₂₆) And heptacosanoic acid (C)₂₇) Montanic acid (C)₂₈) Montanic acid (C)₂₉) Triacontanoic acid (C)₃₀) And undecanoic acid (C)₃₁) And tridecanoic acid (C)₃₂) Pediculosic acid (C)₃₃) And tetradecanoic acid (C)₃₄) And tridecanoic acid (C)₃₅) Unsaturated fatty acids include, without limitation, n-3 unsaturated fatty acids such as α -linolenic acid, stearidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, n-6 unsaturated fatty acids such as linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachidonic acid, n-9 unsaturated fatty acids oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonic acid, mead acid (mead acid), and mixtures or combinations thereof.

Polybasic acid

Suitable polycarboxylic acid compounds for use as a pH-dependent release agent include, without limitation, any polycarboxylic acid compound. Illustrative examples of water-immiscible polyacids include, without limitation, dicarboxylic acids having carbyl or carbenyl (carbenyl) groups containing from 8 to 50 carbon atoms and mixtures or combinations thereof. Polymeric carboxylic acids or polymers containing carboxylic acid groups, in which the polymer is oil-soluble or is oil-immiscible with water. Illustrative examples of hydrophilic polyacids include, without limitation, polyacrylic acid, polymethacrylic acid, polylactic acid, polyglycolic acid, mixtures and combinations thereof, copolymers thereof, CARBOPOL available from Lubrizol CorporationAn agent (registered trademark of Lubrizol Corporation), other carboxylic acid-containing polymers, or mixtures or combinations thereof.

Fatty acid esters

The fatty acid esters include esters of any of the fatty acids listed above, including, without limitation, monohydric alcohol esters wherein the monohydric or polyhydric alcohol contains from 1 carbon atom to 20 carbon atoms, wherein one or more of the carbon atoms may be replaced by O, NR (R is a carbyl group having 1-5 carbon atoms) or S. Exemplary monohydric alcohols used to form the free fatty acid esters include methanol, ethanol, propanol, butanol, pentanol, or mixtures thereof.

Fatty acid salts

Suitable biocompatible fatty acid salts for use in the present invention include, without limitation, alkali metal salts of any of the above-listed fatty acids, alkaline earth metal salts of any of the above-listed fatty acids, transition metal salts of any of the above-listed fatty acids, or mixtures or combinations thereof. In certain embodiments, the metal salt comprises lithium, sodium, potassium, cesium, magnesium, calcium, barium, copper, zinc, cobalt, iron, or mixtures or combinations thereof.

Second complexing agent and/or antitoxic agent

Suitable second complexing agents and/or second anti-toxic agents for use in the compositions of the present invention include, without limitation, phospholipids, amphoteric and/or zwitterionic agents or mixtures or combinations thereof. Phospholipids include any phospholipid or mixtures and combinations thereof, such as (1) diacyl glyceride phospholipids or glycerophospholipids, including, without limitation, phosphatidic acid (phosphatidate) (PA), phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin) (PC), Phosphatidylserine (PS), phosphoinositides such as Phosphatidylinositol (PI), phosphophosphatidylinositol (PIP), diphosphatidylphosphatidylginositide (PIP2), and triphosphatidphosphatidylinositol (PIP3), and (2) sphingophospholipids such as ceramide phosphocholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol. The amphoteric agent comprises acetate, betaine, glycinate, imidazoline, propionate, other amphoteric agents, or mixture thereof. Zwitterionic agents include, without limitation, biocompatible zwitterionic phospholipids, biocompatible zwitterionic betaines, biocompatible amphoteric/zwitterionic surfactants, biocompatible quaternary salts, biocompatible amino acids, other biocompatible compounds capable of forming zwitterions or in zwitterionic form, or mixtures or combinations thereof.

Suitable biocompatible zwitterionic phospholipids for use in the present invention include, without limitation, phospholipids of the general formula:

wherein R is¹And R²Is a saturated or unsaturated substituent of 8 to 32 carbon atoms; r³Is H or CH₃And X is H or COOH; and R is⁴Is ═ O or H₂. Mixtures and combinations of zwitterionic phospholipids of this formula and mixtures and combinations of NSAIDs may also be used.

Illustrative examples of zwitterionic phospholipids of the above formula include, without limitation, phosphatidylcholines such as Phosphatidylcholine (PC), Dipalmitoylphosphatidylcholine (DPPC), other di-saturated phosphatidylcholines, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine sphingomyelin or other ceramides, or various other zwitterionic phospholipids, oleaginous phospholipids such as soybean-derived lecithin oil, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilinolinoylphosphatidylcholine (DLL-PC), Dipalmitoylphosphatidylcholine (DPPC), soybean phosphatidylcholine (Soy-PC or P-phosphatidylcholine)Cs) and Egg phosphatidylcholine (Egg-PC or PC)_E). In the saturated phospholipid DPPC, saturated aliphatic substituents R₁And R₂Is CH₃-(CH₂)₁₄，R₃Is CH₃And X is H. In the unsaturated phospholipid DLL-PC, R₁And R₂Is CH₃-(CH₂)₄--CH＝＝CH--CH₂--CH＝＝CH-(CH₂)₇，R₃Is CH₃And X is H. In Egg PC, which is a mixture of unsaturated phospholipids, R₁Containing predominantly saturated aliphatic substitutions (e.g. palmitic or stearic acid), and R₂Predominantly unsaturated aliphatic substitutions (e.g., oleic acid or arachidonic acid). In Soy-PC-in addition to saturated phospholipids (palmitic and stearic acid) it is a mixture of unsaturated phospholipids (oleic, linoleic and linolenic acids). In certain embodiments, the phospholipid is a zwitterionic phospholipid including, without limitation, dipalmitoyl lecithin, phosphatidylcholine, or a mixture thereof.

Exemplary acetates include, without limitation, lauroamphoacetate, alkylamphoacetate, cocoamphoacetate, cocoamphodiacetate, sodium cocoamphoacetate, sodium lauroamphoacetate, disodium cocoamphodiacetate, disodium caprylamphodiacetate, disodium lauroamphoacetate, disodium wheat germ amphodiacetate, cocoamphoacetate and cocoamphodiacetate, disodium cocoamphodiacetate, and mixtures or combinations thereof.

Exemplary betaines include, without limitation, cocamidopropyl betaine, sodium lauroamphoacetate, Cocamidopropyl Hydroxysultaine (CHSB), lauryl dimethyl betaine, cetyl betaine, lauroamphoacetate, alkylamphoacetate, cocoampho (di) acetate, cocoamphoacetate, cocoamphodiacetate, disodium cocoamphodiacetate, sodium cocoamphoacetateSodium lauroyl amphoacetate, disodium cocoyl amphodiacetate, disodium capryloyl amphodiacetate, disodium lauroyl amphoacetate, disodium wheat germ amphodiacetate, disodium cocoyl amphoacetate, and alkylamide betaine; alkyl dimethyl betaine, cocamidopropyl betaine, tallow di (hydroxyethyl) betaine, cetyl dimethyl betaine, alkylamidopropyl sulphobetaine, alkyl dimethylamine betaine, cocamidopropyl dimethyl betaine, alkylamidopropyl dimethylamine betaine, cocamidopropyl betaine, lauryl betaine, laurylamidopropyl betaine, cocopropyl betaine, lauramidobetaine, polydimethylsiloxanepropypg-betaine, N-alkyldimethylbetaine, cocobiguanide derivative (coco biguanidine derivative), cetyl betaine, oleamidopropyl betaine, isostearamidopropyl betaine, oleyl betaine, wheat germ oleamidopropyl betaine, cocamidopropyl betaine, lauramidopropyl betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazoline.Salt betaine; cocamidopropyl betaine, isostearamidopropyl betaine, myristamidopropyl betaine, palmitoamidopropyl betaine, cocamidopropyl hydroxybetaine, ammonium chloride cocamidopropyl hydroxysultaine, and potassium chloride cocamidopropyl hydroxybetaine, undecenamidopropyl betaine, wheat germ amidopropyl betaine, or mixtures and combinations thereof.

Exemplary glycinates include, without limitation, Amphalak 7CX, Amphalak X07, cocoamphocarboxyglycinate, amphocarboxyglycinate, oleoamphocarboxyglycinate, cocoiminodiglycinate, octanoamphocarboxyglycinate, bis-2-hydroxyethyl tallowglycinate, lauroamphoglycinate, oleopolyamphetamine, -C_10/12Fatty acid aminoethyl-N- (2-hydroxyethyl) -glycinate, C_12/18-fatty acid aminoethyl-N- (2-hydroxyethyl) -glycinate, dihydroxyethyl tallow glycinate, and mixtures or groups thereofAnd (6) mixing.

Exemplary imidazolines include, without limitation, 2-alkyl-1- (ethyl- β -oxypropanoic) imidazoline sodium salt based on octanoic acid, 1-hydroxyethyl-2-alkylimidazoline, cocoylimidazoline, tall oil imidazoline, lauryl imidazoline, cocoylimidazoline dicarboxymethylation, sodium coprocene dicarboxylate imidazoline, oleyl imidazoline, and mixtures or combinations thereof.

Exemplary propionate salts include, without limitation, cocoiminodipropionate, octyliminodipropionate, cocoalkylaminopropionic acid, cocoamphodipropionate, lauraminopropionic acid, disodium tallow-P-iminodipropionate, monosodium N-lauryl P-iminodipropionate, disodium lauriminodipropionate, sodium lauriminopropionate, 2-ethylhexyl aminopropionate, cocoaminodipropionate, cocoaminopropionic acid, lauraminopropionic acid, sodium lauriminodipropionate, disodium cocoamphodipropionate, disodium capryloyl amphodipropionate, disodium lauramphodipropionate, sodium cocoamphopropionate, sodium lauriminodipropionate, sodium alkyl iminopropionate, and mixtures or combinations thereof.

Exemplary other amphoteric agents include, without limitation, sodium N-coco-3-aminobutyrate, N-coco-3-aminobutyric acid, ethoxylated fatty alcohol carboxyym, cocamidopropyl hydroxybetaine, sodium cocoyl amphoteric hydroxypropyl sulfonate, sodium caprylyl amphoteric hydroxypropyl sulfonate, and mixtures or combinations thereof.

Pharmaceutical agent

Suitable pharmaceutical agents for use in the compositions of the present invention include, without limitation, any pharmaceutical agent capable of being dispersed in a carrier of the present invention. In certain embodiments, the pharmaceutical agent is a solid. In other embodiments, the pharmaceutical agent is a liquid. In other embodiments, the pharmaceutical agent is a weak acid pharmaceutical agent. In other embodiments, the pharmaceutical agent is a weak base pharmaceutical agent.

Hydrophobic drugs and/or nutrients

Hydrophobic therapeutic agents suitable for use in the pharmaceutical composition of the present invention are not particularly limited, as surprisingly the carrier is capable of dissolving and delivering a wide range of hydrophobic therapeutic agents. Hydrophobic therapeutic agents are compounds with little or no aqueous solubility. The hydrophobic therapeutic agents useful in the present invention have an inherent aqueous solubility (i.e., the aqueous solubility of the unionized form) of less than about 1 weight percent, and typically less than about 0.1 weight percent or 0.01 weight percent. Such therapeutic agents may be any agent that has therapeutic or other value when administered to an animal, particularly a mammal, such as pharmaceuticals, nutraceuticals, and cosmetics (cosmeceuticals). It will be appreciated that although the invention has been described with particular reference to its value in the form of an aqueous dispersion, the invention is not limited thereto. Thus, hydrophobic drugs, nutritional agents or cosmetics that derive their therapeutic or other value from, for example, topical or transdermal administration, are still considered suitable for use in the present invention.

Specific non-limiting examples of hydrophobic therapeutic agents that may be used in the pharmaceutical compositions of the present invention include the following representative compounds, and their pharmaceutically acceptable salts, isomers, esters, ethers, and other derivatives: analgesics and anti-inflammatory agents such as aloprine, auranofin, azapropazone, benorilate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxybuprazone, phenylbutazone, piroxicam, refocoxib, sulindac, tetrahydrocannabinol, tramadol, and tromethamine (tromethamine); anthelmintics such as albendazole, benfenadine hydroxynaphthoate, canabendazole, diclofenac, ivermectin, mebendazole, oxanqquine, oxfendazole, metaphenylene pyrimidine, praziquantel, pyrantel hydroxynaphthoate and thiabendazole; antiarrhythmic drugs such as amiodarone hydrochloride, propiram, flecainide acetate, and quinidine sulfate; anti-asthmatics such as zileuton, zafirlukast, terbutaline sulfate, montelukast, and albuterol; antibacterial agents such as alatroxacin, azithromycin, baclofen, benzathine, cinoxacin, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, glapafloxacin, imipenem, levofloxacin, lomefloxacin, moxifloxacin hydrochloride, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampin, rifabutin, rifapentine, sparfloxacin, spiramycin, sulfonamides (sulphabenzamide), sulfadoxine, sulfamethazine (sulphamerazine), sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim, trovafloxacin and vancomycin; antiviral agents such as abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, and stavudine; anticoagulants such as cilostazol, clopidogrel, dicoumarin, dipyridamole, aceroloumarin, oproxil interleukin, phenindione, ticlopidine and tirofiban; antidepressants such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine hydrochloride, maprotiline hydrochloride, mianserin hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, sertraline hydrochloride, trazodone hydrochloride, trimipramine maleate, and venlafaxine hydrochloride; antidiabetics such as acetohexamide, chlorpropamide, glyburide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, and troglitazone; antiepileptics such as beclaramide, carbamazepine, clonazepam, ethotoxin, felbamate, fosphenytoin sodium, lamotrigine, mefenytoin, mesuccinamide, tolbital, oxcarbazepine, methadol, phenylacetamide, phenobarbital, phenytoin, phenosuximide, primidone, sultiacin, tiagabine hydrochloride, topiramate, valproic acid, and vigabatrin; antifungal agents, such as amphotericin, butenafine hydrochloride, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine hydrochloride, terconazole, tioconazole, and undecylenic acid; anti-gout agents such as allopurinol, probenecid, fensulone; antihypertensives such as amlodipine, benidipine, benazepril, candesartan, captopril, darodipine, diltiazem hydrochloride, diazoxide, doxazosin hydrochloride, enalapril (elanapril), eprosartan, losartan mesylate, felodipine, fenoldopam, fosinopril, guanabenz acetate, irbesartan, enalapril, lisinopril, minoxidil, nicardipine hydrochloride, nifedipine, nimodipine, nisoldipine, phenoxybenzamine hydrochloride, prazosin hydrochloride, quinapril, reserpine, terazosin hydrochloride, telmisartan and valsartan; antimalarial drugs such as amodiaquine, chloroquine, chlorpromazine hydrochloride, halofantrine hydrochloride, mefloquine hydrochloride, proguanil hydrochloride, pyrimethamine and quinine sulfate; anti-migraine agents such as dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, mexigote maleate, naratriptan hydrochloride, pizotifen malate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan; antimuscarinic agents such as atropine, diphenoxylate hydrochloride, biperiden, prophenamine hydrochloride, hyoscyamine, hydrobenzomine hydrochloride, and tropicamide; antineoplastic agents and immunosuppressive agents such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene, busulfan, camptothecin, cytarabine, chlorambucil, cyclosporine, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mycophenolate, nilutamide, paclitaxel, procarbazine hydrochloride, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan hydrochloride, and toremifene citrate; antiprotozoal agents such as atovaquone, benznidazole, clioquinol, decoquinate, diiodoquine, dichlornitryl furoate, dinitramide, furazolone, metronidazole, nimorazole, nitrofural, ornidazole and tinidazole; antithyroid agents such as carbimazole, byacacetil, and propylthiouracil; antitussives such as benzonatate; anxiolytics, sedatives, hypnotics and antipsychotics such as alprazolam, amobarbital, barbital, phenirazepam, bromodiazepam, bropirilidol, brotizolam, butobarbital, carbazone, chlordiazepoxide, chlormezole, chlorpromazine, chlorprothixene, clonazepam, clobazam, chlordiazepam, diazepam, droperidol, norethixene, fluazinone, flunitrazepam, trifluoropropazine, flupenthixol decanoate (flupenthixol decanoate), fluphenazine decanoate, fluazepam, gabapentin, haloperidol, lorazepam, chloromazepam, meddarazepam, milnacipran, meton, mexol, mequinazine, ritalin, midazolam, cininden, mirtazapine, oxazapine, oxypheniramate, pseudomepiquat, pramipeline, pramipexole, doxazone, pseudomepiquat, pramipeline, pramipexole, mepiquat, pramipeline, pramipexole, thioridazine, triazolam, zolpidem, and zopiclone; beta-blockers such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, and propranolol; inotropic agents of the heart such as amrinone, digitoxin, digoxin, enoximone, floridin C and digoxin; corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoximetasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone; diuretics such as acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, metolazone, spironolactone and triamterene. Anti-parkinsonian drugs such as bromocriptine mesylate, lisuride maleate, pramipexole, ropinirole hydrochloride, and tolcapone; gastrointestinal agents such as bisacodyl, cimetidine, cisapride, diphenoxylate hydrochloride, domperidone, famotidine, lansoprazole, loperamide, mesalamine, nizatidine, omeprazole, ondansetron hydrochloride, rabeprazole sodium, ranitidine hydrochloride, and sulfasalazine; histamine H and H-receptor antagonists such as acrivastine, astemizole, chlorpheniramine, cinnarizine, cetirizine, clemastine fumarate, cyclizine, cyproheptadine hydrochloride, dexchlorpheniramine, dimenhydrinate, fexofenadine, flunarizine hydrochloride, loratadine, meclizine hydrochloride, oxamide, and terfenadine; keratolytic agents such as avermectin A ester (acetretin), calcipotriol, calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, tretinoin, tazaretin (targretin), and tazarotene; lipid regulators such as atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol and simvastatin; muscle relaxants such as dantrolene sodium and tizanidine hydrochloride; nitrates and other anti-anginal drugs such as amyl nitrate, glycerol trinitrate, isosorbide mononitrate and pentaerythritol tetranitrate; nutritional agents such as calcitriol, carotene, dihydrotachysterol, essential fatty acids, non-essential fatty acids, dihydrovitamin K1, vitamin a, vitamin B2, vitamin D, vitamin E and vitamin K. Opioid analgesics such as codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine; sex hormones such as clomiphene, cortisone acetate, danazol, dehydroepiandrosterone, ethinyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, ethinylestradiol methyl ether, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, diethylstilbestrol, testosterone, and tibolone; stimulants such as amphetamine, dextroamphetamine, dexfenfluramine, fenfluramine and mazindol; and others such as becaplamine, polynaphthapine hydrochloride, L-thyroxine, methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene hydrochloride, sibutramine hydrochloride, sildenafil citrate, tacrine, tamsulosin hydrochloride, and tolterodine.

Preferred hydrophobic therapeutic agents include sildenafil citrate, amlodipine, tramadol, celecoxib, rofecoxib, oxaprozin, nabumetone, ibuprofen, terbinafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megestrol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudoephedrine, troglitazone, rosiglitazone, finasteride, vitamin a, vitamin D, vitamin E, and pharmaceutically acceptable salts, isomers and derivatives thereof. Particularly preferred hydrophobic therapeutic agents are progesterone and cyclosporine.

Suitable proton pump inhibitors for use in the present invention include, without limitation, omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole, and mixtures thereof.

It is to be understood that this list of hydrophobic therapeutic agents and therapeutic types thereof is merely illustrative. In fact, a particular feature and surprising advantage of the compositions of the present invention is the ability of the compositions of the present invention to solubilize and deliver a wide range of hydrophobic therapeutic agents, regardless of the type of function. Of course, mixtures of hydrophobic therapeutic agents may also be used when desired. These carrier attributes would also be equally effective as delivery vehicles for hydrophobic therapeutic agents yet to be developed.

In certain embodiments, suitable pharmaceutical agents for use in the compositions of the present invention include, without limitation, weak acid drugs, or mixtures and combinations thereof. Exemplary weak acid drugs include, without limitation, anti-inflammatory drugs, steroids, sterols, NSAIDs, COX-2 inhibitors, or mixtures thereof. Exemplary weak base drugs include, without limitation, weak base antibiotics, caffeine, codeine, ephedrine, chlordiazepoxide, morphine, pilocarpine, quinine, toluidine butylurea, other weak base agents, and mixtures or combinations thereof. Exemplary anti-inflammatory drugs include steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, acetaminophen, and COX-2 inhibitors, or mixtures and combinations thereof.

Suitable NSAIDS include, without limitation: (a) propionic acid drugs including fenoprofen calcium, flurbiprofen, suprofen, and benzeneLoxfen, ibuprofen, ketoprofen, naproxen and/or oxaprozin; (b) acetic acid drugs including diclofenac sodium, diclofenac potassium, aceclofenac, etodolac, indomethacin, ketorolac tromethamine and/or ketorolac; (c) ketone drugs including nabumetone, sulindac, and/or tolmetin sodium; (d) a fenamate drug comprising meclofenamate sodium and/or mefenamic acid; (e) the oxicams piroxicam, lornoxicam and meloxicam; (f) salicylic acid drugs including diflunisal, aspirin, magnesium salicylate, bismuth subsalicylate, and/or other salicylic acid agents; (g) pyrazoline drugs including oxyphenbutazone and/or phenylbutazone; and (h) mixtures or combinations thereof.

Suitable COX-2 inhibitors include, without limitation, celecoxib, rofecoxib, or mixtures and combinations thereof.

Acid labile drugs

Suitable acid-labile pharmaceutically active agents include, without limitation, peptides, proteins, nucleosides, nucleic acids, DNA, RNA, glycosaminoglycans, any other acid-labile drug, or mixtures or combinations thereof. Examples of acid-labile drugs that can be used in the carrier systems disclosed herein are, for example, (+) -N {3- [3- (4-fluorophenoxy) phenyl]-2-cyclopenten-1-yl } -N-hydroxyurea, amylase, chlortetracycline, bacitracin, β carotene, cephalosporins, chloramphenicol, cimetidine, cisapride, cladribine, chlorohexidineAcid salts, deramciclane, didanosine, didanoside, dihydrostreptomycin, erythromycin, etoposide, famotidine, hormones (in particular estrogens, insulin, epinephrine and heparin), lipasesMelameiline, neomycin, pancreatin, penicillin salts, polymyxin, pravastatin, prasugamide, protease, quinaprilQuinoline-2-carboxylic acid [4- (R) carbamoyl-1- (S-3-fluorobenzyl-2- (S), 7-dihydroxy-7-methyloctyl group]Amide, quinolineQuinoline-2-carboxylic acid [ 1-benzyl-4- (4, 4-difluoro-1-hydroxy-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-butyl]Amides, ranitidine, streptomycin, subtilin, sulphanilamide and acid labile proton pump inhibitors such as esomeprazole, lansoprazole, minoprazole (minoprazole), omeprazole, pantoprazole or rabeprazole. Digestive proteins such as amylases, lipases, and proteases may be included in the disclosed vector systems. Amylases, lipases and lipases suitable for use as digestive enzyme supplements or digestive enzyme substitutes in mammals, especially humans, are preferred. The amylase, lipase and/or protease may be of microbial or animal origin, in particular of mammalian origin. Pancreatin is an acid-labile drug. Other therapeutic proteins or peptides can be used with the disclosed carriers to increase bioavailability. Other therapeutic proteins may include, without limitation, insulin, erythropoietin, or fragments or derivatives thereof. Examples of glycosaminoglycans include, without limitation, heparin or fragments thereof. The above list of acid labile drugs is not intended to be exhaustive, but is merely illustrative, as one of ordinary skill in the art will appreciate that many other acid labile drugs or combinations of acid labile drugs may also be used.

Nutrient agent

Suitable nutrients for use in the compositions of the present invention include, without limitation, any nutritional agent that can be in conjunction with the carrier of the present invention. In certain embodiments, the nutritional agent is a solid. In other embodiments, the nutritional agent is an oil-soluble liquid or an oil-miscible liquid.

Biocompatible oil

Suitable biocompatible oils include, without limitation, any oils approved by the FDA or other governmental agency for human, mammalian or animal consumption. Exemplary biocompatible oils include, without limitation, oils of vegetable or animal origin or their derivatives or synthetic oils. In certain embodiments, the natural oil is a phospholipid-rich oil, such as lecithin oil from soy. Illustrative examples of oils of vegetable or animal origin or their derivatives or synthetic oils include, without limitation, essential oils, vegetable oils or hydrogenated vegetable oils such as peanut oil, canola oil, avocado oil, safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin a, vitamin D, vitamin E, and the like, animal oils, fish oils, krill oils, and the like, or mixtures thereof.

In certain embodiments, the biocompatible oil is a neutral lipid. Suitable neutral lipids include, without limitation, any neutral lipid such as a triglyceride. For a partial list of representative neutral lipids, such as triglycerides, specific reference is made to U.S. patent nos. 4,950,656 and 5,043,329. Saturated as well as unsaturated triglycerides may be employed in the compositions of the present invention and include triglycerides such as tripalmitin (saturated), triolein and trilinolein (unsaturated). However, these specific triglycerides are listed here for convenience only and are merely representative of various useful triglycerides and further are not intended to be inclusive.

Animal fats and oils include, but are not limited to, lard, duck fat, butter, or mixtures or combinations thereof.

Vegetable oils include, without limitation, coconut oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, sesame oil, canola oil/rapeseed oil, or mixtures and combinations thereof.

Other additives, excipients or adjuvants

The formulations or compositions of the present invention may also contain other chemicals such as antioxidants (e.g., vitamin A, C, D, E, etc.), trace metals and/or multivalent cations (aluminum, gold, copper, zinc, calcium, etc.), surfactants and/or solvents (e.g., propylene glycol/PPG, dimethyl sulfoxide/DMSO, medium chain triglycerides/MCT, etc.), non-toxic dyes and odorants may be added to the formulations as they are prepared for improved stability, flowability/spreadability, permeability, effectiveness, and consumer acceptance. These additives, excipients and/or adjuvants may also act as active agents.

Experiments of the invention

The carriers of the invention and compositions comprising the carriers of the invention possess the ability to target the release of an active agent to selected regions of the Gastrointestinal (GI) tract. Carrier-mediated targeted release is particularly useful for the following active ingredients: (a) is harmful to the upper GI tract (esophagus, stomach, and duodenum), (b) is acid labile, (c) is impermeable/insoluble compounds in GI fluids, (d) is sensitive to first pass metabolism, and (e) causes gastric irritation, discomfort, or dyspepsia. In certain embodiments, the targeted release is a pH-dependent release such that the active agent(s) are minimally released at the low pH of the stomach (e.g., a pH of less than about 3- < pH3) and effectively released at the higher pH of the upper duodenum (e.g., at a pH of greater than or equal to 4-5). In certain embodiments, the targeted release is a pH-dependent release such that the active agent(s) are minimally released at the low pH of the stomach (e.g., pH less than about 3- < pH3) and upper duodenum (e.g., at a pH greater than or equal to 4-5) and are effectively released at the higher pH of the small intestine in the presence of high concentrations of bile. In certain embodiments, the pH-dependent release of the active agent(s) is due to the inclusion of a pH-dependent release agent, such as an oil comprising at least one carboxylic acid group or at least one oil-soluble or oil-miscible compound comprising at least one carboxylic acid group, in the carrier. In other embodiments, the oil comprising at least one carboxylic acid group or the at least one oil-soluble or oil-miscible compound comprising at least one carboxylic acid group is a free fatty acid. Fatty acids are particularly useful for tailored release along the GI tract, as most fatty acids are in a non-ionized or neutral form at gastric pH, but ionized at intestinal pH, so that they can selectively release an active ingredient payload. The study outlined in this section provides evidence that the vector is useful for the following purposes: 1) pH-dependent release, 2) targeted dissolution along the GI tract, 3) targeted release capable of reducing GI toxicity of the active agent, 4) targeted release of multiple active agents, and 5) utilization of a pH-dependent release carrier for improving bioavailability of active agents such as acid-labile active substances, compounds insoluble in GI fluids, and compounds sensitive to first-pass metabolism.

pH-dependent release of active substances

Our previous studies have shown that purified Phosphatidylcholine (PC) (e.g., Phospholipon90G) and lecithin oil (e.g., phosphol 35SB (PS35SB)) increase aspirin partitioning (LogP) in a pH-dependent manner_{cyclohexane/0.1N HCl})). Partitioning (Log P) values were maximal at 0.1N HCl, with little or no change in partitioning at neutral pH. These data indicate the pH-dependent partitioning of aspirin (ASA) when the ASA is dispersed in a lecithin oil carrier (i.e., with the properties of lecithin NF). The reason for pH-dependent partitioning is believed to be that the carrier or specific carrier components are caused by interactions between the carrier and/or components thereof and the pharmaceutical agent (e.g., NSAID). Since lecithin is primarily a complex mixture of phospholipids, triglycerides and free fatty acids, it is unclear whether the free fatty acids inherent in lecithin or lecithin carriers impart pH sensitivity to aspirin distribution. Thus, the pH-dependent change in hydrophobicity provided by free fatty acids was tested by two methods: partitioning (Log P) and in vitro dissolution.

Preparation of ASA-FFA and FFA/PC Carrier compositions

In this study, ASA-FFA and FFA/PC carrier compositions were prepared with different weight ratios of aspirin to FFA. The composition was prepared by mixing powdered ASA into each carrier and heating the mixture to a temperature of 35 ℃ for about 30 minutes. The composition formulations are given in table I.

TABLE I

Composition of ASA-FFA and ASA-FFA/PC compositions

Phosphatidylcholine was added as purified phosphatidylcholine 90g (lipoid llc).

SFFA is soy free fatty acid (Peter Cremer Company).

Engineered lecithin oil (Lipoid LLC) containing about 45 wt.% phospholipids.

Free fatty acids increase aspirin (ASA) partitioning in a pH-dependent manner

The compositions of table I were tested in a two-phase dispensing system. In this system, the Log P value of aspirin (ASA) is measured in two immiscible solvents: cyclohexane and 0.1N HCl. Cyclohexane was used to mimic a completely hydrophobic surface such as the extracellular gastric mucosa. HCl (0.1N) was used to simulate gastric fluid. In U.S. patent nos. 4,950,656, 5,043,329, 5,763,422 and 5,955,451, triglycerides in combination with zwitterionic phospholipids are used to reduce toxicity, increase cyclohexane solubility of NSAIDs at pH above their pKa, and improve NSAID efficacy. U.S. patent nos. 5,763,422 and 5,955,451 specifically demonstrate that DPPC increases the solubility of ASA in cyclohexane at pH above their pKa, and the addition of triglycerides such as trioleate and tripalmitin increases this increased solubility. These prior art teachings show that phospholipids and mixtures of phospholipids and triglycerides increase the solubility of ASA in cyclohexane at a pH close to the pKa of ASA, similar to the operation of phase transfer agents. However, these patents do not include the teaching that free fatty acids can function as acceptable carriers for pharmaceutical agents such as ASA, or that they are carriers capable of pH-dependent release of ASA.

We show here that the Log P value of ASA-SFFA formulations can be tailored to have a Log P value comparable to a 1:1 weight ratio formulation of ASA and Phosal35SB (PS35SB), an engineered lecithin oil. We also show that (1) ASA carriers consisting of FFA alone have Log P values comparable to ASA-PS35SB formulations, (2) ASA carriers with low levels of phospholipids (e.g. ≦ 10 wt.%) have Log P values comparable to ASA-PS35SB formulations; and (3) the FFA-free ASA carrier has similar release characteristics as immediate release aspirin. Thus, the carrier may be tailored to release the active agent into different pH environments and/or the release level may be adjusted within a specified region of the GI tract based on: (1) the ratio of FFA and second complexing agent or other carrier component (e.g., fig. 3 and 14) and/or (2) the ratio of carrier to active agent (e.g., fig. 1). We believe that Log P values predict increased NSAID GI safety or decreased NSAID GI toxicity as shown in the animal studies described herein (e.g., fig. 12 and 13).

Referring now to fig. 1, soy pure ffa (sffa) alone increases the partitioning of aspirin into the water-immiscible phase in a concentration-dependent manner; thus, the ratio of active agent to carrier modulates the dispensing characteristics of the composition. Compositions comprising 1:1 weight ratio of aspirin and 100% FFA carrier have Log P values similar to 1:1 weight ratio of aspirin and high phospholipid lecithin oil carrier PS35SB (e.g., -45% phospholipid), indicating that 100% FFA carrier can contribute to increased lipid solubility of aspirin, similar to high phospholipid lecithin carrier. We also show that FFA in the carrier interact with aspirin at the molecular level, as shown by FTIR data herein. This interaction may be in the form of a non-covalent association complex between aspirin and FFA. We also demonstrate below that 100% FFA or an oil-based carrier comprising sufficient FFA is capable of pH-dependent release of a pharmaceutical agent such as an NSAID. This data and other data sets presented herein show that carriers with sufficient pH-dependent release agents such as FFA are capable of releasing NSAIDs in a pH-specific manner (i.e., the composition has minimal release at low pH and effective release at higher pH), should be generalizable to pharmaceutical and/or nutritional agents that are neutral, weak acids and potentially weak bases in their solid form.

Referring now to fig. 2, the FFA-induced increased partitioning of aspirin into water-immiscible solvents such as cyclohexane is pH-dependent. The increased partitioning of aspirin across artificial hydrophobic membranes by FFAs suggests that FFAs alone can alter the physicochemical and/or release behavior of aspirin. This observation further indicates that a binary ratio of aspirin and FFA can improve the gastrointestinal safety of aspirin in a similar manner to that seen in high phospholipid lecithin oil carriers such as PS35 SB. While not intending to be bound by any particular theory, the interaction of FFA and ASA may involve an interaction between the carboxylic acid group of aspirin and the carboxylic acid group of FAA. Carriers with high concentrations of FFA and no or low concentrations of phospholipids appear to have similar properties to the high phospholipid lecithin oil carriers. These carriers contained about 46 wt.% phospholipids and were derived from crude soy lecithin. They are engineered lecithin oils in which the original triglycerides have been removed and replaced with a mixture of sunflower oil and about 11 wt% oleic and linoleic acids. Two such lecithin oil products are Phosal35SB (PS35SB) and Epikuron (135F). This FFA-aspirin behavior supports compositions that contain no phospholipids or contain significantly low levels of phospholipids, at levels of 0 to less than 10 wt% phospholipids and no triglycerides or generally low levels of triglycerides, at levels of 0 to less than 10 wt% neutral lipids. Alternatively, we believe that FFA can act as a pH-dependent release agent, the reason for this being primarily the nature of FFA. At low pH, FFAs are uncharged and act essentially as biocompatible oils. However, as pH increases, FFA ionizes to form FFA salts, which are known surfactants. Surfactants are known to increase the release of pharmaceutical agents such as NSAIDs from oil-based carriers because we utilize a surfactant-rich buffer system to effect the solubilization of NSAIDs in a pilot commercial NSAID-PS35SB formulation.

In U.S. patent application 12/883873, increased NSAID GI safety is mediated by an oil-based carrier comprising greater than 10 wt.% phospholipid; in fact, the compositions used in the examples contained about 46 wt.% phospholipid, which is close to the phospholipid content of PS35SB (a high phospholipid lecithin oil carrier). Furthermore, the use of carriers comprising any amount of phospholipid in a customized manner to increase the bioavailability and toxicity of the NSAID is not contemplated. When FFA-ASA compositions have similar Log P values compared to PS35SB-ASA compositions, we determined that FFA can be used as a key ingredient for pH controlled release of active agents to develop novel carriers for pharmaceutical and/or nutritional agents such as NSAIDs. In the data below, we demonstrate that the FFA-containing carriers are effective to release the pharmaceutical and/or nutritional agents at a pH greater than about pH3, while the FFA-free oil-based carriers are effective to release the active agents at a pH less than about 3.

We also determined that FFA carriers can be altered by adding low levels of phospholipids to achieve similar Log P values when aspirin is an NSAID. The fact that these FFA carriers have similar Log P values for ASA is unexpected in view of the teachings of the prior art, where phospholipid content is believed to be a key component in reducing the GI toxicity of NSAIDs. As shown in fig. 3, the high FFA carrier is an effective carrier for PC and provides similar aspirin partition values compared to PS35SB carrier containing about 45 wt.% PC with 5 wt.% to 10 wt.% phospholipid (here PC) content; and thus, the carrier is customizable by the ratio of FFA to second complexing agent in the carrier. These data indicate that the level of phospholipids required to mediate GI safety can be significantly reduced from about 45 wt.% phospholipids to ≦ 10 wt.%. The data also indicate that FFA carriers can be effective NSAID carriers in the absence of any phospholipid. FFA carriers with low phospholipid content also have additional stability and cost-effectiveness over existing phospholipid carriers, which have been shown to undergo considerable phospholipid degradation-loss of the ester side chains.

The fact that the vehicle containing low levels of phospholipids or no phospholipids behaves in a similar manner to the vehicle containing about 45 wt.% phospholipids, Phosal35SB (PS35SB) is entirely unexpected. Even more surprising is that the partitioning of ASA in pure FFA carrier shows a clear pH dependence similar to PS35 SB. We believe we now have an alternative carrier for use with pharmaceuticals and/or nutraceuticals, avoiding the problems of relatively expensive, hydrolysable and heat-labile phospholipids.

We illustrate some of the properties of the carriers of the present invention by reference to an aspirin (ASA) carrier composition, wherein the carrier comprises neutral lipids, free fatty acids, and phospholipids. One type of high phospholipid carrier is the triple strength lecithin product sold as Phosal35 SB. Until now, NSAID complexing agents in phospholipid-containing carriers have been considered to be phospholipids, with phosphatidylcholine being present in the greatest concentration. However, we believe that the free fatty acid may comprise a second component that may form a reversible complex with ASA. We also believe that the neutral lipids may also form a third component that can form a reversible complex with ASA. In addition to providing components for the non-covalent complexation of ASA, other carrier components may also play a role in the activity of ASA complexes comprising ASA-PC complexes and in the dispersion of the composition in water. The present study was directed to a dissolution procedure for a triple strength lecithin-ASA composition to evaluate pH dependent release to simulate API release across the GI tract.

The pH-dependent increase in hydrophobicity leads to pH-dependent dissolution

In this analysis, ASA release from triple strength lecithin oil PS35SB carrier-ASA composition (PS35SB-ASA) was compared to immediate release aspirin. PS35SB-ASA was filled into hard shell capsules and immediate release aspirin tablets were tested. Dissolution rates were measured in the United States Pharmacopeia (USP) Type II appatatus using various media formulations.

In this analysis, the release of ASA from PS35SB-ASA was compared to a conventional aspirin tablet. PS35SB-ASA compositions filled into hard shell capsules and plain aspirin tablets were tested. The release of aspirin from both dosage forms was evaluated according to USP <711> using a type II dissolution apparatus at 37 ℃ in vessels containing 900mL of the various citrate phosphate buffers at 3.5, 4.5, 5.5, 6.9, 7.4 at a paddle speed of 150 rpm.

The release rate was monitored by sampling the dissolution vessel at 5, 10, 15, 30, 45, 60, 75 and 90 minutes, as well as an infinite sample. The fraction of aspirin released and dissolved from both dosage forms was monitored by HPLC.

The HPLC method used to measure the release of acetylsalicylic acid and salicylic acid was at 1.2 mL/min, with an isocratic elution of 60/40/0.2 water/acetonitrile/phosphoric acid mobile phase. The column used was ODS3 "Inertsil", 5 μm, 250X 4.6mm from ESSciences. The standard was prepared by dissolving and diluting aspirin manufactured by Rhodia into the mobile phase.

Referring to fig. 4, the dissolution profile of the immediate release ASA tablets is shown at different pH values, while fig. 5 shows the dissolution profile of the PS35SB-ASA composition at different pH values.

For all pH levels, the immediate release aspirin tablets immediately begin to disintegrate when subjected to dissolution and completely dissolve within the first 5 minutes.

In contrast, PS35SB-ASA filled capsules showed that shell disintegration began after approximately 10 minutes. Upon capsule rupture, the fill material is released, dispersed, and dissolved out in a pH-dependent manner, as shown in fig. 5.

Aspirin released from the PS35SB-ASA composition (see fig. 5) clearly showed an increase with increasing pH, indicating that aspirin release from the lecithin oil matrix was pH dependent. While not intending to be bound by any theory, it is believed that the increased release rate at higher pH is caused by ionization of the carboxylic acid group of aspirin. Thus, the release of aspirin from the PS35SB carrier or matrix increased with pH, as demonstrated above in fig. 5. However, it has been clear that the pH-dependent nature of PS35SB may be due solely to the presence of sufficient fatty acids in the PS35SB carrier, since for the ASA shown in fig. 6, the carrier comprising only triglycerides and phospholipids shows a reduction in pH-dependent behavior to no pH-dependent behavior.

To determine whether the free fatty acids in lecithin oil PS35SB mediated pH dependent release, the release of aspirin from 4 formulations containing 325mg aspirin in tablet or capsule form was measured in simulated gastric fluid (0.1HCl) according to USP <711> as outlined in table II.

TABLE II

Capsule filling formulations

Phosal35SB, an engineered lecithin oil, shown in gray with component breakdown based on 49 wt.% Phosal35 SB.

Purified soy phosphatidylcholine (S100, Lipoid LLC)

Triglycerides derived from soybean oil.

FFA used in the name of the company of the independent patent is oleic acid (Croda)

Other ingredients present in Phosal35SB

Formulations a-C were prepared by mixing ASA into the carrier with mixing at 40 ℃ as described herein. Lecithin oil contains about 40 wt.% phosphatidylcholine, 40 wt.% triglycerides, 13 wt.% free fatty acids. As shown in fig. 6, release of aspirin from the lecithin oil was minimal. Since release from TG/PC only vectors is rapid and greatly reduced by the addition of FFA; thus, the pH sensitive release provided by lecithin oil as described in figure 5 is primarily due to the presence of FFA.

Targeted release of aspirin along the GI tract

As previously shown, the pH sensitive hydrophobicity results in pH sensitive release and dissolution. Due to the great difference in physiological environment between the stomach, upper duodenum and intestine, the dissolution in vitro of the three vectors described in table III, the dissolution profile of the formulation comprising oleic acid vector, oleic acid/2.5 wt.% PC vector and PS35SB vector was evaluated in simulated gastric, duodenal and intestinal fluids to assess targeted release. The formulations were prepared by adding the ingredients listed in table III and stirring the mixture at 35 ℃ for 30 minutes, except that the ASA formulation was a tablet and the other formulations were filled into hypromellose capsules.

TABLE III

Ingredients used in the formulations

Preparation	Components	Weight (g)	wt.％
				ASA	Aspirin	19.6000	100
P1	Oleic acid	19.6113	49.00
					S100*	0.0000	0.00
	Aspirin	19.6142	49.00

Silicon dioxide	0.8002	2.00
			P2	Oleic acid	18.7541	46.51
S100*	1.0072	2.50
				Aspirin	19.7604	49.00
Silicon dioxide	0.8046	2.00
			AC2	PS35SB**	25.7060	49.00
Aspirin	25.7077	49.00
				Silicon dioxide	1.0494	2.00

Purified soybean phosphatidylcholine (Lipoid LLC)

An engineered lecithin oil carrier

Referring now to fig. 7, the dissolution profiles of ASA, P1, P2 and AC2 were tested in a USP type II apparatus at 37 ℃ at a paddle speed of 150rpm in simulated gastric fluid consisting of 0.1N HCl having a pH of 1.

Referring now to FIG. 8, the dissolution profile at 150rpm in "simulated upper duodenal fluid" pH 4.5.

Referring now to fig. 9, the dissolution profile at 150rpm in "simulated intestinal fluid" pH7 dissolution buffer (bicarbonate buffer containing 20mM bile acid and 1% pancreatin). This medium is a fed variant (fed variant) of USP intestinal fluid (pH7.2 phosphate buffer, 1% pancreatin).

Referring now to fig. 10A & B, a parallel comparison of the average dissolution profiles of 0 wt.% PC and 2.5 wt.% PC formulations in different media: 0.1N HCl, dissolution buffer (bicarbonate buffer containing bile acids and enzymes), acetate buffer, and phosphate buffer.

The above dissolution data provide compelling support for the use of fatty acid-based carriers (i.e., carriers containing sufficient fatty acid in an amount sufficient to enable pH-dependent release of the carrier) as carriers for the following active agents: active agents with GI toxicity such as NSAIDs, active agents that degrade in low pH environments such as in gastric fluid, active agents that are better absorbed in the upper part of the small intestine, and/or active agents that are targeted for release after passage through the stomach but do not require release at the high pH found in the lower GI tract are known.

Referring now to fig. 11, a picture of the upper GI tract-stomach-small intestine (duodenum, jejunum, and ileum) is provided to show significant differences in physicochemical properties of various segments of the GI tract. Differences in pH and bile acid concentration and composition, digestive enzymes can be exploited to achieve targeted release of active substances using various lipid carriers. The ASA formulations of the present invention containing FFA clearly show pH dependent ASA release according to pH changes in various parts from stomach to small intestine. Thus, the carrier comprises an amount of FFA sufficient to reduce or minimize ASA release in the stomach or at low pH, while increasing or maximizing ASA release in the small intestine as pH increases along the distal portion of the small intestine. The carrier of the present invention comprising an amount of FFA is thus well suited for a tailored release of active agents such as drugs and/or nutrients in the duodenum and to reduce or minimize the release of said active agents in the stomach. As will be shown herein, the pH profile of the carriers of the present invention comprising such sufficient amounts of FFA can be generalized to NSAIDs and should be generalized to all solid active agents dispersed in these carriers based on the fact that the solid material is dispersed in the carrier.

Targeted release of aspirin along the GI tract may reduce gastric damage

Since FFA alone, FFA in combination with low PC, lecithin provided selective release and dissolution of aspirin in simulated intestinal fluid and release of aspirin in the stomach was known to induce erosive damage, the ability of selective carrier-mediated release to stomach and intestinal damage was evaluated in rats. Rats were administered by oral gavage a microcapsule containing 40mg/kg of aspirin in the vehicle formulation in table VIII, along with a methylcellulose negative control and powdered immediate release aspirin.

Experimental controls used in this study included: (1) a control composition (NAC) comprising methylcellulose from Sigma Chemical Company (product number M-0512, lot number 74F-0466, stored at controlled ambient temperature); (2)325mg OTC aspirin from Walgreen Co (AC1), product number P53405, and (3) 325mg aspirin in Phosal35SB vector (AC 2).

Two compositions of the invention, P1 and P2, and AC2 were prepared. AC2, P1, and P2 had the ingredient formulations shown in table IV and were stored at controlled ambient temperatures and protected from light during the study.

TABLE IV

Ingredient formula

Formulations P1, P2 and AC2 were prepared by the following method: 1) the lipid components were mixed and incubated at 40 ℃ for 1 hour, and occasionally mixed to ensure that the lipid carrier was homogeneous; 2) mixing aspirin into a lipid carrier; 3) adding a viscosity modifier to the lipid carrier/aspirin mixture; 4) the formulations were mixed until homogeneous and incubated at 40 ℃ for 60 minutes; and 5) the formulations are stored at ambient conditions and thoroughly mixed prior to use.

In this study 40 male Sprague-Dawley rats of about 10 weeks of age were used. Animals were randomly assigned to 5 treatment groups of 8 rats each.

TABLE V

Animals randomized to each treatment group

The test articles were packaged into microcapsules such that one microcapsule would provide a40 mg/kg/day gastric aspirin dose per animal. For the preparation of OTC aspirin, the tablets were pulverized using a mortar and pestle and filled into microcapsules. For P1, P2, and AC2, the appropriate amount of filler material (based on the aspirin content of the filler) was added to the microcapsules. The dosing formulations for the 3 day treatment were prepared based on the following assumptions: each animal gained an average of 3.0g of body weight over the 3 day test period. For example, a 1 st balance average body weight +3.0g rat is assembled with a microcapsule containing an initial dose of aspirin.

Animals were fasted (ad libitum drinking) 8am to 3pm prior to dosing; a cage of bottom wire is required to prevent the animal from eating any bedding or manure particles. The dose of aspirin was administered by oral gavage between 2pm and 3pm and P1, P2 and AC2 for 3 consecutive days (study days 1, 2 and 3) to maximize the potential effect of 40mg NSAID/kg body weight/day of study drug in the stomach.

Maintaining the animals in a fasted state for 1 hour after administration; food was then ad libitum until the next morning.

After 3 days of treatment, rats were sacrificed and the following tissues were collected for analysis: stomach, small intestine (jejunum and ileum). The extent of erosive damage in the stomach is assessed by microscopy and the extent of gastric or intestinal bleeding is assessed by measuring intraluminal liquid hemoglobin.

Gastric examination was performed under a dissecting microscope to look for evidence of erosion and ulceration and injury associated with drug administration. Specifically, after washing with distilled water for Hb determination, the stomach was opened by incision along a small bend, rinsed with physiological saline, and blotted dry with #2 filter paper. Gastric lesions that could not be removed by flushing the luminal surface of the dissected stomach with saline, as observed under a dissecting microscope, were counted and measured. Stomach lesions scored by animal were recorded.

Two types of gastric lesions were observed: linear and small dots (needle tip): (1) the needle point lesions (longest dimension of 0.1-1.0mm) were each assigned 1mm²A score of (1); and (2) measuring the length and width of a linear lesion (length greater than 1 mm). Assigning lesions equal to mm²Lesion area of meter [ Length (mm) × Width (mm)]The score of (c).

The gastric lesion score of the animal was determined as the sum of the scores for the needle tip and the linear lesion, an estimate of the total area of the gastric lesion. The gastric lesion score of the treated group was determined as the average of the gastric lesion scores of the animals of the group.

The hemoglobin (Hb) concentration in the sonicated solutions of stomach and small intestine washes and fecal pellets was determined by benzidine method and measuring the Optical Density (OD) at 515 nm.

Targeted release of aspirin to reduce gastric damage

Gastric lesions were measured and scored as described below-defined as needle points or larger (linear) lesions on the gastric mucosa observable under a dissecting microscope. The gastric lesion scores for each treatment group are given in figure 12. The gastric lesion scores (fig. 12) were lower in all groups treated with P1, P2, and AC2 than those treated with AC 1.

A significant difference between gastric lesion scores was observed between groups [ F (4, 35) ═ 10.42, p < 0.0001, Tukey's HSD ]. Gastric lesions scored significantly higher in animals treated with AC1(15.5 + -3.7) than in the group treated with P1(3.6 + -1.2; P < 0.01), P2(5.3 + -1.5; P < 0.01), AC2(1.8 + -0.7; P < 0.01), or control (0; P < 0.01). Gastric lesions in control NAC were scored to be no different from groups treated with P1, P2, and AC 2. No significant differences were observed in gastric lesion scores between groups treated with P1, P2, and AC 2.

This reduction in erosive damage to the stomach by P1, P2 and AC2 was not accompanied by any significant bleeding such as significant changes in intracavitary hemoglobin levels, with the exception that P1 treated rats had significantly lower Hb concentrations than AC1, as shown in fig. 13. These data indicate that targeted release of aspirin to the intestine via lecithin oil alone, a free fatty acid, or free fatty acid with small amounts of phospholipid, results in reduced gastric damage.

P1, P2, and AC2 have been shown to provide pH dependence and thus selective release of aspirin in intestinal fluid with minimal release of aspirin in gastric fluid (fig. 7-9). All three formulations provided similar improvement in erosive damage to the stomach, and these data suggest that FFA-containing carriers provide targeted release along the GI tract and that such targeted release may minimize GI damage. This observation is particularly surprising, since FFA alone has a tendency to induce damage to the upper GI tract.

Use of carriers to increase bioavailability and other applications of poorly permeable bioactive agents

Aspirin is poorly soluble at gastric pH, but is a highly permeable pharmaceutically active agent. In contrast, in the intestine, aspirin is highly soluble, but poorly permeable across epithelial cells. For poorly permeable compounds, aspirin was used as a model compound, and the relative solubility and partitioning of aspirin across intestinal epithelial cells was assessed using the octanol/0.1N HCl system.

In this study, the partitioning behavior of carrier compositions with different ratios of oleic acid, a Free Fatty Acid (FFA) to purified Triglyceride (TG), in an octanol/0.1N HCl partitioning system was studied. The carrier was mixed with aspirin (ASA) to form a 1:1 weight ratio of ASA to carrier composition. The mixing preparation procedure is substantially similar to the mixing method given above. The vector comprises: (1)100 wt.% FFA, referred to as ASAFFA, (2)80 wt.% FFA and 20 wt.% TG, referred to as ASA80 FAA: 20TG, (3)60 wt.% FFA and 40 wt.% TG, referred to as ASA60 FAA: 40TG, (4)40 wt.% FFA and 60 wt.% TG, referred to as ASA40 FAA: 60TG, (5)20 wt.% FFA and 80 wt.% TG, referred to as ASA20 FAA: 80TG, and (6)100 wt.% TG, referred to as ASA TG. The formulations were prepared using two different types of triglycerides: is derived from soybean oil and has C₁₆-C₂₀Long Chain Triglycerides (LCT) with side chains and having C₆-C₁₂Side chain Medium Chain Triglycerides (MCT) such as MIGLYOL812 (registered trademark of Sasol north america).

Referring now to fig. 14, the dispensing data clearly shows that varying the ratio of FFA to carrier component (e.g., FG) adjusts the dispensing across the simulated gastrointestinal membrane. In addition, the chemical nature or selection of the other components of the carrier further controls partitioning. For example, chain length of glycerides (e.g., TG) is also an important factor in regulating partitioning. These findings suggest two important potential applications of FFA-containing vectors: 1) increase the bioavailability of poorly permeable compounds across the gastrointestinal membrane, and 2) enable the targeting of the absorption of the active substance through the lymphatic circulation and avoid first-pass losses. Due to Log P in the presence of FFA_{Octanol (I)}Increased, and known higher Log P_{Octanol (I)}In connection with the increased bioavailability of poorly permeable active substances, carriers comprising free fatty acids may be used to increase the bioavailability of poorly permeable compounds.

Since the chain length of TG is a known factor for lymphatic partitioning of active agents, the long chain (C)₁₆Or above) FFA and Long chain (C)₁₆Or above) the use of TG in combination enables targeted release along the GI tract in combination with improved lymphatic partitioning. With increased lymphatic absorption of the active substance, the extent of first-pass loss can be reduced by reducing the fraction of orally administered bioactive agent that is absorbed into the mesenteric circulation and thus reducing first-pass metabolism in the liver.

FTIR study of various ASA formulations

Referring now to fig. 15, FTIR spectra of pure aspirin (ASA), a 1:1 weight ratio formulation of ASA and PS35SB, a 1:1 weight ratio formulation of ASA and linoleic acid, and ASA and trioleate at a 1:1 weight ratio are shown in a collective plot so that the interaction behavior between ASA and different carriers can be compared. First, it is clear that ASA interacts with all three carriers. In other words, the three carriers resulted in shifts and spectral feature changes in the ASA ester and carboxylic acid peaks, with the largest shift seen for the acid peak, with all carriers shifting the acid absorption peak to higher reciprocal centimeter values. We believe that these interactions between ASA and carrier components may have some effect on carrier properties such as partitioning properties, dissolution properties, pH dependent release properties and/or other properties. Due to the altered mediating carrier properties of the ionizable free carboxylic acid group of aspirin, it may be possible to generalize carrier-mediated-targeted release to all weak acids. Thus, the pH-dependent change in hydrophobicity was evaluated for several structurally distinct weak acid NSAIDs.

Popularization of vector-targeted release to all weakly acidic bioactive agents

Salicylic acid

Solvation/evaporation vs. mixing Studies

In this set of experiments, we found that the method of preparing the composition is not critical to the behavior of the resulting composition. The prior art shows that the preparation method will result in a significant change in the behavior of the carrier. These examples show that for carriers comprising sufficient FFA to render the carrier pH-dependent, the compositions can be prepared by simply mixing the ingredients together in the absence of a solvent or solvent system or by dissolving the components in a solvent or solvent system followed by removal of the solvent. Of course, all of these processes are carried out without the addition of water, i.e., the ingredients and solvents are generally free of water or contain only minimal or residual amounts of water. In other words, the process used to prepare the compositions of the present invention is not aqueous, even though some solvents may be water miscible such as ethanol. Thus, the composition formed by mixing or solvent dissolution followed by removal of the solvent is an oil-based composition containing only minimal water or residual water concentrations, and is typically an oil dispersion of the active agent in an oil-based carrier.

SA formulation A

This example illustrates the preparation of a composition comprising Salicylic Acid (SA) in a 1:1 weight ratio and a carrier comprising about 40 wt.% purified Phosphatidylcholine (PC) and pure Triglyceride (TG), referred to as SA formulation a, by mixing.

SA formulation a was prepared by mixing 50 wt.% SA into a vehicle comprising 30 wt.% triglycerides derived from soybean oil and 20 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

SA formulation B

This example illustrates the preparation of a composition comprising Salicylic Acid (SA) and a carrier comprising lecithin oil Phosal35SB (PS35SB) in a 1:1 weight ratio (referred to as SA formulation B).

SA formulation B was prepared by mixing 50 wt.% SA into a vehicle comprising PS35SB at a temperature of about 40 ℃ for about 30 minutes as described above.

SA formulation C

This example illustrates the preparation of a mixture comprising Salicylic Acid (SA) in a 1:1 weight ratio and purified phospholipid LIOID comprising 42 wt.% of the mixturePreparation of a composition of S100 (registered trademark of Lipoid LLC), 28 wt.% of purified Triglyceride (TG) (Spectrum chemical Manufacturing Corporation) and 30 wt.% of a carrier of oleic acid (Spectrum chemical Manufacturing Corporation) (referred to as SA formulation C).

SA formulation C was prepared by mixing 50 wt.% SA into a vehicle comprising 14 wt.% triglyceride derived from soybean oil, 15 wt.% oleic acid, and 21 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

SA formulation D

This example illustrates the preparation of a composition comprising Salicylic Acid (SA) and a carrier comprising 5 wt.% purified phospholipid, 46.5 wt.% purified Triglyceride (TG), and 48.5 wt.% oleic acid in a 1:1 weight ratio (referred to as SA formulation D).

SA formulation D was prepared by mixing 50 wt.% SA into a vehicle comprising 23.25 wt.% triglycerides derived from soybean oil, 24.25 wt.% oleic acid, and 2.5 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

Table VI lists the SA formulation compositions in weight percent.

TABLE VI

Formulation composition for Salicylic Acid (SA) study

Phosal35SB an engineered lecithin oil, shown in gray, with component breakdown based on 50 wt.% Phosal35 SB.

Purified phosphatidylcholine

Triglycerides derived from soybean oil.

Other ingredients present in Phosal35SB

Assignment study of SA vs SA formulations A-D

In this study, the pure Salicylic Acid (SA) partitioning between cyclohexane and water was studied at pH1 and pH7 simulating gastric and duodenal fluids versus salicylic acid partitioning between cyclohexane and water in SA formulations a-D. The study was conducted by adding SA, either of SA formulations a-D to the cyclohexane/water partition system and measuring the differential partition of SA between the two phases as the value Log P.

Referring now to fig. 16, it is clear that the partitioning of SA is different at pH1 versus pH7. Log P for SA at pH1 was-1.11 and Log P at pH7 was 0.00. The partitioning of SA between cyclohexane and water in SA formulations a-D produced Log P values at pH1 that were not more negative than the Log P values of SA at pH 1. The partitioning of SA between cyclohexane and water in SA formulations a-D produced Log P values at pH7 that were much more negative than the Log P values of SA at pH7.

Dissolution study of SA vs SA formulations A-C in a two-stage dissolution System

In this study, the dissolution of pure Salicylic Acid (SA) was studied relative to the dissolution of salicylic acid in SA formulations a-C using a two-stage dissolution procedure. The procedure involved measuring SA dissolution in pH1 dissolution media containing 0.1N HCl to simulate gastric fluid and mechanical stirring at 75rpm stirring speed. After 60 minutes, the pH of the medium was adjusted from pH1 to pH7.2 by adding phosphate buffer to a final concentration of 0.05M while maintaining the same stirring speed. Dissolution is expressed as% LC, which is the percentage of SA dissolved into the medium. The measurements were performed at 10 minutes, 20 minutes, 30 minutes, 50 minutes, 60 minutes, 70 minutes, 90 minutes, 110 minutes, 120 minutes, 150 minutes, and 180 minutes.

Naproxen

Preparation of NAP formulations A-D

NAP formulation A

This example illustrates the preparation of a composition comprising Naproxen (NAP) in a 1:1 weight ratio and a carrier comprising about 40 wt.% purified Phosphatidylcholine (PC) and pure Triglyceride (TG), referred to as NAP formulation a.

NAP formulation A50 wt.% NAP was mixed to contain 30 wt.% of a triglyceride derived from soybean oil (Spectrum Chemical Manufacturing Corporation) and 20 wt.% of a triglyceride derived from LIPIOID at a temperature of about 40 ℃ as described aboveS100(Lipoid LLC, registered trademark) in approximately 30 minutes.

NAP formulation B

This example illustrates mixing a mixture comprising Naproxen (NAP) and PHOSAL in a 1:1 weight ratioPreparation of a composition of 35SB (PS35SB) (registered trademark of Lipoid LLC) carrier (referred to as NAP formulation B).

NAP formulation B was prepared by mixing 50 wt.% NAP into a vehicle containing 50 wt.% PS35SB at a temperature of about 40 ℃ for about 30 minutes, as described above.

NAP formulation C

This example illustrates the preparation by mixing a composition comprising Naproxen (NAP) in a 1:1 weight ratio and a carrier comprising 42 wt.% purified phospholipid (Lipoid LLC), 28 wt.% purified Triglyceride (TG) (Spectrum Chemical Manufacturing Corporation), and 30 wt.% oleic acid (Spectrum Chemical Manufacturing Corporation) (referred to as NAP formulation C).

NAP formulation C was prepared by mixing 50 wt.% NAP into a vehicle containing 14 wt.% triglyceride derived from soybean oil (Spectrum Chemical Manufacturing Corporation), 15 wt.% oleic acid (Spectrum Chemical Manufacturing Corporation), and 21 wt.% purified phosphatidylcholine (LipoidLLC) at a temperature of about 40 ℃ for about 30 minutes as described above.

NAP formulation D

This example illustrates the preparation by mixing a composition comprising Naproxen (NAP) in a 1:1 weight ratio and a carrier comprising 5 wt.% purified phospholipid (Lipoid LLC), 46.5 wt.% purified Triglyceride (TG) (Spectrum Chemical Manufacturing Corporation), and 48.5 wt.% oleic acid (Spectrum Chemical Manufacturing Corporation) (referred to as NAP formulation D).

NAP formulation D was prepared by mixing 50 wt.% Naproxen (NAP) into a vehicle containing 23.25 wt.% triglycerides derived from soybean oil, 24.25 wt.% oleic acid, and 2.5 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

NAP assignment study relative to NAP formulations A-D

In this study, the pure Naproxen (NAP) partitioning between cyclohexane and water was studied at pH1 and pH7, which simulate gastric and duodenal fluids, relative to the NAP partitioning between cyclohexane and water in NAP formulations a-D. The study was conducted by adding NAP, either of NAP formulations a-D to the cyclohexane/water partitioning system and measuring the differential partitioning of NAP between the two phases as the value Log P.

Referring now to fig. 17, it is clear that the partitioning of NAP is different at pH1 versus pH7. The LogP of NAP was 0.65 at pH1 and-2.06 at pH7. The partitioning of NAP between cyclohexane and water at pH1, measured by Log P, is higher for NAP formulations A-D than the Log P value of NAP at pH 1. The partitioning of NAP between cyclohexane and water at pH7 by Log P in NAP formulations A-D was also higher than the Log P value of NAP at pH7. Thus, although NAP showed significant pH-dependent release, NAP formulations a-D also showed pH-dependent release behavior.

Indometacin

Preparation of INDO formulations A-D

INDO formulation A

This example illustrates the preparation of a composition comprising indomethacin (indoo) and a carrier comprising about 40 wt.% purified Phosphatidylcholine (PC) and pure Triglyceride (TG), in a 1:1 weight ratio, referred to as indoo formulation a, by mixing.

The indoo formulation a was prepared by mixing 50 wt.% indoo into a vehicle containing 30 wt.% triglyceride derived from soybean oil (lot No. 1AI0411) from Spectrum OL103 and 20 wt.% purified phosphatidylcholine (cat No. 790569-10/0) from LipoidS100 at a temperature of about 40 ℃ for about 30 minutes as described above.

INDO formulation B

This example illustrates the preparation of a composition comprising indomethacin (indoo) and a carrier comprising lecithin oil Phosal35SB (PS35SB) in a 1:1 weight ratio (referred to as indoo formulation B) by mixing.

The indoo formulation B was prepared by mixing 50 wt.% INDO into a vehicle containing 50 wt.% PS35SB at a temperature of about 40 ℃ for about 30 minutes as described above.

INDO formulation C

This example illustrates the preparation of a composition comprising indomethacin (indoo) and a carrier comprising 42 wt.% purified phospholipid, 28 wt.% purified Triglyceride (TG) from Spectrum OL103 (lot 1AI0411) and 30 wt.% oleic acid in a 1:1 weight ratio (referred to as indoo formulation C).

The indoo formulation C was prepared by mixing 50 wt.% indoo into a vehicle comprising 14 wt.% triglyceride derived from soybean oil, 15 wt.% oleic acid, and 21 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

INDO formulation D

This example illustrates the preparation of a composition comprising indomethacin (indoo) and a carrier comprising 5 wt.% purified phospholipid, 46.5 wt.% purified Triglyceride (TG) and 48.5 wt.% oleic acid in a 1:1 weight ratio (referred to as indoo formulation D).

The indoo formulation D was prepared by mixing 50 wt.% indoo into a vehicle comprising 23.25 wt.% triglyceride derived from soybean oil, 24.25 wt.% oleic acid, and 2.5 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

INDO partitioning study relative to INDO formulations A-D

In this study, the partitioning of pure indomethacin (indoo) between cyclohexane and water was studied at pH1 and pH7 simulating gastric and duodenal fluids versus the partitioning of indoo between cyclohexane and water in indoo formulations a-D. The study was conducted by adding either of the INDO, INDO formulations a-D to the cyclohexane/water distribution system and measuring the differential partitioning of the INDO between the two phases as the value Log P.

Referring now to fig. 18, it is clear that the partitioning of INDO is different at pH1 versus pH7. Log P of INDO was 1.05 at pH1 and Log P was-1.81 at pH7. The partitioning of indoo between cyclohexane and water at pH1, measured by Log P, in indoo formulations a-D was higher than the Log P value of NAP at pH 1. The partitioning of indoo between cyclohexane and water at pH7 in indoo formulations a-D, measured by Log P, was also higher than the Log P value of indoo at pH7. Thus, although indoo showed significant pH-dependent release, indoo formulations a-D also showed pH-dependent release behavior.

Mefenamic acid

Preparation of MFA formulations A-D

MFA formulation A

This example illustrates the preparation of a composition comprising mefenamic acid (MFA) in a 1:1 weight ratio and a carrier comprising about 40 wt.% of purified Phosphatidylcholine (PC) and pure Triglycerides (TG), referred to as MFA formulation a.

MFA formulation a was prepared by mixing 50 wt.% MFA into a vehicle containing 30 wt.% of soybean oil-derived triglycerides from Spectrum OL103 (lot No. 1AI0411) and 20 wt.% of purified phosphatidylcholine from Lipoid S100 (cat No. 790569-10/0) at a temperature of about 40 ℃ for about 30 minutes as described above.

MFA formulation B

This example illustrates the preparation of a composition comprising mefenamic acid (MFA) and a carrier comprising lecithin oil Phosal35SB (PS35SB) in a 1:1 weight ratio, referred to as MFA formulation B.

MFA formulation B was prepared by mixing 50 wt.% MFA into a vehicle comprising 50 wt.% PS35SB at a temperature of about 40 ℃ for about 30 minutes as described above.

MFA formulation C

This example illustrates the preparation of a composition comprising mefenamic acid (MFA) and a carrier comprising 42 wt.% purified phospholipid, 28 wt.% purified Triglyceride (TG) and 30 wt.% oleic acid in a 1:1 weight ratio, referred to as MFA formulation C.

MFA formulation C was prepared by mixing 50 wt.% MFA into a vehicle containing 14 wt.% of soybean oil-derived triglyceride from Spectrum OL103 (lot No. 1AI0411), 15 wt.% oleic acid, and 21 wt.% purified phosphatidylcholine for about 30 minutes at a temperature of about 40 ℃ as described above.

MFA formulation D

This example illustrates the preparation of a composition comprising mefenamic acid (MFA) and a carrier comprising 5 wt.% purified phospholipid, 46.5 wt.% purified Triglyceride (TG), and 48.5 wt.% oleic acid in a 1:1 weight ratio (referred to as MFA formulation D).

MFA formulation D was prepared by mixing 50 wt.% MFA into a vehicle comprising 23.25 wt.% triglycerides derived from soybean oil, 24.25 wt.% oleic acid, and 5 wt.% purified phosphatidylcholine at a temperature of about 40 ℃ for about 30 minutes as described above.

Assignment study of MFA to MFA formulations A-D

In this study, the partitioning of pure mefenamic acid (MFA) between cyclohexane and water was studied at pH1 and pH7 simulating gastric and duodenal fluids versus the partitioning of MFA between cyclohexane and water in MFA formulations a-D. The study was conducted by adding MFA, either of MFA formulations a-D, to a cyclohexane/water partitioning system and measuring the differential partitioning of MFA between the two phases as the value Log P.

Referring now to fig. 19, it is clear that the partitioning of MFA is different at pH1 versus pH7. The Log P of MFA was 0.00 at pH1 and 0.47 at pH7. The partitioning of MFA between cyclohexane and water in MFA formulations a-D at pH1, as measured by Log P, was significantly higher positive compared to the Log P value of MFA at pH1, indicating little difference between oil-based carriers. The partitioning of MFA between cyclohexane and water in MFA formulations a-D at pH7, as measured by Log P, showed only slightly higher values than the Log P value of MFA at pH7, with the exception of MFA formulation a, which showed slightly lower values than the Log P value of MFA at pH7. Thus, while MFA showed significant pH-dependent release, MFA formulations a-D also showed pH-dependent release behavior.

Summary of weak acid partitioning data

From the data given above for aspirin, salicylic acid, naproxen, indomethacin, and mefenamic acid, it is clear that carriers containing sufficient free fatty acid release these weak acids in a pH-dependent manner so that weakly acidic bioactive agents can be targeted to higher pH values when they leave the low pH environment of the stomach. This targeted release of the active agent from the lipid matrix appears to be due to the ionized state of the free fatty acids in the carrier relative to pH and other physiological environments of the selected regions of the GI tract. Thus, targeted release of any biologically active agent should be possible and particularly useful for the following active ingredients: a) injurious to the upper GI tract (stomach and duodenum), b) acid labile, c) compounds that are insoluble/impermeable in GI fluids, and d) sensitive to first pass metabolism.

Ending of a transaction

All references mentioned herein are incorporated by reference. Although the present invention has been disclosed with reference to preferred embodiments thereof, it will be understood by those skilled in the art from a reading of the present specification that numerous changes and modifications may be made without departing from the scope and spirit of the invention as set forth above and in the claims.

Claims

1. A pharmaceutical composition formulated for oral administration comprising a solid biologically active agent suspended in a non-aqueous liquid carrier, wherein the pharmaceutical composition is a solid-in-oil suspension, wherein the non-aqueous liquid carrier:

(a) comprises at least 5 wt.% of free fatty acids having at least 8 carbons;

(b) comprises ≤ 10 wt.% zwitterionic phospholipid; and

(c) the amount of bioactive agent released at pH <3 is less than the amount released at pH > 3.

2. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for targeted release of a biologically active agent to the small intestine.

3. Use of a pharmaceutical composition according to claim 1 in the manufacture of a medicament for increasing the bioavailability of an orally administered biologically active agent.

4. The pharmaceutical composition of claim 1, or the use of claim 2 or 3, wherein the biologically active agent is an acid labile drug.

5. The pharmaceutical composition of any one of claims 1 or 4, or the use of claim 2 or 3, wherein the biologically active agent is:

(a) an acid labile drug selected from the group consisting of: antidepressants, antidiabetics, antiepileptics, antifungals, antimalarials, antimuscarinics, antineoplastics, immunosuppressants, antiprotozoal agents, antitussives, antipsychotics, beta-blockers, cardiac inotropic agents, anti-Parkinsonism agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid modulators, muscle relaxants, antianginals, nutritional agents, opioid analgesics, and stimulants;

(b) an acid labile drug selected from the group consisting of: hormones, proteins, peptides, nucleotides and proton pump inhibitors;

(c) an acid labile drug selected from the group consisting of: nucleosides, sex hormones, and therapeutic proteins;

(d) an acid labile drug selected from the group consisting of: digesting the protein;

(e) an acid labile drug selected from the group consisting of: heparin, insulin, erythropoietin, pancreatin, lansoprazole, omeprazole, pantoprazole, rabeprazole, benzathine, polymyxin, sulfanilamide, and erythromycin;

(f) an acid labile drug selected from the group consisting of: cortex consolidationAlcohol, histamine, nitrate, DNA, RNA, glycosaminoglycan, (+) -N {3- [3- (4-fluorophenoxy) phenyl]-2-cyclopenten-1-yl } -N-hydroxyurea, chlortetracycline, bacitracin, β carotene, cephalosporins, chloramphenicol, cimetidine, cisapride, cladribine, clorineAcid salts, deramciclane, didanosine, digitoxin, dihydrostreptomycin, erythromycin, etoposide, famotidine, estrogen, epinephrine, heparin, melamemine, novobiocin, penicillin salts, polymyxin, pravastatin, protease, quinaprilQuinoline-2-carboxylic acid [4- (R) carbamoyl-1- (S-3-fluorobenzyl-2- (S), 7-dihydroxy-7-methyloctyl group]Amide, quinolineQuinoline-2-carboxylic acid [ 1-benzyl-4- (4, 4-difluoro-1-hydroxy-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-butyl]-amide, ranitidine, streptomycin, sulfanilamide, esomeprazole, lansoprazole, minoprazole, omeprazole, pantoprazole, rabeprazole, amylase, lipase, pancreatin, insulin and erythropoietin;

(g) an acid labile drug selected from the group consisting of: subtilin, insulin fragments and erythropoietin fragments;

(h) an acid labile drug selected from the group consisting of: ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin, diclofenac, mefenamic acid, or any mixture thereof; or

(i) An acid labile drug selected from the group consisting of: aspirin, naproxen, indomethacin, mefenamic acid, and COX2 inhibitor.

6. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the solid bioactive agent is a weak acid NSAID.

7. The pharmaceutical composition or use of claim 6, wherein the composition comprises less gastrointestinal toxicity than the NSAID alone.

8. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, having a weight ratio of carrier to biologically active agent of from 1:10 to 10: 1.

9. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein:

(a) less than 20% of the bioactive agent is released from the carrier at a pH < 3; and

(b) greater than 50% of the bioactive agent is released from the carrier at a pH > 3.

10. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the pharmaceutical composition comprises less than 1 wt% water.

11. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the free fatty acid comprises a mixture of oleic acid and linoleic acid.

12. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the carrier further comprises a neutral lipid.

13. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the carrier further comprises at least one ingredient selected from the group consisting of: adjuvants, antioxidants, viscosity modifiers, preservatives, suspending agents, drying agents, agents to enhance permeability and any mixtures thereof.

14. The pharmaceutical composition of claim 1 or 4, or the use of claim 2 or 3, wherein the carrier comprises >0 wt.% to ≦ 10 wt.% zwitterionic phospholipid.