HK1111105B - Coated drug delivery formulations - Google Patents

Description

Coated drug delivery formulations

RELATED APPLICATIONS

This application is a continuation-in-part application of co-pending U.S. application No.10/132,665, filed on day 24, 4/2002, 10/132,665, which is a continuation-in-part application of U.S. application No.09/931,399, filed on day 16, 8/2001, now U.S. patent No.6,759,058, which U.S. application No.09/931,399 claims priority to U.S. provisional application No.60/286,386, filed on day 25, 4/2001, the entire teachings of which are incorporated herein by reference.

Background

Technical Field

The present invention relates generally to delivery systems for formulations containing biologically active agents. In one embodiment, the invention relates to coated proliposomal (proliposomal) formulations for poorly water-soluble drugs.

Description of the related Art

The pharmaceutical formulations can be administered by various routes of administration. For example, administration can be oral, intravenous, subcutaneous, and by aerosol. Encapsulating drugs in liposomes is used to reduce toxicity and improve the therapeutic effect of certain drugs. For example, oral effects of compounds such as insulin, factor VIII, tryptophan, phenylalanine, heparin, vitamin K, etc. after encapsulation in liposomes have been studied. Although they represent an improvement over the prior art, oral liposomal formulations have been criticized for their instability, leakage and possible destruction in gastric fluids.

The use of proliposomes represents an alternative to conventional liposomal formulations. Proliposomes are dry, free-flowing granular products that disperse upon addition of water to form a multilamellar liposome suspension. By using proliposomes, the stability problems associated with conventional liposomes, including aggregation, susceptibility to hydrolysis and oxidation, can be avoided. The use of proliposomes is well known in the pharmaceutical art.

Of the various routes of administration, the oral route is advantageous for certain drugs in certain circumstances due to its versatility, safety, and patient comfort. Although oral ingestion of drugs represents a safe and versatile method of drug delivery, the efficacy of many drugs can be reduced because they are unstable or inactive under the acidic conditions of the stomach. Enteric coating materials are used to compensate for this deficiency. Non-enteric coatings also offer several advantages for oral and non-oral routes of administration. Thus, in some embodiments, the present invention provides novel formulations coated with an enteric or non-enteric coating, and methods of making these formulations.

Disclosure of Invention

Although the use of proliposomes and the use of enteric and non-enteric coatings are each known in the art, the combination of a coating and a proliposomal formulation has not been disclosed. When the coating of some embodiments of the invention is combined with the proliposomal formulation of some embodiments of the invention, drug delivery is unexpectedly enhanced. In many embodiments of the present invention, this novel and unexpected enhancement resulting from the unique combination of coating and proliposomal formulations relates to increased drug absorption, stability and bioavailability.

In many embodiments of the present invention, the combination of a coating and a proliposomal formulation overcomes the disadvantages of drug delivery systems known in the prior art. For example, the need to use toxic amounts of delivery agents, the instability of the system, the inability to protect the active ingredient, the inability to effectively deliver poorly or unstable water-soluble drugs, the inadequate shelf life of the system, the inability of the drug delivery system to facilitate absorption of the active agent, and the difficulties inherent in manufacturing the system have limited the use of prior systems for oral administration of unstable materials. Several embodiments of the present invention overcome one or more of these disadvantages.

In some embodiments, the formulation comprising the bioactive agent is produced by using one or more enteric coatings. In other embodiments, the formulation comprising the biologically active agent is produced by using one or more non-enteric coatings.

The term "enteric coating" as used herein shall be given its ordinary meaning and shall also include substances that retain the activity of acid-labile drugs in the stomach after oral ingestion such that the active ingredient is released and absorbed in the intestine. Enteric coating materials are known in the pharmaceutical art and include alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and the like. Enteric coatings may be used for oral administration routes. Enteric coatings may be used for non-oral routes of administration. For example, enteric coatings may be used for transdermal applications as well as other non-oral routes.

The term "acid labile" as used herein shall be given its ordinary meaning and shall also include drugs, compositions or substances that degrade in an acidic environment, dissolve in an acidic environment, are unstable in an acidic environment, and/or are inactive in an acidic environment.

The term "non-enteric coating" as used herein shall be given its ordinary meaning and as such includes acid-labile materials and/or materials that degrade in the stomach or other acidic environment. Non-enteric coatings are used for oral and non-oral routes of administration.

Several embodiments of the present invention are particularly advantageous because they provide a simple and inexpensive system to facilitate the administration of drugs and other agents. In many embodiments, the drug delivery system according to some embodiments of the present invention enhances the stability and bioavailability of the bioactive agent.

In one embodiment of the invention, a method of making a formulation suitable for patient administration is provided. In one embodiment, the method comprises providing one or more phospholipids, providing one or more bioactive agents, simultaneously exposing at least a portion of the bioactive agents and at least a portion of the phospholipids to a non-aqueous solvent, removing the non-aqueous solvent, thereby producing a powder. The powder comprises one or more phospholipids and one or more active agents. In some embodiments, the method further comprises coating the powder with one or more coatings, thereby producing coated particles. The coating is contacted with at least a portion of the powder. The coating may be acid labile, enteric or non-enteric, or a combination of two or more thereof.

In one embodiment, the acid-labile coating is a material selected from the group consisting of one or more of: cellulose-based agents, povidone, and polyethylene. In one embodiment, the cellulose-based reagent is selected from the group consisting of one or more of: methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose.

In another embodiment, the coated particles are formulated into a dosage form suitable for administration to a patient. In one embodiment, the coated particles are formed into suspensions, tablets and/or capsules.

In several embodiments, the coating (e.g., enteric or non-enteric coating, such as an acid-labile coating) is adapted for administration by various routes selected from the group consisting of one or more of: oral, buccal, sublingual, nasal, topical, transdermal, ocular, vaginal, rectal, intravesical, pulmonary, intraarterial, intravenous, intradermal, intramuscular, subcutaneous, intraperitoneal, intrathecal and intraocular.

In one embodiment, the bioactive agent is selected from the group consisting of one or more of: testosterone, famotidine, halofantrine, and glyburide. One skilled in the art will appreciate that several agents may be used in accordance with embodiments of the present invention. In one embodiment of the invention, the biologically active agent is a pharmaceutically active agent. In one embodiment, the bioactive agent is a poorly water soluble drug.

In another embodiment, the biologically active agent is a sustained release agent. In some embodiments, a modified coating may be applied to assist the sustained release effect according to methods known in the art. Thus, in some embodiments, the coating can control the release of the bioactive agent in a time-based manner.

In some embodiments, one or more phospholipids are used. In one embodiment, the phospholipid is a phosphatidyl phospholipid. The phospholipids include, but are not limited to, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, egg yolk PC, soy PC, DMPG, DMPA, DPPG, DPPA, DSPG, DSPA, phosphatidylserine, and sphingomyelin (sphingomyelin).

In one embodiment of the invention, the coating substance is an enteric coating. In another embodiment, the coating is a non-enteric coating. In one embodiment, a coating is used. In another embodiment, more than one coating is used. In some embodiments, several different coatings are used, but all are either enteric or non-enteric coatings. In some embodiments, the coated formulation is prepared by applying enteric and non-enteric coatings. Thus, in one embodiment, the advantages of both types of coatings may be obtained because enteric coatings and non-enteric (e.g., acid-labile coatings) are applied to powders comprising the bioactive agent. The same type of coating or different types of coatings may be used to maximize certain desired results, such as sustained release, increased absorption, decreased gastrointestinal effects, increased bioavailability, and the like.

In one embodiment, enteric coatings include, but are not limited to, cellulose acetate phthalate, alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate, methacrylate-methacrylic acid copolymers, polyvinyl acetate phthalate, styrene maleic acid copolymers, shellac, and cellulose acetate.

In another embodiment, non-enteric coatings include, but are not limited to, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, povidone, and polyethylene.

In one embodiment, the coating comprises a plasticizer. One advantage of a plasticizer is that it increases the flexibility of the coating. Further, in some embodiments, the plasticizer reduces the likelihood of coating rupture and pore formation.

In another embodiment, the coating is a film plasticizer selected from the group consisting of phthalates, citrates and triacetin.

In another embodiment of the invention, the formulation is formed into tablets, capsules and/or suspensions. Suspensions include non-solid, gelatinous forms and liquids. In alternative embodiments, carriers, diluents and/or lubricants are also included in the formulations.

In one embodiment, removing the non-aqueous solvent comprises at least partially evaporating the solvent.

In one embodiment, the powder is coated with one or more acid labile coatings. In some embodiments, coating comprises spraying the powder with a coating. In several embodiments, the powder is coated with one or more acid-labile coatings without exposing the bioactive agent to an aqueous solvent. The term "powder" as used herein shall be given its ordinary meaning and shall also include fine particles (e.g., granules), residues and concentrates.

In other embodiments, at least one additional component is combined with the bioactive agent. The additional ingredients may be active or inactive. Additional ingredients include, but are not limited to, carriers, diluents, and lubricants. Additional ingredients also include, but are not limited to, microcrystalline cellulose, starch, lactose, talc, mannitol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, ethyl cellulose, fatty acids, fatty acid salts, glyceryl behenate, glucose, and dicalcium phosphate.

In one embodiment, one or more surfactants are used. In one embodiment, a surfactant is added along with the drug and phospholipid. Surfactants include, but are not limited to, polysorbates, bile salts, and alkyl glycosides. In one embodiment, the surfactant is used at a concentration of about 1% to about 50%, preferably about 5% to about 20%. Thus, in one embodiment, the invention includes a method of making a formulation suitable for administration to a patient, comprising: (i) providing at least one phospholipid, at least one surfactant and at least one bioactive agent, (ii) exposing the surfactant, bioactive agent and phospholipid to a non-aqueous solvent, (iii) evaporating the non-aqueous solvent, thereby producing a powder, and (iv) coating the powder with one or more coatings without exposing the bioactive agent to an aqueous solvent, thereby producing a coated particle, wherein the one or more coatings contact at least a portion of the powder. In one embodiment, the method further comprises forming the coated particles into a dosage form suitable for administration to a patient. In one embodiment, greater than about thirty parts aqueous solvent is required for dissolution of each part solute of the biologically active agent. In another embodiment, the bioactive agent is water insoluble or poorly water soluble.

In one embodiment of the invention, a method of making a composition for delivering a chemical agent is provided. In one embodiment, the method comprises providing one or more phospholipids and providing one or more chemical agents. In one embodiment, the chemical agent is unstable in the aqueous phase. The chemical agent and phospholipid are then exposed to or bound to a non-aqueous solvent. The non-aqueous solvent is removed (e.g., by evaporation), thereby producing a powder. It will be appreciated by those skilled in the art that the solvent may be removed by other means, such as evacuation. The powder is then coated or covered with one or more coatings, thereby producing coated particles. The coating contacts at least a portion of the powder. The chemical agent is not exposed to the aqueous phase prior to application of the coating. The coated particles are then synthesized or formed into a form suitable for delivery of the chemical agent. Chemical agents include compounds such as nucleic acids, enzymes, food processing agents, and the like. The coating includes an acid labile coating, an enteric coating, a non-enteric coating, or a combination thereof.

Other embodiments of the invention relate to compositions and formulations prepared according to the above-described methods. In some embodiments, a proliposomal formulation is provided comprising a lipophilic agent, a phospholipid, and a coating. In one embodiment, a method of delivering a pharmaceutical formulation to a mammal by administering the formulation to the mammal is provided. In some embodiments, the present invention relates to the prevention, diagnosis or treatment of disease in a mammal using the drug delivery system of the present invention.

In one embodiment, the invention includes the use of a formulation obtained by a method according to any of the embodiments described herein in the manufacture of a medicament for increasing testosterone levels in a mammal.

In one embodiment, the invention includes a formulation obtained by the method of any of the embodiments described herein.

In one embodiment, the invention includes a formulation comprising testosterone obtainable by a method according to any one of the embodiments described herein.

Brief Description of Drawings

Figure 1 shows a comparison of the dissolution rates of testosterone and pure testosterone using various proliposomal formulations.

Figure 2 shows a comparison of the dissolution rates of famotidine and pure famotidine using proliposomal formulations (DSPC).

Detailed description of the preferred embodiments

Several embodiments of the present invention relate to coated proliposomal formulations comprising a biologically active (e.g., pharmaceutically active) agent, a phospholipid and a coating material.

In some embodiments of the present invention, the substrate is,enteric coatings are used. In other embodiments, an acid labile coating is used. In one embodiment, the coated formulation improves the solubility and bioavailability of the drug. The effect is more pronounced on drugs with very low water solubility, such as halofantrine and testosterone. The dissolution rates observed for higher water-soluble drugs, such as famotidine, are less pronounced. In one embodiment, the invention consists of a drug delivery system that provides faster onset of drug action, longer duration of action and increased C compared to administration alone_max. In some embodiments, enteric-coated proliposomal formulations (e.g., EnProLipf) are provided^TM)。

In a preferred embodiment, the formulation comprises:

(a) poorly water-soluble drugs;

(b) distearoylphosphatidylcholine (DSPC), Dipalmitoylphosphatidylcholine (DPPC) or Dimyristoylphosphatidylcholine (DMPC); and

(c) cellulose acetate phthalate.

In one embodiment, the biologically active agent is a pharmaceutically active agent. In one embodiment, the pharmaceutically active agent is a poorly water soluble drug. A poorly water soluble drug as used herein should be given its ordinary meaning and should include agents that require greater than about thirty (30) parts solvent per part solute dissolved.

Examples of poorly water-soluble drugs include, but are not limited to, griseofulvin, famotidine, meclizine, cyclosporine, carbamazepine, methotrexate, itraconazole, dipyridamole, mercaptopurine, halofantrine, amiodarone, lomustine, testosterone, misoprostil (misoprostil), etoposide, rifamycin, azathioprine, glyburide, tolbutamide, aminoglutethimide, paclitaxel, clofibrate, nifedipine, methyldopa, ramipril, dicumarol, and the like. It will be appreciated by those skilled in the art that the present invention is not limited to poorly water soluble drugs, but encompasses a wide range of pharmaceutically active and inactive agents. Various embodiments of the present invention may be used to deliver drugs that are sparingly soluble, poorly soluble, or hydrophilic. In one embodiment, the pharmaceutical formulation (and method of making the same) comprises testosterone (natural or synthetic), a testosterone precursor, a testosterone derivative, an agent that increases testosterone, a testosterone modulator, or a combination of two or more of these compounds. Thus, in one embodiment, the invention comprises a formulation or method for the manufacture of a medicament for treating or preventing testosterone deficiency in a mammal. In another embodiment, the invention comprises a formulation or method for preparing a medicament for increasing normal levels of testosterone in a mammal.

In a preferred embodiment, DSPC, DPPC or DMPC is used as phospholipid. One skilled in the art will appreciate that other phospholipids may be used, including but not limited to egg PC, soy PC, DMPG, DMPA, DPPG, DPPA, DSPG, DSPA, phosphatidylserine, and sphingomyelin.

In a preferred embodiment, cellulose acetate phthalate is used as the enteric coating. However, those skilled in the art will appreciate that alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate, methacrylate-methacrylic acid copolymers, polyvinyl acetate phthalate, styrene maleic acid copolymers, shellac, cellulose acetate, and the like may also be used. It will also be appreciated by those skilled in the art that enteric coatings used in various embodiments of the invention may include combinations of the above coatings.

In one embodiment of the invention, the coating substance is a non-enteric coating. In one embodiment, the non-enteric coating comprises an acid labile material. In some embodiments, the non-enteric coating comprises a cellulose-based material. Non-enteric coatings include, but are not limited to, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, povidone, and polyethylene. It will also be appreciated by those skilled in the art that non-enteric coated materials useful in various embodiments of the invention may include a combination of enteric and non-enteric coatings as described above.

In one embodiment, the coating comprises a plasticizer. One advantage of a plasticizer is that it increases the flexibility of the coating. In addition, the plasticizer reduces the likelihood of coating cracking and pore formation. Plasticizers include, but are not limited to, phthalates, citrates, and triacetin.

In one embodiment of the invention, the enteric coated proliposome delivery system will be used for antiemetic purposes by preventing the release of harmful ingredients in the stomach, thereby reducing vomiting and other side effects.

In another embodiment of the invention, the enteric coated proliposomal formulation is used to deliver a drug that is susceptible to degradation in the intestinal tract.

In another embodiment, the invention is used for administration by various routes. Several embodiments are also useful for increasing the delivery of drugs or other substances in the food industry, where immobilization of enzymes is essential to various aspects of food processing. Accordingly, in some embodiments, methods of making delivery formulations for delivering one or more chemical agents are provided.

In other embodiments, methods of treating a mammal comprising administering to the mammal a bioactive agent, a phospholipid and a coating material are provided.

One skilled in the art will appreciate that embodiments of the present invention are not limited to the delivery of drugs or biological/pharmaceutical agents. Many naturally occurring or synthetic substances, including diagnostic agents and therapeutic substance delivery, may be delivered according to the present invention. These substances include, but are not limited to, anorectics, analgesics, antiarthritics, adrenomimetic blockers, steroids, vaccines, peptides, proteins, hormones, antibodies, antibiotics, antivirals, vitamins, nucleotides, nutrients, enzymes, genes, genetic material, cytotoxins, bacteria, microorganisms, viral agents, and the like. A placebo may also be administered using various embodiments of the invention. Carriers, diluents, lubricants and the like may also be administered using several embodiments of the present invention, including but not limited to microcrystalline cellulose, starch, lactose, talc, mannitol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, ethylcellulose, fatty acids, fatty acid salts, glyceryl behenate, glucose and dicalcium phosphate.

In addition, one skilled in the art will appreciate that the amount of active drug or substance used in some embodiments of the invention will be based on the dosage required for administration and/or required for treatment. It will be understood by those skilled in the art that "treatment" refers to any desired purpose of administering a pharmaceutically active ingredient, including preventing, controlling, treating, maintaining or improving health, and the like. By varying the concentration of the components, the size, number and/or amount of the tablets, capsules, suspensions or liquids, a wide range of doses can be administered orally. Similarly, varying the concentration of the biologically active agent can vary the dosage administered by non-oral routes. The coating may also be adjusted to affect the pharmacokinetics of the biological agent. Sustained release drugs may also be administered according to various embodiments of the present invention. The coating may also affect the sustained release properties of the formulation.

It should also be understood by those skilled in the art that the present invention is not limited to delivery of a single drug formulation. In fact, more than one pharmaceutical agent may be delivered simultaneously using the drug delivery system of the present invention. For example, in a "dose," the recipient may receive a combination of one or more drugs, at least one drug and a carrier, and the like.

In one embodiment of the invention, the drug delivery system is synthesized in the following manner: at least one pharmaceutically active agent and at least one phospholipid are dissolved in a solvent in suitable proportions and concentrations. After dissolution, the solvent was evaporated to give a dry, powdery substance. The dried material was passed through a sieve-like apparatus. The dried material is then coated with a coating (enteric, non-enteric, or both), preferably in solution, which can be sprayed onto the dried material. The coated particles are then used to synthesize a tablet, capsule or liquid formulation suitable for delivery to a mammal. Alternatively, the coated particles are prepared in a manner suitable for non-oral administration (e.g., a patch for transdermal delivery or a spray for inhalation).

Several embodiments of the present invention are particularly advantageous because they enable the application of an enteric coating after the pharmaceutically active agent and phospholipid are mixed. This enables the preparation of different dosage forms, including tablets, capsules, suspensions or liquids. In addition, various embodiments of the present invention can facilitate the preparation of tablets of various sizes. In one embodiment, the size of the tablet is preferably controlled by adjusting the pore size of the mesh or sieve.

In one embodiment, one or more surfactants are used. In one embodiment, a surfactant is added along with the drug and phospholipid. In other embodiments, the surfactant is added prior to making the powder, prior to coating the powder, or prior to forming the particles or microparticles into a dosage form. The surfactant used herein should be given its ordinary meaning and should also include substances that lower the surface tension of liquids. In some embodiments, the surfactant is an organic compound comprising hydrophobic and hydrophilic groups, and thus in some embodiments, the surfactant is semi-soluble in organic and aqueous solvents. In one embodiment, the surfactant is an amphoteric compound, so it tends not to be in either phase (aqueous or organic). Thus, in some embodiments, the surfactant is located at the phase boundary of the organic and aqueous phases. In some embodiments, the surfactants may also aggregate together and form micelles.

Surfactants include, but are not limited to, polysorbates, bile salts, and alkyl glycosides. Surfactants also include soaps, sulfonates, sulfates, fatty acid isethionates, fatty acid sarcosinates, fatty acid sulfamates (taurides), N-acyl amino acids, fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, protein hydrolysates, polyol fatty acid esters, sugar esters, sorbitan esters, amine oxides, quaternary ammonium compounds, alkyl betaines, alkyl amino betaines, amino-propionates, amino glycoglycerols, fatty acid amidosulfates, fatty acid amidosulfonates, N-acyl amino acids, fatty alcohol polyglycol ethers, alkyl phenol polyglycol ethers, fatty acid polyglycol esters, fatty acid esters, sorbitan esters, amine oxides, quaternary ammonium compounds, alkyl betainesAmino acid ester (salt), imidazolineBetaines and thiobetaines. In some embodiments, surfactants are used at concentrations of about 1% to about 50%, preferably about 5% to about 20%.

Some embodiments of the present invention that use one or more surfactants have certain advantages. For example, the surfactant may (1) form mixed micelles, which upon dilution may produce liposomes; (2) the protein molecules in the preparation are kept intact; (3) improved encapsulation of hydrophilic molecules; and (4) the helper liposomes become deformable, thus allowing them to deliver drugs through the absorption barrier.

I have previously described a process for preparing a medicament in the form of a tablet or capsule with an enteric coating. However, a particular advantage of various embodiments of the present invention is the ability to produce formulations in suspension or liquid form. Suspension or liquid forms are sometimes preferred because they do not affect gastric and intestinal motility to the same extent as capsules or tablets. It is important for most drugs that the pharmaceutically active compounds are not removed in the gastrointestinal tract before they have the opportunity to exert a local effect or to enter the blood stream. When the formulation is in suspension or liquid form, it is generally retained in the intestine for a longer period of time and thus absorption is increased compared to capsules or tablets. Aspects of the invention also provide flexibility in formulation surface area. While tablets are generally limited to a fixed surface, several embodiments of the present invention allow the use of capsules, suspensions, and liquids, which can provide greater surface area and thus facilitate increased absorption and bioavailability.

I previously described a method of delivering a drug in which the drug was exposed to an aqueous phase. According to several embodiments of the invention, the lipid and drug are exposed to chloroform or similar solvents. There was no exposure to the aqueous phase. For water sensitive drugs and drugs that are unstable in water, such as antibodies, the absence of an initial aqueous phase preserves the integrity of these drugs. Furthermore, no liposomes were formed as there was no exposure to the aqueous phase. Accordingly, several embodiments of the present invention are directed to non-liposomal pharmaceutical formulations. As used herein, "non-liposomal" is defined as a formulation that is not exposed to the aqueous phase and, therefore, does not form liposomes prior to application of the enteric coating.

Without wishing to be limited by the following description, it is believed that one embodiment of the present invention operates as follows: after the proliposomal formulation is formed, the formulation is delivered orally to the mammal. When the proliposomal formulation encounters an aqueous phase at a pH equal to or greater than about 7.0, liposomes are formed and the drug molecules are transported through the gastrointestinal membrane.

Particular route of administration

According to one aspect of the invention, the formulation is administered by a variety of routes including, but not limited to, oral, buccal, sublingual, nasal, topical, transdermal, ocular, vaginal, rectal, intravesical, pulmonary, intraarterial, intravenous, intradermal, intramuscular, subcutaneous, intraperitoneal, intrathecal and intraocular.

With respect to the transdermal route, several embodiments of the present invention are particularly advantageous because drug iontophoresis transdermal delivery is hindered if the drug molecule is not charged at a pH suitable for such delivery. However, enteric coated proliposomal formulations according to various embodiments of the present invention can be successfully used for transdermal delivery. Enteric coatings protect the drug at acidic pH. Non-enteric coatings may also be used. The charge on the liposomes facilitates delivery of the drug by iontophoretic transdermal delivery. Certain embodiments of the present invention are particularly useful for water insoluble drugs or poorly water soluble drugs. Typically, in order to deliver a drug by iontophoresis, the drug must first be dissolved. Therefore, it is difficult to administer a water-insoluble drug or a poorly water-soluble drug by this method. However, according to several embodiments of the present invention, water-insoluble drugs or poorly water-soluble drugs may be introduced into liposomes for delivery through this route. To facilitate the preparation of a drug for transdermal delivery, the formulation may be suspended in an aqueous phase to facilitate absorption through the skin. In one embodiment, the pH of the solution is preferably neutral to facilitate dissolution of the coating.

In one embodiment of the present invention, a method of nasal administration is provided. If local rather than systemic action of the drug is desired, the proliposomal formulations of the several embodiments described herein are desirable because they are non-irritating to the mucosa. The formulation is believed to be non-irritating because the mucosa is primarily in contact with the lipid bilayer, rather than directly with the irritating drug. The release of the drug from the liposomes is a sustained manner and readily mixes with the secretions overlying these membranes.

In another embodiment of the present invention, a method of pulmonary administration is provided. Proliposomes have been shown to be a very useful and very effective system for pulmonary drug delivery. The proliposomal formulation can be administered using a dry powder inhaler. Administration of proliposomal formulations by the pulmonary route can improve pulmonary absorption, resulting in a local drug effect in the respiratory tract, prolonging the time that the drug is present in the circulation and reducing systemic side effects. Thus, from a toxicological point of view, proliposomes appear to be particularly suitable systems for drug delivery to the lung.

Enteric and/or non-enteric coatings may be used according to the route of administration described herein. If the drug formulation described herein is administered for delivery to an environmentally acidic target, the enteric coating may not dissolve, thus hindering drug release. In some cases, it may be desirable for this to occur. In several embodiments, however, a non-enteric coating is provided. In some embodiments, the non-enteric coating comprises a polymer that dissolves under acidic, basic, and neutral pH conditions. One skilled in the art will appreciate which type of coating should be used according to embodiments of the present invention depending on the desired target tissue for delivery of the drug.

One skilled in the art will have sufficient information to make and use the non-liposomal formulations of the present invention with an understanding of the description of cellulose acetate phthalate provided below.

The following examples illustrate various embodiments of the present invention and are not intended to limit the invention in any way.

Example 1:

halofantrine and distearoylphosphatidylcholine (1: 3 ratio) were dissolved in chloroform and the solvent was evaporated using nitrogen. The dry powder was passed through a #60 mesh screen. Cellulose acetate phthalate (50mg) was dissolved in acetone (6ml) and sprayed onto a mixture of halofantrine and distearoylphosphatidylcholine.

Dissolution was carried out using USP dissolution apparatus type II, using 40mg of the formulation. The dissolution medium (250ml) was phosphate buffered saline (pH 7.4). The temperature of the dissolution medium was maintained at 37. + -. 0.5 ℃ and the rotation speed of the slurry was set at 50 rpm. Samples (5ml) were taken at 5, 10, 15, 30, 45, 60, 90, 120, 180 and 240 minutes. The same volume of phosphate buffered saline was added to maintain a constant volume of dissolution medium.

Samples were analyzed by High Performance Liquid Chromatography (HPLC). In the mobile phase, 46.5: 53.5(0.025M potassium phosphate/sulfuric acid/triethylamine solution): acetonitrile was combined, mixed and filtered. Sodium lauryl sulfate (1.1g/L mobile phase) was added to the filtered solution.

The parameters of the analysis step are as follows. The flow rate was set at 1.2 ml/min. The temperature was room temperature. The run time was 30 minutes. The ultraviolet light detector is set at a wavelength of 254 nm. The retention times for (+) -halofantrine and (-) halofantrine were 25 minutes and 28 minutes, respectively.

Pharmacokinetic parameters of the enteric coated proliposomal preparation of halofantrine were evaluated as follows. The proliposomal product was prepared as a suspension in 0.78% methylcellulose. Non-liposomal suspension formulations (controls) were prepared by dispersing halofantrine powder in 1% methylcellulose. Under halothane anesthesia, the catheter was inserted into Sprague-Dawley in the right jugular vein of the rat. After overnight rest, rats were orally perfused with 7mg/kg halofantrine suspension as either proliposomes (7 rats) or controls (6 rats). Successive blood samples were obtained from the catheter until 48h post-dose. Plasma concentrations of the halofantrine enantiomers were measured using a stereoselective H PLC method. AUC was measured using non-compartmentalized (noncompartmental) pharmacokinetic method_0-24、C_maxAnd t_max. Significance of differences was assessed using Student unpaired t-test. The results (mean. + -. SD) are shown in Table 1.

TABLE 1 pharmacokinetic results of halofantrine study

a ═ p < 0.05 vs control; b ═ p < 0.05, compared with the enantiomer

The proliposomal formulation showed higher bioavailability of both enantiomers compared to the control formulation. AUC and C for the halofantrine enantiomers_maxRespectively increased by more than 40% and 80%. Although the average t of the two enantiomers in the precursor liposome preparation_maxLower, but not statistically significant, differences from the control.

Example 2:

testosterone and phospholipid (DMPC, DPPC or DSPC; ratio 1: 1) were dissolved in chloroform. Chloroform was evaporated using nitrogen. The dried powder was passed through a #60 mesh screen. Cellulose acetate phthalate (40mg) was dissolved in acetone (5ml) and the resulting solution was sprayed onto a solid dispersion containing testosterone and phospholipids. The powder was dried with nitrogen.

Dissolution was carried out using USP dissolution apparatus type II, using 45mg of formulation. The dissolution medium (300ml) was phosphate buffered saline (pH 7.4). The temperature of the dissolution medium was maintained at 37. + -. 0.5 ℃ and the rotation speed of the slurry was set at 50 rpm. Samples (5ml) were taken at 2, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 80, 100 and 120 minutes. The same volume of phosphate buffered saline was added to maintain a constant volume of dissolution medium. Dissolved samples were analyzed by measuring absorbance at 254 nm.

As shown in figure 2, the dissolution rate and solubility of testosterone for the proliposomal formulation was significantly greater than that of pure testosterone. The solubility of the proliposomal formulation containing DMPC was highest, followed by DSPC and DPPC. This can be explained by the phase transition temperature (Tc) of these lipids. The Tc of DPPC was 41 ℃ which is very close to the temperature of the dissolution study (37 ℃). The Tc of DMPC and DSPC were 23 ℃ and 56 ℃ respectively. At 37 ℃ DMPC exists in a fluid state and DSPC exists in a gel state. Since the Tc of DPPC is similar to the temperature of the dissolution study, the formulation may be unstable, thus preventing the dissolution of testosterone. However, the data indicate that by using an enterically coated proliposomal formulation, the rate of dissolution and solubility of testosterone is increased.

Example 3:

famotidine and distearoylphosphatidylcholine (DSPC; ratio 1: 3) were dissolved in chloroform. Chloroform was evaporated using nitrogen. The dried powder was passed through a #60 mesh screen. Cellulose acetate phthalate (50mg) was dissolved in acetone (5ml) and the resulting solution was sprayed onto a solid dispersion containing testosterone and phospholipids. The powder was dried with nitrogen.

Dissolution was carried out using USP dissolution apparatus type II, using 87mg of the formulation. The dissolution medium (300ml) was phosphate buffered saline (pH 7.4). The temperature of the dissolution medium was maintained at 37. + -. 0.5 ℃ and the rotation speed of the slurry was set at 50 rpm. Samples (5ml) were taken at 2, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 80, 100 and 120 minutes. The same volume of phosphate buffered saline was added to maintain a constant volume of dissolution medium. The dissolved sample was analyzed by measuring the absorbance at 285 nm.

The dissolution rate of famotidine preparation is obviously higher than that of pure famotidine. However, there was no significant increase in the solubility of famotidine in PBS. The drug begins to act more rapidly in some embodiments due to the faster dissolution rate achieved by the proliposomal formulation.

Example 3:

one embodiment of the present invention is compared to a control method for manufacturing a pharmaceutical formulation. A control method for the following examples is disclosed by Ganter in U.S. Pat. No.5,635,206, incorporated herein by reference, as in example 1, except that the percentages of water used are 5% and 0%. Using a poorly water soluble sample drug: glibenclamide and benzocaine.

The following table summarizes the protocols used and the results.

TABLE 2 Experimental protocol feedstocks used in the Glibenclamide comparative study

Raw materials	Amount used in control method using 5% water	Amount used in control method using 0% water	Amounts used in applicants' method
				Glibenzoyl urea	12％	12％	12％
Lecithin (DMPC)	63％	63％	63％
				Water (W)	5％	0％	0％
Ethanol	20％	25％	25％

TABLE 3 Experimental protocol materials used in the comparative study of benzocaine

Raw materials	Amount used in control method using 5% water	Amount used in control method using 0% water	Amounts used in applicants' method
				Benzocaine	12％	12％	12％
Lecithin (DMPC)	63％	63％	63％
				Water (W)	5％	0％	0％
Ethanol	20％	25％	25％

TABLE 4 results of a Glibenclamide comparative study

Glibenzoyl urea	Control method with 5% water	Control method with 0% water	Applicant's method
				Form of the composition	Milky emulsion	Milky emulsion	Powder of
Yield (%)	69.40％	55.30％	97.80％
				Absorbance of the solution	3.8177	3.9141	1.9446
Particle size	2.544μm	5.978μm	8.638μm

TABLE 5 results of a benzocaine comparison study

Benzocaine	Control method with 5% water	Control method with 0% water	Applicant's method
				Form of the composition	Clear solutionLiquid for treating urinary tract infection	Clear solution	Powder of
Yield (%)	68.09％	68.20％	97.80％
				Absorbance of the solution	3.6030	3.6130	3.7377
Particle size	1.190μm	3.830μm	9.163μm

The results for glyburide and benzocaine indicate that some embodiments of the invention have unexpected and significant advantages over the control method at 5% water and 0% water. For example, some embodiments of the invention may result in: (1) significantly higher yields; (2) more effective and efficient mixing with lipids, which is indicated by lower absorbance values in the aqueous phase; (3) larger particle size, which has the advantages of coating and increased absorption and stability in the gastrointestinal tract; and/or (4) a powdered form, which is easier to handle and coat than a milky form. Some embodiments of the invention have one or more of the above advantages. In one embodiment, the quality and quantity of the formulation is significantly improved because the method does not expose the drug to an aqueous phase and evaporates the non-aqueous solvent to produce a product that can be coated.

Although a number of preferred embodiments of the invention and variations thereon have been described in detail, other useful modifications and methods will be apparent to those skilled in the art. It is therefore to be understood that various applications, modifications and substitutions may be made of equivalents without departing from the spirit of the invention and scope of the appended claims.

Claims (32)

1. A method of making a formulation suitable for administration to a patient, comprising:

providing at least one phospholipid;

providing at least one surfactant, said surfactant being a polysorbate;

providing at least one poorly water-soluble bioactive agent;

exposing at least one surfactant, at least one poorly water soluble bioactive agent, and at least one phospholipid to a non-aqueous solvent;

removing the non-aqueous solvent, thereby producing a powder; and

coating the powder with one or more coatings without exposing the bioactive agent to an aqueous solvent, thereby producing coated particles, wherein the one or more coatings are in contact with at least a portion of the powder, thereby producing a formulation suitable for administration to a patient,

and the surfactant is located at the phase boundary of the organic phase and the aqueous phase.

2. The method of claim 1, further comprising forming the coated particles into a dosage form suitable for administration to a patient.

3. The method of claim 1, wherein greater than about thirty parts of aqueous solvent are required for each part of solute dissolution of the one or more bioactive agents.

4. The method of claim 1, wherein the one or more bioactive agents are water insoluble.

5. The method according to any one of the preceding claims, wherein the non-aqueous solvent is at least partially removed by evaporation.

6. A method according to any preceding claim, wherein the non-aqueous solvent is substantially or completely removed by evaporation.

7. The method of any preceding claim, wherein the at least one surfactant is selected from the group consisting of: polysorbates, bile salts, and alkyl glycosides.

8. The method of any preceding claim, wherein a portion of the surfactant, bioactive agent, and phospholipid are exposed to the non-aqueous solvent simultaneously.

9. The method of any one of the preceding claims, wherein the one or more coatings comprise an acid-labile coating.

10. The method of any one of the preceding claims, wherein the one or more coatings comprise an enteric coating.

11. The method of any one of the preceding claims, wherein the one or more coatings comprise a non-enteric coating.

12. The method of any preceding claim, wherein the one or more coatings are materials selected from the group consisting of one or more of: cellulose-based agents, povidone, and polyethylene.

13. The method of claim 12, wherein the cellulose-based reagent is selected from the group consisting of one or more of: methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose.

14. The method of any preceding claim, wherein the dosage form is selected from the group consisting of one or more of: suspensions, tablets and capsules.

15. The method of any one of the preceding claims, wherein the one or more coatings are adapted to be administered by various routes selected from the group consisting of one or more of: oral, buccal, sublingual, nasal, topical, transdermal, ocular, vaginal, rectal, intravesical, pulmonary, intraarterial, intravenous, intradermal, intramuscular, subcutaneous, intraperitoneal, intrathecal and intraocular.

16. The method of any one of the preceding claims, wherein the biologically active agent is testosterone.

17. The method of any one of the preceding claims, wherein the biologically active agent is famotidine.

18. The method of any one of the preceding claims, wherein the biologically active agent is halofantrine.

19. The method of any one of the preceding claims, wherein the biologically active agent is glyburide.

20. The method of any one of the preceding claims, wherein the biologically active agent comprises a sustained release agent.

21. The method of any one of the preceding claims, wherein the coating is capable of controlling the release of the biologically active agent in a time-based manner.

22. The method of any one of the preceding claims, wherein the phospholipid comprises a phosphatidyl phospholipid.

23. The method of any one of the preceding claims, wherein the phospholipid is selected from the group consisting of one or more of: distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, egg yolk PC, soy PC, DMPG, DMPA, DPPG, DPPA, DSPG, DSPA, phosphatidylserine and sphingomyelin.

24. The method of any of the preceding claims, further comprising adding a plasticizer.

25. The method of any preceding claim, further comprising adding a plasticizer, wherein the plasticizer is selected from the group consisting of one or more of: phthalates, citrates and triacetin.

26. The method of any one of the preceding claims, wherein the step of coating the powder with one or more coatings comprises spraying the powder.

27. The method of any one of the preceding claims, further comprising combining at least one additional component with the bioactive agent.

28. The method of claim 27, wherein the at least one additional ingredient is selected from the group consisting of one or more of: carriers, diluents and lubricants.

29. The method of claim 27, wherein the at least one additional ingredient is selected from the group consisting of one or more of: microcrystalline cellulose, starch, lactose, talc, mannitol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, ethylcellulose, fatty acids, fatty acid salts, glyceryl behenate, glucose, and dicalcium phosphate.

30. Use of a formulation obtainable by a method according to any preceding claim in the manufacture of a medicament for increasing testosterone levels in a mammal.

31. A formulation obtainable by the method of any preceding claim.

32. A formulation obtainable by the method of any preceding claim, wherein the formulation comprises testosterone.