HK1162295A - Non-polymeric compositions for controlled drug delivery - Google Patents

Abstract

The present invention provides a novel liquid composition suitable for in situ formation of storage systems for controlled transfer of bioactive substances. The composition of the present invention comprises: (a) a hydrophobic non polymeric carrier material; (b) A biocompatible organic solvent that is miscible with water and can dissolve hydrophobic non polymeric materials; (c) Ionic complexes formed by amphiphilic molecules and a biologically active substance with a net charge in neutral pH water. The present invention also provides a method for manufacturing and using the composition.

Description

Controlled administration non-polymeric compositions

Technical Field

The present invention relates to the field of controlled release administration of biologically active substances, as well as compositions and methods for controlled release administration of biologically active substances using hydrophobic non-polymeric materials as carriers.

Background

Hydrophobic non-polymeric materials, particularly highly viscous non-polymeric liquid materials, have been disclosed as biodegradable systems for the controlled release administration of biologically active compounds (Smith and Tipton, Pharmaceutical Research, 13(9), S300, 1996). Hydrophobic non-polymeric materials are generally substantially insoluble in water. The hydrophobic non-polymeric material may be a highly viscous liquid having a viscosity of at least 5000cP at 37 ℃ and which does not crystallize under ambient or physiological conditions. When these materials are mixed with a small amount of plasticizing solvent, the mixture has a much lower viscosity than the non-polymeric liquid material alone. This low viscosity solution can be readily formulated with a biologically active compound to provide a low viscosity liquid formulation that can be readily administered to a subject to form a long acting pharmaceutical agent of high viscosity in situ.

Representative examples of in situ forming reservoir systems comprising hydrophobic non-polymeric liquid carrier materials are disclosed in U.S. Pat. Nos. 5747058, 5968542, 6051558 and 6992065. The compositions described in these patents comprise a hydrophobic high viscosity non-polymeric liquid material such as Sucrose Acetate Isobutyrate (SAIB), a water soluble or water miscible organic solvent, and a biologically active substance. Such compositions can be readily prepared and administered to a subject in the form of a low viscosity solution. Once in the body, the solvent disperses or diffuses into the surrounding tissue, which results in precipitation or coagulation of the non-polymeric material to form a highly viscous gel, semi-solid or solid depot encapsulating the biologically active substance. The bioactive agent is then released by dissolution, diffusion and/or degradation of the depot.

Non-polymeric carrier materials are typically degraded by hydrolysis of ester or ester linkages. Cleavage of the ester promotes affinity groups, such as amine groups, within the enzyme or other biologically active substance. This easy degradation is advantageous for medical use, but the susceptibility of the formulation to degradation is also a major problem for the preparation of stable formulations. The same degradation can occur by interaction between the biologically active substance and the non-polymeric carrier material whenever the biologically active substance is brought together with the non-polymeric liquid carrier material. Such interactions adversely affect the physical and chemical properties of the composition, leading to undesirable degradation of the non-polymeric material and the production of impurities in the bioactive substance. The instability of the carrier material with the biologically active substance in the formulation has resulted in the inability to prepare suitable compositions with reasonable shelf-life and has prevented the formulation from forming a stable depot upon administration to achieve the desired release properties.

In addition, due to the hydrophobic nature of the non-polymeric carrier material, many biologically active agents, particularly hydrophobic peptides, and charged and polar proteins may be incompatible with the non-polymeric carrier material, resulting in unstable liquid formulations. Phase separation is generally observed when a non-polymeric carrier material is combined with an uncomplexed biologically active substance or a simple salt thereof, such as an acetate or chloride salt. Phase separation during formulation, storage and in situ depot formation leads to inhomogeneous formulations or depots leading to uncontrolled release characteristics. Furthermore, the initial burst is a typical characteristic of this type of liquid formulation, as demonstrated in prior art us patents 5,747,058 and 5,968,542. Uncontrolled burst release is undesirable, particularly for bioactive substances with narrow therapeutic indices.

Accordingly, there is a need to develop a controlled release composition that prevents or minimizes undesirable interactions between the non-polymeric carrier material and the biologically active substance. There is also a need to develop a controlled release composition that can be formulated and stored as a single phase homogeneous composition of a non-polymeric carrier material and a biologically active substance. There is also a need to develop single phase homogeneous compositions that provide depot with low burst effect.

Disclosure of Invention

The present invention provides a novel liquid composition suitable for forming in situ reservoir systems for the delivery of biologically active substances in a controlled manner. The composition of the present invention comprises: (a) a hydrophobic non-polymeric carrier material; (b) a water-miscible biocompatible organic solvent that dissolves the hydrophobic non-polymeric material and substantially reduces the viscosity of the composition for ease of preparation and administration; (c) an ionic complex formed by an amphiphilic molecule and a biologically active substance having a net charge in water at neutral pH. Wherein the non-polymeric material is substantially water insoluble and may be a highly viscous liquid having a viscosity of at least 5.000cP at 37 ℃ and which does not crystallize at ambient temperature or physiological conditions. The composition of the present invention may further comprise an additive to achieve the desired release properties. The invention also provides a method of making and using the composition.

Accordingly, the biologically active substance is preferably combined with the amphiphilic molecule to form an ionic complex which is substantially insoluble in water or biological fluids. The ionic complex of the biologically active substance is then dispersed in a solution of the hydrophobic non-polymeric carrier material in a water-miscible solvent such as N-methyl-2-pyrrolidone (MMP) to form a homogeneous solution or suspension. Generally, phase separation occurs when an uncomplexed bioactive substance or simple salt thereof, such as acetate or hydrochloride, is brought together with a hydrophobic, non-polymeric material in an organic solvent. However, unexpectedly, it has been found that the use of ionic complexes of the biologically active substance of the present invention with amphiphilic molecules prevents or minimizes phase separation to maintain physical stability of the formulation. Furthermore, uncomplexed biologically active substances or their simple salts, for example acetate or hydrochloride, are susceptible to chemical degradation during formulation and subsequent storage. The chemical degradation can be prevented or minimized by the complexation of the biologically active substance of the invention with amphiphilic molecules. The enhanced chemical and physical stability of the composition will allow the development of a stable product with desirable release properties and reasonable shelf life.

When the non-polymeric liquid composition of the present invention is contacted with an aqueous environment, such as a biological fluid in the body of a patient, the water-soluble or water-miscible solvent disperses or diffuses into the surrounding water or biological fluid. At the same time, the hydrophobic non-polymeric liquid carrier material precipitates or coagulates to form a highly viscous gel or solid reservoir in which the biologically active substance is entrapped or encapsulated. Due to the rapid diffusion of the solvent, a high initial burst of the biologically active substance is usually observed during the formation of the depot. However, it has unexpectedly been found that the complexes of the biologically active substance of the present invention with suitable amphiphilic molecules significantly reduce burst release and improve the overall release profile of the biologically active substance relative to formulations comprising uncomplexed biologically active substance or a simple salt thereof, such as acetate. Once the depot is formed, the biologically active substance is released from the non-polymeric matrix by dissolution, diffusion and/or degradation of the non-polymeric carrier material.

According to the present invention, the composition optionally includes additives that modify the composition to achieve a desired release profile of the biologically active substance. Additives include, but are not limited to, burst effect reducing materials, release rate retarders, release rate accelerators, solubilizing agents, and the like. The additive may be a polymeric or non-polymeric material, including biodegradable or non-biodegradable polymers, carbohydrates or carbohydrate derivatives, organic or inorganic compounds.

The compositions of the present invention may be viscous or non-viscous liquids, or gels, that can be easily injected using a syringe or similar device. The composition may be administered by subcutaneous injection, intramuscular injection, intraperitoneal injection or intradermal injection to form a depot in situ. The compositions may also be administered orally or topically or transmucosally. When administered to the body of a subject, the controlled release of the biologically active substance can be controlled for a desired period of time, depending on the composition of the system. By appropriate selection of the non-polymeric carrier material and other excipients, the time of controlled release of the biologically active substance can be controlled over a period of from weeks to a year.

Other objects and features of the present invention will become apparent from the following detailed descriptions considered in conjunction with the accompanying drawings. It is to be understood that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the invention, for which reference should be made to the appended claims. It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described in this regard.

Drawings

In the drawings:

figure 1 shows photographs of the formulation taken at room temperature for 1 hour (a) and 24 hours (b).

FIG. 2 shows the reaction of octreotide with a mixture comprising (a) OCT-Ac; (b) OCT-SDS; (c) in vitro release in SAIB/NMP formulation of OCT-DSS.

FIG. 3 shows the synthesis of leuprolide from a mixture comprising (a) LA-Ac; (b) LA-SDS; (c) LA-DSS; (d) in vitro release of LA-OL in SAIB/NMP formulations.

Figure 4 shows the in vitro release of pramipexole from SAIB/NMP formulations containing (a) PPL-HCl and (b) PPL-SDS.

Detailed Description

The present invention provides a non-polymeric liquid composition suitable for forming in situ a depot system with sustained drug properties for delivery of biologically active substances in a sustained and controlled manner. Preferred non-polymeric liquid compositions of the present invention are combinations of at least one hydrophobic non-polymeric carrier material, a biologically active substance, an amphiphilic molecule, and a water-soluble or water-miscible biocompatible solvent. Preferably, the biologically active substance is combined with the amphiphilic molecule to form an ionic complex which is substantially insoluble in water. Optionally, additives may be included to modify the composition to achieve the desired release characteristics. The composition may be in the form of a viscous or non-viscous liquid. The composition is a homogeneous solution or a homogeneous suspension. All components of the present invention are biocompatible and stable during formulation and storage under appropriate conditions.

The composition of the invention is preferably injectable by means of a syringe or any other similar device. The composition may be administered to the subject's body by subcutaneous injection, intramuscular injection, intraperitoneal injection, or intradermal injection to form a depot in situ. The compositions may also be administered orally or topically or transmucosally. When administered to a target body, the hydrophobic non-polymeric carrier material precipitates or coagulates by contact with an aqueous environment or body fluid, the solvent disperses or diffuses into the surrounding liquid, and a viscous gel, semi-solid, or solid reservoir is formed. The reservoir may be porous or non-porous. The contained bioactive substance is substantially trapped within the reservoir and gradually released over a period of time. Preferably, the composition of the invention has an initial release of less than 20%, more preferably less than 10%, most preferably less than 5% within 24 hours. By appropriate selection of the non-polymeric carrier material and other components of the composition, the time of controlled release of the biologically active substance can be controlled over a period of from weeks to a year.

As used herein, the terms "a", "an", and the like are intended to be interpreted as "one or more" and "at least one" unless explicitly indicated otherwise.

The carrier material is any biodegradable, biocompatible, and substantially insoluble hydrophobic, non-polymeric material in water and biological liquids. The hydrophobic non-polymeric carrier material is preferably a highly viscous liquid having a viscosity of at least 5000cP at 37 ℃ and which does not crystallize under ambient or physiological conditions. The term "hydrophobic" refers to the physical property of a molecule that is not readily dissolved or mixed in or wetted by water. In particular, as used herein, it means that the solubility of the material in water is less than 1% by weight at 25 ℃. The term "non-polymeric" refers to esters or mixed esters having substantially no repeating units in the acid portion of the ester. Some non-limiting examples of hydrophobic non-polymeric liquid carrier materials are described in prior art U.S. patent nos. 5,747,058 and 5,968,542, which are incorporated herein by reference in their entirety.

In particular, the hydrophobic non-polymeric carrier material may be one or more non-polymeric esters or mixed esters. Representative esters are formed from polyols having less than 20 hydroxyl groups esterified with a carboxylic acid. Suitable polyols include monofunctional and polyfunctional alcohols of 2 to 24 carbon atoms, sugar alcohols, monosaccharides, disaccharides, oligosaccharides and polyether alcohols. More particularly, the polyol can be dodecanol, hexylene glycol, glycerol, mannitol, sorbitol, glucose, fructose, sucrose, inositol, polyglycerol, polyethylene glycol, and the like.

Carboxylic acids used to form the hydrophobic non-polymeric carrier material include organic acids having more than two carbon atoms, such as fatty acids. These carboxylic acids can be saturated, unsaturated, aromatic (aryl and aralkyl) and linear or branched structures. These carboxylic acids may also have one or more hydroxyl groups or other groups, such as rings, nitro groups, and the like. More particularly, these carboxylic acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, lipoic acid, caproic acid, enanthic acid, oleic acid, palmitic acid, stearic acid, myristic acid, benzoic acid, glycolic acid, lactic acid, D-hydroxycaproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid (hexadecanoic acid), stearic acid (octadecanoic acid), arachidic acid (eicosanoic acid), behenic acid, and other fatty acids.

The hydrophobic non-polymeric carrier material is preferably biodegradable and does not produce any non-biocompatible or toxic degradation products. When the hydrophobic non-polymeric carrier material is mixed with a water-miscible solvent, a solution with a low viscosity can be obtained. The low viscosity solutions can be readily used with biologically active substances to prepare the compositions of the present invention. The low viscosity allows the composition to be easily applied to the target body. The properties of the composition may vary depending on parameters such as the miscibility of the non-polymeric material in the solvent, the concentration of the non-polymeric material in the formulation, the concentration of the biologically active substance, and/or the presence or absence of additives. These parameters of the composition can be adjusted to obtain the desired properties.

In a preferred embodiment, Sucrose Acetate Isobutyrate (SAIB) is used as the hydrophobic non-polymeric carrier material. SAIB is a mixed ester of sucrose esterified with diacetic acid and hexaisobutyric acid groups. The ester is completely amorphous and has a viscosity exceeding 100000cP at 30 ℃. The viscosity of the ester can be significantly reduced by slightly raising the temperature or adding a solvent. In one embodiment, SAIB is heated and mixed with the biologically active substance to prepare a suspension. Alternatively, SAIB may be mixed with a large number of different biocompatible solvents to obtain a low viscosity solution that can be readily formulated with biologically active substances.

Suitable solvents that may be selected for use in the compositions of the present invention are biocompatible and water soluble or miscible dispersible. As used herein, the terms "dissolve" and "miscible" are equivalent and are used interchangeably and refer to a solvent having a solubility in water of at least 1%, preferably at least 3%, more preferably at least 7% by weight at 25 ℃. When combined with a hydrophobic non-polymeric carrier material, the solvent can significantly reduce the viscosity of the mixture to form a lower viscosity liquid carrier material. Such lower viscosity liquid compositions may further be formulated with biologically active substances for controlled release administration. Non-limiting examples of suitable solvents include acetone, benzyl alcohol, butylene glycol, caprolactam, caprolactone, dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, ethyl lactate, glycerol formal, glycogens (tetraethylene glycol), N-methyl-2-pyrrolidone (NMP), polyethylene glycol, methoxypolyethylene glycol, alkoxypolyethylene glycol, propylene carbonate, 2-pyrrolidone, triacetin, triethyl citrate, and combinations of the foregoing.

As used herein, the term "biologically active substance" is meant to include any material having diagnostic and/or therapeutic properties, including, but not limited to, small molecules, macromolecules, peptides, proteins, or enzymes. Non-limiting examples of therapeutic properties are anti-metabolic, anti-fungal, anti-inflammatory, anti-hypertensive, anti-psychotic, analgesic, anti-diabetic, hypnotic, sedative, anesthetic, anti-cancer, anti-infective, antibacterial, anti-viral, hormonal, nutritional, stimulant, and antagonistic properties.

More specifically, suitable biologically active substances of the present invention include any compound that is ionizable, has a net charge in water at neutral pH, and is capable of forming an ionic complex with an amphiphilic molecule. Preferably the compound comprises an electron donor base, for example a basic nitrogen atom, such as an amine, imine or ring nitrogen. The bioactive substances of the present invention include, but are not limited to, doxorubicin, 4-hydroxyphenylethylamine, methamphetamine, amitriptyline, reboxetine, bupropion, mirtazapine, venlafaxine, duloxetine, fluoxetine, paroxetine, escitalopram, citalopram, sertraline, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, doxycycline, diltiazem, cyclobenzaprine, bacitracin, noscapine, erythromycin, polymyxin, vancomycin, nortriptyline, quinidine, ergotamine, benztropine, verapamil, flunarizine, imipramine, kanamycin, neomycin, amoxicillin, amikacin, arbacin, bemycin, butricidin, dibekacin, dihydrostreptocin, dihydrostreptomycin, tiamulin, isopamicin, micronomicin (micin), micronomicin, Netilmicin, paromomycin (paromycin), ribostamycin (ribostamycin), rapamycin, sisomicin, streptomycin and tobramycin, pyrimethamine, naltrexone, lidocaine, prilocaine, mepivacaine, bupivacaine, tetracaine, ropivacaine, haloperidol (haloperinone), and risperidone.

The biologically active substances of the invention also include oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF), prolactin, luteinizing hormone (luteinizing hormone), Luteinizing Hormone Releasing Hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones (including human, porcine and bovine), growth hormone releasing factor, insulin, erythropoietin (including all proteins with erythropoietic activity), somatostatin, glucagon, interleukins, alpha-interferons, beta-interferons, gamma-interferons, gastrins, tetrapeptide gastrin, pentapeptide gastrin, urogastrin, incretin, calcitonin, enkephalin, endorphin, angiotensin, Thyrotropin Releasing Hormone (TRH), Tumor Necrosis Factor (TNF), parathyroid hormone (PTH), and, Nerve Growth Factor (NGF), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage stimulating factor (GM-CSF), macrophage stimulating factor (M-CSF), heparinase, vascular endothelial growth factor (VEG-F), Bone Morphogenetic Protein (BMP), human atrial natriuretic peptide (hANP), glucagon-like peptide (GLP-I), exenatide, casein (PYY), renin, bradykinin, bacitracin, polymyxin, colistin, gramicin, cyclosporin (including synthetic analogs and pharmaceutically active fragments thereof), enzymes, cytokines, antibodies, vaccines, antibiotics, antibodies, glycoproteins, follicle stimulating hormone, kyotorphin, phagocytosis hormone (taftsin), thymopoietin, thymostimulin, thymohumoral factor, serum thymic factor, Colony stimulating factors, motilin, bombesin, dynorphin (dinorphin), neurotensin, ranopeptide, urokinase, kallikrein, peptide analogs and antagonists, angiotensin II, blood clotting factors VII and IX, lysozyme, gramicidines, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, secretin, cholecystokinin, human placental lactogen, human chorionic gonadotropin, protein synthesis promoting factors, gastrin, vasoactive intestinal peptide, platelet derived growth factors, and synthetic analogs and modifications and pharmaceutically active fragments of the foregoing.

According to the invention, the biologically active substance is complexed with an amphiphilic molecule by ionic interaction. The association with the amphiphilic molecule stabilizes the biologically active substance in the composition of the invention. The complex, together with other formulation components, produces a delivery system that is practically sufficiently stable to provide a physically consistent, controlled delivery system. More particularly, the amphiphilic molecules serve to prevent or minimize chemical degradation of the bioactive agent, to maintain the physicochemical stability of the compositions of the present invention, and to reduce the initial burst of bioactive agent from the depot formed by the composition. Such a system can be used to consistently treat patients with various diseases.

Suitable amphiphilic molecules of the present invention are any material having a hydrophobic portion and a hydrophilic portion. The hydrophilic portion of the amphiphilic molecule is ionic and is preferably anionic. The amphiphilic molecule may be an organic sulfuric acid, organic sulfonic acid, organic phosphoric acid, or organic carboxylic acid. In particular, organic sulfuric acid and organic sulfonic acid are preferable. The amphiphilic molecules may also be different salts or ionic (dissociated) forms of the molecule. The hydrophobic portion of the amphiphilic molecule may be any hydrophobic group such as an alkyl, aryl or aralkyl group. The hydrophobic moiety may be saturated, unsaturated, aromatic (aryl and aralkyl) and linear or branched structures. The hydrophobic moiety is preferably an alkyl or substituted alkyl group of at least 4 carbon atoms. The amphiphilic molecule and the biologically active substance together form an ionic complex that is substantially insoluble in water under ambient conditions. The term "substantially insoluble" means that the solubility of the complex is less than 5%, preferably less than 1%, by weight at ambient conditions.

Some particular examples of amphiphilic molecules of the present invention include, but are not limited to, sodium salt of mono C12-18-alkyl sulfate, dialkyl succinate derivatives having 3-16 carbon atoms, dioctyl succinate, benzenesulfonic acid, naphthalene-1, 5-disulfonic acid, camphorsulfonic acid, (+) - (1S) -camphene-10-sulfonic acid, dodecylsulfuric acid, p-toluenesulfonic acid, naphthalene-2-sulfonic acid, cholesterol sulfate, heptanesulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, oleic acid, palmitic acid, methylenepamoic acid, benzoic acid, stearic acid, undecylenic acid, and phospholipids. Examples also include different salt or ionic (dissociated) forms of the molecule.

According to the present invention, the composition optionally includes additives that modify the composition to achieve a desired release profile of the biologically active substance. Additives may be included to adjust the release rate and stabilize the biologically active substance. Suitable additives may be any polymeric or non-polymeric material, including biodegradable or non-biodegradable polymers, carbohydrates or carbohydrate derivatives, organic or inorganic compounds.

Some suitable additives are described in U.S. patent 5,747,058, which is incorporated herein by reference in its entirety. Preferably, suitable additives are biocompatible and/or biodegradable polymers. Such polymers include, but are not limited to, polylactic acid, polyglycolide, polycaprolactone, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, povidone, polycarbonates, polyphosphoesters, polyoxaesters, polyorthocarbonates, polyphosphazenes, succinates, polymalic acids, polyamino acids, polyvinylpyrrolidone, polyethylene glycol, polyloxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers, and mixtures thereof.

According to the present invention, the composition optionally includes a reducing agent, an antioxidant, and a free radical scavenger to stabilize the composition. Examples are, but not limited to, cysteine or methionine, d-alpha tocopherol acetate, racemic alpha tocopherol, ascorbyl palmitate, butylhydroxyanisole (butylated hydroxyanisole), t-butylhydroxyanisole (butylated hydroxyanisole), butylated hydroxyanisole (butylated hydroxyanisole), hydroxycoumarin (hydroxycoumarin), butylhydroxytoluene, cephalin (cephalam), ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate (propylhydroxybenzoate), trihydroxybutyrophenone (trihydroxybutyrophenone), dimethylphenol, di-t-butylphenol (ditertbutylphenol), vitamin E, and lecithin.

Accordingly, the compositions of the present invention can be readily prepared. In one embodiment, the complex of the biologically active substance and the amphiphilic molecule may be prepared in any suitable manner. For example, an appropriate amount of amphipathic molecules, in solution or not, may be added to a suitable solution, e.g., an aqueous solution, of the biologically active substance to precipitate the complex from solution. The precipitate is then recovered using suitable means, for example using centrifugation or filtration. In another embodiment, both the biologically active substance and the amphiphilic molecule are dissolved in water and the two solutions are then mixed. Upon contact, complexation occurs between the biologically active substance and the amphiphilic molecule, and a precipitate is formed. In another embodiment, both the biologically active substance and the amphipathic molecule are dissolved in an organic solvent and the complex is then recovered by removing the by-products and evaporating the solvent.

The ratio of biologically active substance to amphiphilic molecule in the complex is preferably from about 0.1: 1 to about 10: 1 on a molar basis. More preferably, the stoichiometry of the ratio is based on the number of charged functional groups of the biologically active substance and the amphiphilic molecule. In order to obtain optimal complexation and subsequent formulation, the value of the molecular weight of the biologically active substance divided by the number of ionised (charged) groups of the biologically active substance is preferably above 100 daltons. The resulting complex of biologically active substance and amphiphilic molecule is preferably substantially water insoluble. Such a complex may be combined with a hydrophobic non-polymeric carrier material, a solvent and other optional additives to form a homogeneous formulation. It has surprisingly been found that the combination of the amphiphilic molecule and the biologically active substance prevents or minimizes degradation of the biologically active substance, maintains the physicochemical stability of the composition of the invention, and reduces the initial burst of the biologically active substance from the composition. Thus, the compositions of the present invention are suitable for storage under suitable conditions over a reasonable shelf life.

As used herein, the term "ionizable group" refers to an atom or group of atoms that can acquire a net charge by adding or removing one or more electrons.

According to the invention, the composition is preferably a homogeneous solution or a homogeneous suspension. Maintaining the consistency or uniformity of the composition is critical to reproducible dosing and to obtain a consistent reservoir system for controlled release delivery of the bioactive agent. In particular, consistency or homogeneity of the composition may be achieved at least by reconstitution or immediate mixing prior to administration. Preferably, the consistency or homogeneity of the composition is maintained throughout the preparation, storage and administration.

According to the invention, the composition comprises from about 99.5% to about 5% of hydrophobic non-polymeric material, preferably between 95% and 25%, relative to the total weight of the composition. The composition further comprises from about 0% to about 50% of a biocompatible solvent, from about 0.1% to about 40% of a biologically active substance and a sufficient amount of an amphiphilic molecule to stabilize the formulation and the biologically active substance. The composition further comprises from about 1% to about 25% of one or more additives.

In one embodiment, the biologically active substance is first formed into a substantially water insoluble complex with an amphiphilic molecule. The composite is then formed with the remaining components of the invention into a complete delivery system for packaging and storage. Preferably, the composition is packaged in a syringe in a ready-to-use formulation. Alternatively, the complex may be mixed with the remaining components of the invention immediately prior to administration to the body of the subject.

In a preferred embodiment, Sucrose Acetate Isobutyrate (SAIB) is used as the hydrophobic non-polymeric carrier material, with NMP being the solvent of choice. The biologically active substance is selected from the group consisting of peptides and proteins, such as octreotide, leuprolide, or glucagon-like peptide-1 (GLP-1). The biologically active substance is preferably combined with an amphiphilic molecule, preferably dioctyl sulfosuccinate or dodecyl sulfate, to form a substantially water insoluble complex. The resulting complexes can be combined with SAIB/NMP solutions to form controlled release formulations.

In another embodiment, the release rate of the composition of the invention is measured in vitro. Approximately 0.1ml of each formulation was injected into 3ml of release buffer (PBS7.4, containing 0.1% sodium azide) in a 4ml glass vial. The bottles were incubated at 37 ℃ and samples were taken at different time points. At each time point, 2ml of release medium was removed and replaced with 2ml of fresh release medium. The samples collected were analyzed by HPLC for the concentration and integrity of the bioactive substances using a YMC-Pack ODS-120A column or equivalent. Three samples were used for each formulation.

According to the present invention, the compositions described herein may be applied to targets where controlled release of a biologically active substance is desired. As used herein, the term "subject" is intended to include a warm-blooded animal, preferably a mammal, most preferably a human.

As used herein, the term "administering" refers to dispensing, distributing, or applying a composition (i.e., a pharmaceutical formulation) to a target by an appropriate route so as to deliver the composition to the desired location of the target. The compositions can be generally applied to the target subcutaneously, intramuscularly, intraperitoneally or intradermally, as well as orally, rectally, vaginally or nasally to provide the desired dose of the biologically active substance based on known parameters for the treatment of various diseases with the biologically active substance.

The term "controlled or controlled release administration" as used herein includes, for example, sustained delivery of the biologically active substance in vivo for a period of time after administration, preferably at least several days to several weeks or months. Controlled administration or controlled release administration of the biologically active substance can be demonstrated, for example, by a sustained therapeutic effect of the agent over a period of time (e.g., for leuprolide, controlled administration of the peptide can be demonstrated by sustained testosterone inhibition over a period of time). Alternatively, controlled administration of an agent can be evidenced by detecting the presence of the agent in the body over a period of time.

In this application, the various embodiments in the claims for a liquid-ready, non-polymeric composition are also envisioned to modify, mutatis mutandis, the ready-to-use method for forming such a composition as well as the ready-to-use method for forming a depot in situ.

Example (b):

the following examples illustrate the features and scope of the present invention. The following examples should not be considered as limiting in any way, but should be understood as merely intended to explain the teachings of how a useful drug delivery system may be prepared according to the present invention.

Example 1 preparation and in vitro Release of formulations comprising octreotide acetate

A solution of Sucrose Acetate Isobutyrate (SAIB) at a concentration of 80% by weight in N-methyl-2-pyrrolidone (NMP) was prepared by mixing 2g of NMP with 8g of SAIB, followed by gentle mixing. A clear, low viscosity solution was obtained. Then 60mg of octreotide acetate was dissolved in 100. mu.l of NMP and then homogenized by mixing with 900. mu.l of a solution of SAIB in NMP (80%) to obtain a preparation containing approximately 6% octreotide acetate.

Approximately 0.1ml of octreotide formulation was injected into 3ml of release buffer (PBS7.4, containing 0.1% sodium azide) in a glass vial. The bottles were incubated at 37 ℃ and samples were taken at different time points. At each time point, 2ml of release medium was removed and 2ml of fresh release medium was added. The released samples were analyzed for peptide concentration and integrity by HPLC using a YMC-Pack ODS-120A column.

And (4) observation: when 100. mu.l of octreotide acetate in NMP solution was mixed with 900. mu.l of SAIB in NMP solution (80%), an opaque suspension with considerable aggregates was surprisingly obtained. Since both SAIB and octreotide acetate are quite soluble in NMP, it is desirable to obtain a clear solution when two solutions in the same solvent (NMP) are mixed. This indicates that octreotide or octreotide acetate is not very compatible with SAIB. When the suspension was left at room temperature, phase separation was observed within a few hours, and two distinct phases were obtained after overnight standing at room temperature. Therefore, such formulations are not suitable for the preparation of stable single phase solution formulations of octreotide in SAIB/NMP.

HPLC analysis of formulations stored at room temperature for various time periods unexpectedly found several particularly distinct peaks on the chromatogram. Those peaks were not observed from the formulation at the beginning, indicating the production of impurities or degradation products of octreotide. The intensity of these peaks increases with time while the octreotide peak decreases with time. This result indicates that the chemical stability of the biologically active substance and other excipients in the formulation prevents the successful development of a single phase stable product. Therefore, this type of formulation must be modified to be suitable for controlled release administration of various bioactive substances.

Example 2 preparation of a Complex of octreotide and dodecyl sulfate (OCT-SDS)

215.2mg of sodium dodecyl sulfate (SDS, MW288.38, 98.5%) were dissolved in 20ml of water (10.76mg/ml, 36.75 mM). 251.7mg (0.212mmol) of octreotide acetate (MW1019.2+120 (acetic acid), 85.8%) were dissolved in water (10 ml). The octreotide solution was mixed with 11.56ml of SDS solution to form a complex in a stoichiometric ratio. The precipitate was separated by centrifugation and then dried under vacuum.

Example 3 preparation of a Complex of Leuprolide and dodecyl sulfate (LA-SDS)

215.2mg of sodium dodecyl sulfate (SDS, MW288.38, 98.5%) were dissolved in 20ml of water (10.76mg/ml, 36.75 mM). 201.4mg (0.142mmol) of leuprolide acetate (MW1209.4, 85.1%) were dissolved in 10ml of water (14 mM). The leuprolide solution was mixed with 7.619ml of SDS solution to form a complex in stoichiometric ratio. The precipitate was separated by centrifugation and then dried under vacuum.

Example 4 preparation of a Complex of octreotide and docusate (OCT-DSS)

Sodium 1, 4-bis (2-ethylhexyl) sulfosuccinate or docusate sodium (DSS, C)_2OH₃₇NaO₇S, MW: 444.56, 506.6mg, 1.139mmol) was dissolved in isopropanol (20ml) (56.97mM), and 201.4mg (0.17mmol) of octreotide acetate (MW1019.2, 85.8%) was dissolved in 10ml water (17 mM). 5.968ml of DSS solution were mixed with octreotide solution and stirred for approximately one hour. The complex was separated by centrifugation, and the obtained precipitate was washed with water and then dried under vacuum.

Example 5 preparation of a Complex of Leuprolide and docusate (LA-DSS)

Sodium 1, 4-bis (2-ethylhexyl) sulfosuccinate (DSS, C)_2OH₃₇NaO₇S, MW: 444.56, 506.6mg, 1.139mmol) was dissolved in isopropanol (20ml) (56.97mM), and 250mg (0.176mmol) of leuprolide acetate (MW1209.4, 85.1%) was dissolved in water (10 ml). 6.178ml of DSS solution was addedMixed with leuprolide solution and stirred for about one hour. The complex was separated by centrifugation, and the obtained precipitate was washed with water and then dried under vacuum.

EXAMPLE 6 preparation of leuprorelin oleate (LA-OL)

77.4mg of leuprolide acetate (MW1209.4, 84.2%) were dissolved in 1ml of deionized water (0.0539 mmol). 31.38mg of oleic acid (# A0241935, MW 282.46, 97%) was added to obtain a molar LA: OL ratio of 1: 2. A white precipitate formed by mixing the solutions. The complex was separated by centrifugation, and the obtained precipitate was washed with water and then dried under vacuum.

Example 7 preparation and in vitro characterization of formulations comprising octreotide

Octreotide acetate (OCT-Ac), octreotide dodecyl sulfate (OCT-SDS) and octreotide docusate (OCT-DSS) composite powder were dissolved in NMP. The solution containing the different salt forms of octreotide was then mixed thoroughly with a solution of SAIB in NMP (90% w/w). As shown in table 1, the octreotide content was about 6% and the SAIB concentration was about 70% for all formulations.

Table 1 formulations containing octreotide

Preparation	Peptide (mg)	SAIB(mg)	NMP(mg)	Peptide content (%)
					OCT-Ac/SAIB/NMP	65.9	653.5	281.8	6％
OCT-SDS/SAIB/NMP	88.5	629.5	280.1	6％
					OCT-DSS/SAIB/NMP	104.0	619.1	278.9	6％

When OCT-Ac was brought together with the SAIB/NMP solution, phase separation occurred immediately. Considerable precipitation of solids was observed, and a heterogeneous formulation was obtained as observed in example 1. Inhomogeneous preparations will block the needle and are not suitable for injection. When a conjugate of octreotide and sodium dodecyl sulfate (OCT-SDS) was combined with a SAIB/NMP solution, a homogeneous suspension was obtained, suitable for injection. This formulation may be prepared immediately prior to administration or may be adapted for storage for a period of time by adjusting formulation parameters. When the conjugate of octreotide and docusate sodium was brought together with the SAIB/NMP solution, a clear homogeneous solution was obtained without phase separation. This formulation can be packaged and stored at room temperature for extended periods of time.

Furthermore, octreotide was found to be unstable in formulations containing OCT-Ac, which was confirmed in example 1 above. As shown in table 2, impurities of octreotide were immediately produced when the components were mixed. After two hours, approximately 4% of octreotide degraded or reacted. More than half of the octreotide degraded after 5 days, indicating that the system is not suitable for controlled administration of the peptide. However, it was unexpectedly found that little or no degradation of octreotide was detected from formulations comprising OCT-SDS and OCT-DSS, even after several days at room temperature (table 2).

Table 2: stability of octreotide in formulations for a period of time at room temperature

Time (sky)	OCT-Ac/SAIB/NMP	OCT-SDS/SAIB/NMP	OCT-DSS/SAIB/NMP
				0.08	96.1	99.4	100
1	90.8	99.3	99.5
				2	71.9	100	100
5	48.7	100	99.8
				7	41.4	100	98.9

Example 8 preparation and in vitro characterization of formulations comprising octreotide

Composite powder of octreotide acetate (OCT-Ac) and octreotide dodecyl sulfate (OCT-SDS) was dissolved in NMP. The solution containing the different salt forms of octreotide was then mixed thoroughly with a solution of SAIB in NMP (90% w/w). As shown in table 3, the final octreotide content was about 6% and SAIB concentration was about 80% for all formulations.

Table 3 formulations containing octreotide

Preparation	Peptide (mg)	SAIB(mg)	NMP(mg)	Peptide content (%)
					OCT-Ac/SAIB/NMP	62.9	745.6	187.3	6％
OCT-SDS/SAIB/NMP	61.4	467.3	130.8	6％

Despite the higher concentration of SAIB used (80% vs. 70% in example 7), phase separation occurred even faster than observed in example 7 when OCT-Ac was combined with the SAIB/NMP solution. Considerable aggregates were formed at the bottom of the formulation (fig. 1 (a)). This heterogeneous formulation is clearly not suitable for injection to form a uniform depot system in situ for controlled release. When OCT-SDS and SAIB/NMP solutions were combined, a homogeneous milky suspension was obtained, suitable for injection. Even after 24 hours, no significant phase separation was observed in the suspension (fig. (b)), which could be easily administered by injection using a syringe.

Example 9 in vitro Release of octreotide from different formulations

Formulations were prepared by mixing octreotide acetate (OCT-Ac), octreotide dodecyl sulfate (OCT-SDS) and octreotide docusate (OCT-DSS) complex powders with a solution of SAIB in NMP (90% w/w). The content of octreotide in each formulation as shown in table 4 was about 6%.

Table 4 formulations containing octreotide

Preparation	Peptide (mg)	SAIB/NMP(mg)	Peptide content (%)
				OCT-Ac/SAIB/NMP	66.0	934.0	6％
OCT-SDS/SAIB/NMP	88.6	911.4	6％

OCT-DS S/SAIB/NMP

104.1

895.9

6％

One small suspension was used for in vitro release. Approximately 0.1ml of each formulation containing octreotide was injected into 3ml of release buffer (PBS7.4 containing 0.1% sodium azide) in a 4ml glass vial. The bottles were incubated at 37 ℃ and samples were taken at different time points. At each time point, 2ml of release medium was removed and replaced with 2ml of fresh release medium. The peptide concentration and integrity of the collected samples were analyzed by HPLC using a YMC-PackODS-120A column. Three samples were used for each formulation.

As shown in figure 2, the release of OCT from formulations containing OCT-Ac showed a high initial burst. More than 60% of octreotide is released within 24 hours and more than 90% of octreotide is released after two weeks. However, surprisingly, the release of OCT from formulations containing OCT-SDS and OCT-DSS did not show many initial burst. Formulations containing both OCT-SDS and OCT-DSS had less than 10% octreotide release over 24 hours, followed by a period of gradual release.

Example 10 in vitro Release of Leuprolide from different formulations

The formulation was prepared by mixing a powder of a complex of leuprolide acetate (LA-Ac), leuprolide dodecyl sulfate (LA-SDS), leuprolide docusate (LA-DSS) and leuprolide oleate (LA-OL) with a solution of SAIB in NMP (90% w/w). The content of leuprolide in each formulation as shown in table 5 was about 6%.

Table 5 formulations containing leuprolide

Preparation	Peptide (mg)	SAIB/NMP(mg)	Peptide content (%)
				LA-Ac/SAIB/NMP	67.1	932.9	6％
LA-SDS/SAIB/NMP	93.9	906.1	6％
				LA-DS S/SAIB/NMP	112.4	887.6	6％
LA-OL/SAIB/NMP	69.8	765.5	6％

One small suspension was used for in vitro release. Approximately 0.1ml of each leuprolide formulation was injected into 3ml of release buffer (PBS7.4, containing 0.1% sodium azide) in a 4ml glass vial. The bottles were incubated at 37 ℃ and samples were taken at different time points. At each time point, 2ml of release medium was removed and replaced with 2ml of fresh release medium. The peptide concentration and integrity of the collected samples were analyzed by HPLC using a YMC-Pack ODS120A column. Three samples were used for each formulation.

As shown in fig. 3, the release of leuprolide from formulations containing LA-Ac and LA-OL showed a high initial burst. Over 80% of leuprolide is released within 24 hours, almost all leuprolide is released after two weeks. Complexation of leuprolide with oleate yields a water-insoluble complex, but it does not reduce the initial burst and total release of leuprolide. Surprisingly, however, the initial burst of leuprolide from formulations comprising LA-SDS and LA-DSS was significantly reduced. Formulations containing both LA-SDS and LA-DSS showed less than 10% leuprolide release over 24 hours, followed by a period of progressive zero-order release.

Example 11 preparation of Doxorubicin Doku ester (DOX-DSS) and Doxorubicin Dodecylsulfate (DOX-SDS)

Sodium 1, 4-bis (2-ethylhexyl) sulfosuccinate (DSS, C)_2OH₃₇NaO₇S, MW: 444.56, 235.3mg, 0.53mmol) was dissolved in isopropanol (2ml), 200mg (0.53mmol) of doxorubicin hydrochloride (DOXHCl, C)₂₇H₂₉NO₁₁HCl, MW 579.98, > 98.0%) was dissolved in water (20 ml). The DSS solution was mixed with the doxorubicin hydrochloride solution and stirred for approximately one hour. The complex was separated by centrifugation at 3500RPM, and the obtained precipitate was freeze-dried under vacuum.

Example 12 in vitro Release of Adriamycin from different formulations

Formulations were prepared using doxorubicin hydrochloride (DOX-HCl) and doxorubicin docusate (DOX-DSS) complex powders. Formulations were prepared by mixing DOX-HCl and DOX-DSS with a solution of SAIB in NMP to obtain DOX concentrations of 6% as shown in Table 6.

TABLE 6 formulations containing doxorubicin

In vitro release studies of DOX from different formulations were performed using one small suspension. Approximately 0.1ml of each DOX formulation was injected into 3ml of release buffer (PBS7.4, containing 0.1% sodium azide) in a 4ml glass vial. The bottles were incubated at 37 ℃ and samples were taken at different time points. At each time point, 2ml of release medium was removed and replaced with 2ml of fresh release medium. The peptide concentration and integrity of the collected samples were analyzed by HPLC using a YMC-Pack ODS120A column. Three samples were used for each formulation.

As shown in fig. 7, the release of DOX from formulations containing DOX-HCl showed a high initial burst. Over 70% of the DOX was released within 24 hours. Surprisingly, however, the release of DOX from formulations comprising DOX-DSS did not show many initial burst. Less than 8% of the DOX is released from the DOX-DSS-containing formulation within 24 hours. The results show that the complex of DOX and DSS significantly reduced the initial burst of DOX by almost 10-fold. The complex is capable of delivering DOX over a sustained period of time.

TABLE 7 formulations containing doxorubicin

Example 13 preparation of a Complex of pramipexole (PPL) and SDS (PPL-SIS)

80.7mg of pramipexole (PPL, MW 302.27) were dissolved in 2ml of deionized water (0.267 mmol). 2.662ml of SDS solution (MW288.38, 57.83mg/ml) were added in a PPL SDS to SDS ratio of 1: 2 (0.534mmol) and the solution was stirred. A white precipitate formed. The pH was adjusted from 4 to 7 with NaOH. The solution was frozen and placed in a freeze-dryer overnight. A white powder was obtained.

Example 14 in vitro Release of pramipexole from SAIB formulations

Formulations containing about 6% PPL in different salt forms were prepared by mixing PPL with a solution of 90% SAIB in NMP. Roughly 100g was injected into a syringe containing 3ml of PBS buffer and 0.1% NaN₃In a glass bottle of (1). Gel-like pellets were formed and the glass vials were placed on a shaker at 37 ℃. The release of PPL was tested by removing 2ml of release medium at a specific time and replacing with 2ml of fresh buffer. The concentration of the release medium was measured by reverse phase HPLC.

TABLE 6 formulations containing doxorubicin

As shown in fig. 4, the pramipexole release of the formulation containing PPL-HCl showed a high initial burst. Over 60% of pramipexole is released within 24 hours and over 90% of octreotide is released after one week. However, surprisingly, the initial burst of pramipexole from the formulation comprising PPLL-SDS was significantly reduced. Less than 5% leuprolide release was observed over 24 hours in formulations containing PPL-SDS, followed by a period of progressive near zero-order release.

Example 15 preparation of Gentamicin docusate (GEN-DSS)

79.7mg of gentamicin sulfate (Mw477.6g/mol and 5 ionised (charged) groups) sulfate (gentamicin sulfate, MW694-723, 88.2%) were dissolved in 2ml of deionised water (0.125 mmol). 4.877mL of DSS solution (MW444.55, 57.11mg/mL) were added to obtain a ratio of 5: 1 for DSS: GEN. A white precipitate formed immediately upon addition of DSS solution. The solution was frozen and placed in a freeze-dryer overnight.

Example 16 preparation of a formulation comprising GEN-DSS

Formulations containing approximately 6% and 2% GEN-DSS of 90% SAIB in NMP were prepared. Roughly 100g was injected into a syringe containing 3ml of PBS buffer and 0.1% NaN₃In a glass bottle of (1). Gel-like pellets formed at room temperature. However, after 37 ℃ in the glass vial, the pellets began to break down and fall apart in a few hours.

Example 17 preparation of Lysozyme docusate (LYZ-DSS)

50.5mg of lysozyme (MW 18,000) were dissolved in 1ml of deionized water (0.0028 mmol). 148.2ul of DSS solution (MW444.55, 58.86mg/ml) was added to obtain a ratio of DSS: LYZ of 7: 1. A white precipitate formed immediately upon addition of DSS solution. The solution was frozen and placed in a freeze-dryer overnight.

Example 18 preparation of a formulation comprising Lysozyme docusate (LYZ-DSS)

A preparation of 90% SAIB in NMP containing about 6% LYZ and LYZ-DSS (85.2% LYZ) was prepared. Roughly 100g was injected into a syringe containing 3ml of PBS buffer and 0.1% NaN₃In a glass bottle of (1). The gel-like beads formed at room temperature were placed on a shaker at 37 deg.C and one day later the beads containing LYZ were separated from the beads having a white opaque central surrounding clear layer. The pellets containing LYZ-DSS remained in one phase as uniform white pellets. An improved reservoir system of a complex of lysozyme and amphiphilic molecule DSS was obtained.

EXAMPLE 19 preparation of naltrexone docusate (NT-DSS)

Sodium 1, 4-bis (2-ethylhexyl) sulfosuccinate (DSS, C)_2OH₃₇NaO₇S, MW: 444.56, 235.3mg, 0.53mmol) was dissolved in isopropanol (2ml), 200mg (0.53mmol) naltrexone hydrochloride (NT, C)₂₀H₂₃NO₄ ^■HCl, MW 377.86, > 99.0%) was dissolved in water (20 ml). The DSS solution was mixed with the naltrexone hydrochloride solution and stirred for approximately one hour. The complex was separated by centrifugation at 3500RPM, and the obtained precipitate was freeze-dried under vacuum.

The invention is not limited by the embodiments described above, which are intended to be exemplary only, but may be modified in various ways within the scope of the appended patent claims.

Thus, while there have been shown and described and pointed out fundamental novel features of the invention as applied to preferred embodiments thereof, it will be understood that various omissions and substitutions and changes in the form and details of the devices illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit of the invention. For example, it is expressly intended that all combinations of those elements and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the invention. Moreover, it should be recognized that structures and/or elements and/or method steps shown and/or described in connection with any disclosed composition or embodiment of the invention may be incorporated in any other disclosed or described or suggested composition or embodiment as a general matter of design choice. It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto.

Claims (28)

1. A slow release liquid composition of a biologically active substance comprising:

(a) a hydrophobic non-polymeric carrier material;

(b) a pharmaceutically acceptable solvent miscible with water; and

(c) an ionic complex of a biologically active substance having a net charge in water at neutral pH and an amphiphilic molecule.

2. The composition of claim 1, wherein the hydrophobic non-polymeric liquid carrier material comprises one or more non-polymeric esters or mixed esters.

3. The composition of claim 1, wherein the hydrophobic non-polymeric carrier material is a high viscosity liquid that does not crystallize under ambient or physiological conditions and has a viscosity of at least 5000cP at 37 ℃.

4. The composition of claim 2 wherein the hydrophobic non-polymeric liquid carrier material is formed from esterification of a polyol having less than 20 hydroxyl groups with a carboxylic acid.

5. The composition of claim 4, wherein the polyol is selected from the group consisting of: monofunctional and polyfunctional alcohols of 2 to 24 carbon atoms, sugar alcohols, monosaccharides, disaccharides, oligosaccharides and polyether alcohols.

6. The composition of claim 4, wherein the polyol is selected from the group consisting of: dodecanol, hexylene glycol, glycerol, mannitol, sorbitol, glucose, fructose, sucrose, inositol, polyglycerol, polyethylene glycol, and the like.

7. The composition of claim 4, wherein the carboxylic acid comprises an organic acid having more than 2 carbon atoms, such as a fatty acid.

8. The composition of claim 7 wherein the carboxylic acid may be saturated, unsaturated, aromatic (aryl and aralkyl) and linear or branched structures.

9. The composition of claim 7, wherein the carboxylic acid is selected from the group consisting of: acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, lipoic acid, hexanoic acid, heptanoic acid, oleic acid, palmitic acid, stearic acid, myristic acid, benzoic acid, glycolic acid, lactic acid, epsilon-hydroxycaproic acid, octanoic acid, decanoic acid, n-dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, arachidic acid, behenic acid and/or other fatty acids.

10. The composition of claim 1, wherein the hydrophobic non-polymeric carrier material is Sucrose Acetate Isobutyrate (SAIB).

11. The composition of claim 1, wherein the pharmaceutically acceptable solvent is at least 1% miscible in water by weight at 25 ℃.

12. The composition of claim 11, wherein the pharmaceutically acceptable solvent is selected from the group consisting of: acetone, benzyl alcohol, butylene glycol, caprolactam, caprolactone, dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, ethyl lactate, glycerol formal, glycogens (tetraethylene glycol), N-methyl-2-pyrrolidone (NMP), polyethylene glycol, methoxypolyethylene glycol, alkoxypolyethylene glycol, propylene carbonate, 2-pyrrolidone, triacetin, triethyl citrate, and combinations of the foregoing.

13. The composition of claim 1, wherein the biologically active substance is a small molecule, a macromolecule, a peptide, a protein, or an enzyme.

14. The composition of claim 1, wherein the value of the molecular weight of the biologically active substance divided by the number of ionizable groups of the biologically active substance is greater than 100 daltons.

15. The composition of claim 1, wherein the biologically active substance is selected from the group consisting of: 4-hydroxyphenylethylamine, methamphetamine, amitriptyline, reboxetine, bupropion, mirtazapine, venlafaxine, duloxetine, fluoxetine, paroxetine, escitalopram, citalopram, sertraline, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, doxorubicin, doxycycline, diltiazem (dilazazam), cyclobenzaprine, bacitracin, noscapine, erythromycin, polymyxin, vancomycin, nortriptyline, quinidine, ergotamine, benztropine, verapamil, flunarizine, imipramine, gentamycin, kanamycin, neomycin, amomcocicin, amikacin, arbacinomycin, banebicin, butricidin, dibekacin, dihydrostreptomycin, bravamycin, isepamicin, micronomicin, and nemulin, Ribostamycin (ribostamycin), rapamycin, sisomicin, streptomycin and tobramycin, pyrimethamine, naltrexone, lidocaine, prilocaine, mepivacaine, bupivacaine, tetracaine, ropivacaine and risperidone.

16. The composition of claim 1, wherein the biologically active substance is selected from the group consisting of: oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF), prolactin, luteinizing hormone (luteinizing hormone), Luteinizing Hormone Releasing Hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones (including human, porcine and bovine), growth hormone releasing factor, insulin, erythropoietin (including all proteins with erythropoietic activity), somatostatin, glucagon, interleukin, interferon-alpha, interferon-beta, interferon-gamma, gastrin, tetrapeptide gastrin, pentapeptide gastrin, urogastrin, secretin, calcitonin, enkephalin, endorphin, angiotensin, Thyrotropin Releasing Hormone (TRH), Tumor Necrosis Factor (TNF), parathyroid hormone (PTH), Nerve Growth Factor (NGF), Granulocyte colony stimulating factor (G-CSF), granulocyte macrophage stimulating factor (GM-CSF), macrophage stimulating factor (M-CSF), heparinase, vascular endothelial growth factor (VEG-F), Bone Morphogenetic Protein (BMP), human atrial natriuretic peptide (hANP), glucagon-like peptide (GLP-I), exenatide, casein (PYY), renin, bradykinin, bacitracin, polymyxin, colistin, brevibacillin, cyclosporine (including synthetic analogs and pharmaceutically active fragments thereof), enzymes, cytokines, antibodies, vaccines, antibiotics, antibodies, glycoproteins, follicle stimulating hormone, kyotoxin (kyotorphin), phagocytosis hormone (taftsin), thymopoietin, thymosin, thymic hormone (thymidysin), thymic humoral factor, serotonergic factor, colony stimulating factor, Motilin, bombesin, dynorphin (dinorphin), neurotensin, ranotin, urokinase, kallikrein, peptide substance analogs and antagonists, angiotensin II, blood coagulation factors VII and IX, lysozyme, gramicidines, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, enterotryptin, cholecystokinin, human placental prolactin, human chorionic gonadotropin, protein synthesis promoting factors, gastrin, vasoactive intestinal peptide, platelet derived growth factor, and synthetic analogs and modifications and pharmaceutically active fragments thereof.

17. The composition of claim 1, wherein the hydrophilic portion of the amphiphilic molecule is ionic.

18. The composition of claim 1, wherein the amphiphilic molecule is selected from the group consisting of: sulfates, sulfonates, or sulfosuccinates as well as the ionic forms and dissociation products described above.

19. The composition of claim 1, wherein the amphiphilic molecule is selected from the group consisting of: dialkyl succinate derivatives having 3 to 16 carbon atoms, dioctyl succinate, benzenesulfonic acid, camphorsulfonic acid, (+) - (1S) -camphene-10-sulfonic acid, dodecylsulfuric acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, p-toluenesulfonic acid, cholesterol sulfate, heptanesulfonic acid, or salts or ionic (dissociated) forms of the above.

20. The composition of claim 1, wherein the composition further comprises an additive.

21. The composition of claim 20, wherein the additive is selected from the group consisting of: polylactic acid, polyglycolide, polycaprolactone, polyanhydrides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyoxaesters, polyorthocarbonates, polyphosphazenes, succinates, polymalicates, polyaminoacids, polyvinylpyrrolidone, polyethylene glycol, polyoxycelluloses, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers, and mixtures thereof.

22. The composition of claim 20, wherein the additive is selected from the group consisting of: cysteine or methionine, d-alpha tocopherol acetate, racemic alpha tocopherol, ascorbyl palmitate, butylhydroxyanisole (butylated hydroxyanisole), tert-butylhydroxyanisole (butylated hydroxyanisole), butylated hydroxyanisole (butylated hydroxyanisole), hydroxycoumarin (hydroxycoumarin), butylhydroxytoluene, cephalin (cephalin), ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate (propylhydroxybenzoate), trihydroxybutyrophenone (trihydroxybenzophenone), dimethylphenol, di-tert-butylphenol (ditertbutylphenol), vitamin E and lecithin.

23. A sustained release composition of a biologically active substance comprising:

(a) sucrose acetate isobutyrate;

(b) a pharmaceutically acceptable solvent miscible with water; and

(c) an ionic complex of a biologically active substance having a net charge in water at neutral pH and an amphiphilic molecule.

24. The composition of claim 23, wherein the pharmaceutically acceptable solvent is selected from the group consisting of: benzyl alcohol, dimethyl sulfoxide (DMSO), ethanol, ethyl lactate, glycerol formal, glycogens (tetraethylene glycol), N-methyl-2-pyrrolidone (NMP), polyethylene glycol, methoxypolyethylene glycol, alkoxypolyethylene glycol, triacetin, triethyl citrate, or combinations thereof.

25. The composition of claim 23, wherein the biologically active substance is selected from the group consisting of: doxorubicin, pramipexole, octreotide, leuprolide, or glucagon-like peptide-1 (GLP-1).

26. The composition of claim 23, wherein the amphiphilic molecule is selected from the group consisting of: dioctyl succinate or dodecyl sulphate.

27. The composition of claim 23, wherein the ratio of sucrose acetate isobutyrate to solvent is from 50: 50 to 95: 5.

28. The composition of claim 23, wherein the ratio of sucrose acetate isobutyrate to solvent is from 70: 30 to 90: 10.