Compositions of small molecule therapeutic compounds

Abstract

The present application relates to compositions of small molecule therapeutic compounds. Described are compositions comprising an aqueous suspension of a small molecule therapeutic agent and an organic acid. The small molecule therapeutic agent is a base and has a water solubility at room temperature of less than about 1.0 g / L. The organic acid has a water solubility at room temperature of between 0.1 and 10 g / L, a molar mass of less than 500 g / mol, and / or maintains the pH of the suspension between 3 and 6.5 in its environment of use. The organic acid enhances the solubility of the small molecule therapeutic agent, and when present in stoichiometric excess, the organic acid drives the release of the small molecule therapeutic agent into the buffered environment of use for an extended period of time such as six months to a year. Also described are devices and methods of treatment comprising the described compositions.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780065098.0, filed on September 22, 2017, entitled “Composition of Small Molecule Therapeutic Compounds”.

[0002] Cross-references to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 399,083, filed September 23, 2016, which is incorporated herein by reference. Technical Field

[0004] The subject matter described herein relates to compositions and formulations of small molecule therapeutic agents, and to drug delivery devices comprising said compositions and formulations for the controlled and continuous delivery of small molecule therapeutic agents. Background Technology

[0005] Important classes of small molecule drugs exhibit poor water solubility at neutral pH. While this property can be advantageous for oral absorption and tissue penetration, it complicates the development of continuous delivery systems that rely on passive diffusion as the primary drug release mechanism; for example, low solubility cannot generate a concentration gradient sufficient to drive adequate outflow from a reservoir containing an aqueous suspension of the drug. Many insoluble drugs are weak organic bases (i.e., molecules comprising at least one functional group, such as primary, secondary, or tertiary amines, aniline, or amidine), and their water solubility improves upon protonation, i.e., when they are converted into salts. However, such salts are unstable at pH values ​​close to or above the pKa of the protonated drug and are readily hydrolyzed. This process complicates diffusion-mediated drug delivery via implants or reservoirs, as the outflow of the drug from the formulation must be combined with a constant inflow of buffering material from physiological fluids. Compositions and devices that address these and other complexities involving the continuous and controlled delivery of small molecule therapeutic agents as weak organic bases are needed. Summary of the Invention

[0006] The following aspects and embodiments described and illustrated are intended to be exemplary and illustrative, and are not intended to limit the scope.

[0007] On one hand, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a combination of a small molecule therapeutic agent and a stoichiometric excess of an organic acid, wherein the small molecule therapeutic agent: (i) has a water solubility of less than about 1 g / L at room temperature and (ii) is a weak base (i.e., a conjugate acid having a pKa between 6 and 9); and the organic acid: (i) has a water solubility of less than about 20 g / L at room temperature and (ii) maintains the pH of the suspension, which is between 3 and 6.5, at a time of at least about 30 days in its use environment.

[0008] On the other hand, compositions comprising an aqueous suspension are provided. The aqueous suspension comprises a combination of a small molecule therapeutic agent and a stoichiometric excess of an organic acid, wherein the small molecule therapeutic agent: (i) has a water solubility of less than about 1 g / L at room temperature and (ii) is a weak base (i.e., a conjugate acid having a pKa between 5 and 9); the organic acid: (i) has a water solubility between 0.1 and 10 g / L at room temperature; (ii) has a molecular weight of less than 500 g / mol; and (iii) maintains the pH of the suspension, which is between 3 and 6.5, at a time of at least about 30 days in its use environment.

[0009] On the other hand, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a combination of a small molecule therapeutic agent and a stoichiometric excess of an organic acid, wherein the small molecule therapeutic agent: (i) has a water solubility of less than about 1 g / L at room temperature and (ii) becomes more soluble upon protonation; and the organic acid: (i) has a water solubility of less than about 20 g / L at room temperature and (ii) maintains the pH of the suspension, which has a pKa equal to or lower than that of the protonated drug, at a time of at least about 30 days in its use environment.

[0010] On the other hand, compositions comprising an aqueous suspension are provided. The aqueous suspension comprises a combination of a small molecule therapeutic agent and a stoichiometric excess of an organic acid, wherein the small molecule therapeutic agent: (i) has a water solubility of less than about 1 g / L at room temperature and (ii) becomes more soluble upon protonation; and the organic acid: (i) has a water solubility between 0.1 and 10 g / L at room temperature, (ii) has a molecular weight of less than 500 g / mol, and (iii) maintains the pH of the suspension, which has a pKa equal to or lower than that of the protonated drug, at a time period of at least about 30 days in its use environment.

[0011] In one embodiment, the aqueous suspension is a heterogeneous mixture comprising a small molecule therapeutic agent and an organic acid, wherein the organic acid is sufficiently dissolved to maintain the pH of the heterogeneous solution at a value equal to or less than physiological pH (~7.4) in its use environment for a specified period of time. In one embodiment, the use environment is in vivo. In another embodiment, the use environment is in vitro in a release medium maintained at 37°C.

[0012] In one embodiment, the organic acid is present in an amount approximately equal to or higher than its saturation concentration at the end of the time period.

[0013] In another embodiment, the organic acid is present in a stoichiometric (molar) amount ranging from about 105% to 1000%, but up to 10,000%, relative to the therapeutic agent. In other embodiments, the organic acid is present in molar amounts exceeding the therapeutic agent in the composition by 110%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500%.

[0014] In another embodiment, the organic acid is crystalline and has a melting temperature greater than about 37°C.

[0015] In yet another implementation, the small molecule therapeutic agent is an antipsychotic drug.

[0016] In other implementation schemes, the antipsychotic drug is risperidone, olanzapine, palapirone, aripiprazole, brexpiprazole, or asenapine.

[0017] In one embodiment, the aqueous suspension comprises an organic acid suspended in an aqueous solution such as an aqueous buffer solution, or is made from said organic acid.

[0018] In another embodiment, the aqueous suspension comprises, or is made from, a pre-formed salt formed between the therapeutic agent and the organic acid, wherein the acid is present in stoichiometric (molar) excess.

[0019] In another embodiment, the therapeutic agent and a stoichiometric (molar) excess of the organic acid are thoroughly mixed by dissolving in a polar organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, and then the intermediate solution is concentrated to dryness.

[0020] In one embodiment, the organic acid is an aromatic carboxylic acid. In one embodiment, exemplary acids are those having a carboxylic acid group bonded to an unsubstituted benzene ring or pyridine ring. In one embodiment, the carboxylic acid is selected from the group consisting of benzoic acid, pyridinecarboxylic acid, nicotinic acid, and isonicotinic acid.

[0021] In another embodiment, the carboxylic acid is a carboxylic acid having a benzene ring and an electron-donating group. In another embodiment, the carboxylic acid has antioxidant properties.

[0022] In another embodiment, the carboxylic acid is selected from the group consisting of o-anisic acid, m-anisic acid, p-anisic acid, p-aminobenzoic acid (PABA), o-aminobenzoic acid (anthranilic acid), o-methylbenzoic acid, m-methylbenzoic acid, p-methylbenzoic acid and salicylic acid.

[0023] In another embodiment, the carboxylic acid is a carboxylic acid having a benzene ring and two electron-donating groups. In another embodiment, the carboxylic acid has antioxidant properties. In one embodiment, and by way of example, the carboxylic acid is vanillic acid.

[0024] In yet another embodiment, the carboxylic acid is a carboxylic acid having at least two carboxylic acid groups bonded to a benzene ring. In one embodiment, and by way of example, the carboxylic acid is phthalic acid.

[0025] In yet another embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid group bonded to a naphthalene ring or a quinoline ring. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of 1-naphthoic acid, 2-naphthoic acid, quinaldinic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid, and 8-quinolinecarboxylic acid.

[0026] In another embodiment, the carboxylic acid comprises an aromatic ring having an electron-donating group selected from the group consisting of hydroxyl, methoxy, amino, alkylamino, dialkylamino, and alkyl groups. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of 6-hydroxy-2-naphthoic acid, 6-hydroxy-3-naphthoic acid, 8-hydroxy-2-quinolinecarboxylic acid, and 8-hydroxy-7-quinolinecarboxylic acid.

[0027] In yet another embodiment, the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly bonded to the biphenyl ring system. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid, and biphenylcarboxylic acid.

[0028] In yet another embodiment, the carboxylic acid is a carboxylic acid having an additional electron-donating substituent besides the hydroxyl group on the carboxylic acid moiety. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of 4'-hydroxy-4-biphenylcarboxylic acid, 4'-hydroxy-2-biphenylcarboxylic acid, 4'-methyl-4-biphenylcarboxylic acid, 4'-methyl-2-biphenylcarboxylic acid, 4'-methoxy-4-biphenylcarboxylic acid, and 4'-methoxy-2-biphenylcarboxylic acid.

[0029] In yet another embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid functional group separated from a benzene ring, pyridine ring, naphthalene ring, or quinoline ring by a chain of 1-4 saturated carbon atoms. In one embodiment, and by way of example, the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.

[0030] In another embodiment, the carboxylic acid is an aliphatic dicarboxylic acid having a carbon chain of 4-8 carbons separating carboxylic acid groups. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of adipic acid ((CH2)4(COOH)2), pimelic acid (HO2C(CH2)5CO2H), octanoic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H), and sebacic acid (HO2C(CH2)8CO2H).

[0031] In another embodiment, the carboxylic acid is an unsaturated dicarboxylic acid or a polyunsaturated dicarboxylic acid containing 4-10 carbons. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of fumaric acid, trans-, trans-mucoconic acid, cis-, trans-mucoconic acid, and cis-, cis-mucoconic acid.

[0032] In other embodiments, the carboxylic acid is cis-cinnamic acid or trans-cinnamic acid. In still other embodiments, the carboxylic acid is trans-cinnamic acid having one or two electron-donating groups selected from hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl. In still other embodiments, the trans-cinnamic acid is selected from the group consisting of o-coumaric acid, m-coumaric acid, p-coumaric acid, o-methylcinnamic acid, m-methylcinnamic acid, p-methylcinnamic acid, o-methoxycinnamic acid, m-methoxycinnamic acid, p-methoxycinnamic acid, and ferulic acid.

[0033] In one embodiment, the organic acid is a phenol or naphthol substituted with about 2-5 electron-withdrawing groups selected from F, Cl, Br, I, CN, and NO2. In one embodiment, and by way of example, the organic acid is pentafluorophenol or 2,4-dinitrophenol.

[0034] In another embodiment, the organic acid is a 1,3-dicarbonyl compound containing an acidic CH bond (pKa < 8). In one embodiment, and by way of example, the organic acid is 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), cyanuric acid, or barbituric acid.

[0035] In another embodiment, the organic acid is an imide. In one embodiment, and by way of example, the imide is a phthalimide or a substituted phthalimide. In another embodiment, the substituted phthalimide has at least one electron-withdrawing substituent.

[0036] In yet another embodiment, the organic acid is an isohydroxamic acid. In one embodiment, and by way of example, the isohydroxamic acid is an aromatic isohydroxamic acid comprising an isohydroxamic acid functional group directly bonded to an aromatic ring. In one embodiment, the aromatic ring is selected from the group consisting of a benzene ring, a pyridine ring, a naphthyl ring, a quinolone ring, and a biphenyl ring. In still another embodiment, the isohydroxamic acid is a phenoxyxamic acid. In yet another embodiment, the isohydroxamic acid comprises 1-4 sp... 3 -Isohydroxamic acids are hydroxamic acids with a chain of hybridized carbon atoms separated from an aromatic ring by an isohydroxamic acid functional group.

[0037] In yet another embodiment, the aromatic ring is selected from the group consisting of benzene ring, pyridine ring, naphthalene ring, quinoline ring, and biphenyl ring.

[0038] In yet another embodiment, the isohydroxamic acid is a diisohydroxamic acid containing two or more isohydroxamic acid functional groups that are directly bonded to a benzene ring, pyridine ring, naphthalene ring, quinoline ring, or biphenyl ring system.

[0039] In other embodiments, the hydroxamic acid comprises an aromatic ring having an electron-donating substituent selected from hydroxyl, methoxy, amino, alkylamino, dialkylamino, and alkyl groups.

[0040] In other embodiments, the hydroxamic acid is an aliphatic dihydroxamic acid containing 6-10 carbon atoms.

[0041] In one embodiment, the isohydroxamic acid is suberohydroxamic acid.

[0042] In other embodiments, the hydroxamic acid is an unsaturated dihydroxamic acid containing 6-10 carbon atoms.

[0043] In another embodiment, the aromatic carboxylic acid is selected from the group consisting of 3-phenylpropionic acid, cinnamic acid, hydroxy derivatives of cinnamic acid, methoxy derivatives of cinnamic acid, nicotinic acid, benzoic acid, amino derivatives of benzoic acid, methoxy derivatives of benzoic acid, and phthalic acid.

[0044] In yet another embodiment, the hydroxy derivative of cinnamic acid is mesocoumaric acid or p-coumaric acid.

[0045] In other embodiments, p-coumaric acid is trans-p-coumaric acid.

[0046] In other embodiments, the methoxy derivative of cinnamic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

[0047] In other embodiments, the amino derivative of benzoic acid is o-amino-benzoic acid (anthranilic acid) or 4-aminobenzoic acid (p-aminobenzoic acid; PABA).

[0048] In another embodiment, the methoxy derivative of benzoic acid is 4-methoxybenzoic acid (p-anesic acid), o-anesic acid, or m-anesic acid.

[0049] In one embodiment, the composition is in a dry form. In another embodiment, the composition is in a dry form and is hydrated in situ when used in its environment.

[0050] On the other hand, a device comprising the composition as described herein is provided. This device is configured for subcutaneous implantation in mammals.

[0051] On the other hand, an implantable device is provided. This device includes a reservoir containing a formulation comprising (i) a quantity of the small molecule therapeutic agent to provide approximately zero-order release of the small molecule therapeutic agent over a delivery period of at least about 30 days and at a rate providing a therapeutic effect, and (ii) an organic acid that: (a) maintains the pH of the formulation, when hydrated between 3.0 and 6.5, in its use environment during the delivery period; (b) is present in stoichiometric (molar) excess relative to the therapeutic agent; and (c) is present at the end of the delivery period in an amount approximately equal to or greater than its saturation concentration in the hydrated formulation.

[0052] On the other hand, an implantable device is provided. This device includes a reservoir containing a formulation comprising (i) a quantity of the small molecule therapeutic agent to provide approximately zero-order release of the small molecule therapeutic agent over a delivery period of at least about 30 days and at a rate providing a therapeutic effect, and (ii) an organic acid that: (a) maintains the pH of the hydrated formulation at a level equal to or less than the pKa of the protonated drug in its use environment during the delivery period; (b) is present in stoichiometric (molar) excess relative to the therapeutic agent; and (c) is present at the end of the delivery period in an amount approximately equal to or greater than its saturation concentration in the hydrated formulation.

[0053] In one embodiment, the formulation is in a dry form. In various embodiments, and by way of example, the formulation is a powder, tablet, or film; or a mixture of two or more powders, tablets, or films.

[0054] In another embodiment, the formulation is hydrated in the presence of an aqueous solution to form an aqueous suspension. In one embodiment, the aqueous solution is an in vivo fluid.

[0055] In another embodiment, the small molecule therapeutic agent is released from the device at a rate that provides a therapeutic effect over a period of time.

[0056] In yet another embodiment, the organic acid has a water solubility of less than about 20 g / L at room temperature. In yet another embodiment, the organic acid has a water solubility between 0.1 and 10 g / L at room temperature and a molar mass of less than 500 g / mol.

[0057] In another embodiment, the organic acid has a water solubility of less than about 20 g / L at room temperature and a pKa between 3 and 6. In yet another embodiment, the organic acid has a water solubility of between 0.1 and 10 g / L at room temperature and a molar mass of less than 500 g / mol, and a pKa between 3 and 6.

[0058] In another embodiment, two or more organic acids, each with a water solubility of 0.1 to 10 g / L, a molar mass of less than 500 g / mol, and a pKa between 3 and 6, are used in combination.

[0059] In yet another embodiment, the organic acid has a melting temperature greater than about 37°C.

[0060] On the other hand, methods for the continuous and controlled delivery of small molecule therapeutic agents are provided. These methods include providing a composition or device as described herein. In some embodiments, the method further includes, for example, administering the device via subcutaneous implantation.

[0061] On the other hand, a method for the continuous, controlled delivery of antipsychotic drugs is provided, wherein the method includes providing a composition or device as described herein. In some embodiments, the method further includes, for example, administering the device via subcutaneous implantation.

[0062] On the other hand, methods for providing maintenance therapy for schizophrenia or bipolar disorder include providing a composition or device as described herein. In some embodiments, the method further includes, for example, administering the device via subcutaneous implantation.

[0063] In addition to the exemplary aspects and embodiments described above, other aspects and embodiments will become apparent from the accompanying drawings and from the following description.

[0064] Other embodiments of the method, apparatus, and composition will become apparent from the following description, drawings, examples, and claims. As will be understood from the foregoing and hereinafter, each feature described herein, and each combination of two or more such features, is included within the scope of this disclosure, provided that the features included in such combinations do not contradict each other. Furthermore, any feature or combination of features may be specifically excluded from any embodiment of the invention. Other aspects and advantages of the invention are set forth in the following description and claims, particularly when considered in conjunction with the appended embodiments and drawings. Attached Figure Description

[0065] Figure 1A-1B For assembly form ( Figure 1A ) and unassembled form ( Figure 1B (Illustration of a drug delivery device.)

[0066] Figure 1C-1F A portion of the first exemplary drug delivery device is shown in cross-section in assembly form. Figure 1C ) and exploded diagram ( Figure 1D ), and isometric views during assembly ( Figure 1E This shows the end cap subassembly. Figure 1F Only an exploded view of the lid assembly is shown. The numbered elements of the sub-assemblies are 1=lid, 2=porous membrane, 3=seal, 4=retaining ring, and 5=drug device reservoir.

[0067] Figure 1G-1K A portion of a second exemplary drug delivery device is shown in a cross-section in assembly form. Figure 1G ) and exploded diagram ( Figure 1H ), and isometric views during assembly ( Figure 1I The end cap assembly is shown. Figure 1J-1K Only the assembly and exploded view of the lid assembly are shown. The numbered elements of the sub-assemblies are 1=lid, 2=porous membrane, 3=seal, 4=drug delivery device reservoir, and 5=retaining ring.

[0068] Figure 2 The cumulative release (in mg) of risperidone from a drug delivery device comprising a heterogeneous aqueous formulation containing risperidone and 4-aminobenzoic acid (PABA) as a function of time (in days) is shown, where the risperidone / PABA molar ratio is 1:1 (rhombus); 1:1.5 (square); 1:2 (solid circle); and 1:2 (hollow circle) in the case of a 50% reduction in membrane surface area.

[0069] Figure 3AThe cumulative release (in mg) of olanzapine from a drug delivery device as a function of time (in days) is shown in the device reservoir of the drug delivery device, which comprises a heterogeneous aqueous formulation containing olanzapine and 4-aminobenzoic acid (PABA, square) or p-methylbenzoic acid (rhomboid) in a molar ratio of olanzapine / organic acid of 1:1.5, or without acid as a control (circle).

[0070] Figure 3B The cumulative release (in mg) of olanzapine from a drug delivery device as a function of time (in days) is shown in the device reservoir of the drug delivery device, which comprises a heterogeneous aqueous formulation containing olanzapine and 4-aminobenzoic acid (PABA, *) or p-methylbenzoic acid (triangular) in a molar ratio of olanzapine / organic acid of 2:1, or without acid as a control (square).

[0071] Figure 4 The plasma concentration (in ng / mL) of risperidone from a subcutaneously implanted drug delivery device containing an aqueous formulation of risperidone and 4-aminobenzoic acid (PABA, round) or sebacic acid (rhomboid) in a device reservoir is shown as a function of time (in days).

[0072] Figure 5 A graph showing the cumulative in vitro release (expressed as a percentage of total risperidone released into the receiving medium) for various risperidone salts (PABA, square; terephthalate, rhombus; sebacic acid, hollow rhombus; vanillate, triangular; hippurate, x symbol; hydroxyphenylpropionate, hollow circle; urate, solid circle).

[0073] Figure 6 In Example 5 ( Figure 5 The graph shows the percentage of risperidone released on day 15 as a function of the water solubility (in mg / mL) of the organic acids used in the composition, wherein the organic acids are terephthalic acid, uric acid, sebacic acid, vanillic acid, hydroxyphenylpropionic acid, hippuric acid, and PABA.

[0074] Figure 7 In Example 5 ( Figure 5 The graph shows the percentage of risperidone released on day 15 as a function of the pH of the organic acid used in the composition, which is terephthalic acid, uric acid, sebacic acid, vanillic acid, hydroxyphenylpropionic acid, hippuric acid, and PABA, and the pH is the pH of the aqueous solution at saturation concentration. Detailed Implementation

[0075] I. definition

[0076] The various aspects will now be described more fully below. However, such aspects can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; moreover, providing these embodiments makes this disclosure comprehensive and complete, and fully conveys its scope to those skilled in the art.

[0077] Where a range of values ​​is provided, all intermediate values ​​between the upper and lower limits of that range, as well as any other stated or intermediate values ​​within the range, are intended to be included in this disclosure. For example, if a range of 1 mg to 8 mg is specified, it is intended to also explicitly disclose values ​​for 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg, as well as values ​​for ranges greater than or equal to 1 mg and values ​​for ranges less than or equal to 8 mg.

[0078] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Thus, for example, references to “polymer” include a single polymer as well as two or more identical or different polymers, and references to “excipient” include a single excipient as well as two or more identical or different excipients, etc.

[0079] The word “about” immediately preceding a numerical value refers to a range of plus or minus 10% of that value. For example, “about 50” refers to 45 to 55, and “about 25,000” refers to 22,500 to 27,500, etc., unless the context of this disclosure provides otherwise or is inconsistent with such interpretation. For example, in a list of numerical values ​​such as “about 49,” “about 50,” and “about 55,” “about 50” refers to a range extending to less than half the interval between the preceding and following values, for example, greater than 49.5 to less than 52.5. Furthermore, given the definition of the term “about” provided herein, the phrase “less than about” or “greater than about” should be understood.

[0080] The compositions disclosed herein may include, consist substantially of, or consist of the disclosed components.

[0081] Unless otherwise stated, all percentages, parts and proportions are based on the total weight of the composition, and all measurements were performed at about 25°C.

[0082] The phrase "pharmaceutically acceptable" in this document refers to compounds, salts, compositions, dosage forms, etc., that are suitable for use in contact with human and / or other mammalian tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and in accordance with a reasonable benefit / risk ratio. In some respects, "pharmaceutically acceptable" means approved by a federal or state regulatory agency, or listed in the United States Pharmacopeia (USP) or other recognized pharmacopoeias for use in mammals (e.g., animals) and, more specifically, for use in humans.

[0083] The term "treatment" is used herein to refer to a method of administration of a small molecule that reduces the frequency of or delays the onset of symptoms of a subject's medical condition (e.g., schizophrenia, bipolar disorder) relative to a subject who has not received the compound or composition. This may include reversing, reducing, or preventing symptoms, clinical signs, and underlying pathology of the condition in a manner that improves or stabilizes the subject's condition (e.g., controls schizophrenia symptoms).

[0084] By reserving the right to limit or exclude any individual member of any such group, one may, by means of the scope, claim to include any sub-scope or combination of sub-scopes within the group, or, in any similar manner, claim a measure less than the full scope of this disclosure for any reason. Furthermore, by reserving the right to limit or exclude any individual substitute, analogue, compound, ligand, structure, or group thereof, or any member of the claimed group, one may, for any reason, claim a measure less than the full scope of this disclosure.

[0085] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety to provide a more comprehensive description of prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0086] For convenience, certain terms used in the specification, embodiments, and claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0087] II. Formulations used to enhance the solubility of small molecule therapeutic agents

[0088] On one hand, compositions or formulations are provided in which a small molecule therapeutic agent is dissolved by the use of a partially soluble organic acid to improve the delivery of the therapeutic agent from a device or drug delivery platform over a sustained period of time. In one embodiment, the composition is an aqueous suspension or slurry. In another embodiment, the composition is a heterogeneous or inhomogeneous mixture or solution. In some embodiments, the solution or mixture may be an aqueous mixture or an aqueous heterogeneous mixture. In another embodiment, the composition is in a dried form (e.g., lyophilized, spray-dried, dehydrated, etc.). In these various embodiments, the composition comprises a small molecule therapeutic agent that can be used as a Brønsted or Lewis base and an organic acid having one or more of the following: (i) a water solubility of less than about 20 g / L at room temperature (e.g., about 25°C) or between about 0.1 and 10 g / L; (ii) a molar mass of less than 500 g / mol; (iii) a stoichiometric (molar) excess relative to the therapeutic agent; and (iv) a suspension (or solution) having a pKa of about equal to or less than that of the protonated therapeutic agent maintained at a pH of at least about 30 days in its use environment. The composition may additionally comprise an aqueous fluid, such as water, a buffer, or a water-solvent mixture. In embodiments where the composition is in dry form, the aqueous fluid hydrates the composition in situ in its use environment.

[0089] As described above, the formulations described herein provide solubility for small molecule therapeutic agents to enable delivery over a sustained period of time. In one embodiment, the sustained period of time refers to a period of at least about two weeks to about six months. In another embodiment, the sustained period of time refers to a period of at least about two weeks, or at least about three weeks, or at least about four weeks to about six months, or about four months, or about three months. In another embodiment, the sustained period of time refers to a period of at least about 15 days, or at least about 21 days, or at least about 30 days, or at least about 45 days, or at least about 60 days. In yet another embodiment, the sustained period of time refers to a period of at least about six months, or nine months, or twelve months.

[0090] As also described above, the formulations described herein partially enhance the solubility of small molecule therapeutic agents by maintaining the formulation within a specific pH range in its environment of use for a predetermined period of time. In one embodiment, the environment of use is in vivo. For example, the formulation may be part of a drug delivery device implanted in the body, and several examples of such devices are provided below. In another embodiment, the environment of use is in vitro in a release medium maintained at approximately 37°C.

[0091] The components of the composition are now described, namely the small molecule therapeutic agent and the organic acid.

[0092] A. Small molecule therapeutic agents

[0093] In one embodiment, the composition comprises a small molecule therapeutic agent that is (i) has a water solubility of less than 1.0 g / L at room temperature and (ii) is an organic base. In one embodiment, "small molecule" refers to a bioactive molecule with a molecular weight of less than or equal to 2,000 Daltons, and is generally used in the context of a small molecule drug (therapeutic agent) as distinct from protein, polypeptide, or peptide therapeutic agents. In another embodiment, the small molecule has a molecular weight of less than or equal to 1,000 Daltons or less than or equal to 500 Daltons. In other embodiments, the small molecule has a molecular weight between 10 and 2000 Daltons, between 10 and 1000 Daltons, between 10 and 500 Daltons, between 50 and 2000 Daltons, between 50 and 1000 Daltons, between 50 and 500 Daltons, between 100 and 2000 Daltons, between 100 and 1000 Daltons, or between 100 and 500 Daltons.

[0094] The anticipated small molecule therapeutic agents include, but are not limited to, agents that are weak organic bases (i.e., conjugate acids with pKa between 6 and 9 or between 5 and 9), and potency that allows a 30-60 day dose to be contained in a delivery device implanted in the human body.

[0095] By way of example, therapeutic agents comprising primary, secondary, or tertiary amines, aniline or aniline derivatives, or amidine functional groups are envisioned as small molecule therapeutic agents that are organic bases. It will be understood that therapeutic agents having structures containing more than one of these functional groups are envisioned. Examples of aniline derivatives include analogs of aniline in which the phenyl group is substituted, for example, with a methyl group (toluidine), substituted with a halogen such as chlorine (2-chloroaniline, 3-chloroaniline, 4-chloroaniline), substituted with an amino group (4-aminobenzoic acid, or 2-aminobenzoic acid, or 3-aminobenzoic acid), substituted with a nitro group (e.g., 2-nitroaniline, 3-nitroaniline, or 4-nitroaniline), and many other analogs.

[0096] In one embodiment, the small molecule therapeutic agent is an antipsychotic drug, including atypical antipsychotic drugs. In another embodiment, the small molecule therapeutic agent has activity for treating diseases of the central nervous system. Exemplary agents include, but are not limited to, risperidone, olanzapine, asenapine, aripiprazole, or epipiprazole.

[0097] In one embodiment, the small molecule drug i) has poor water solubility at physiological pH (~7.4) and ii) is used as a Brønsted or Lewis base. As described below, a suspension or slurry is produced in the presence of an aqueous fluid and a stoichiometric excess of an organic acid, wherein the organic acid i) has a solubility in water between 0.1 and 10 g / L or less than or equal to 20 g / L at 25°C, and ii) is at least partially soluble in the presence of the drug and a physiological buffer solution.

[0098] B. Organic acids

[0099] In addition to the small molecule therapeutic agent, the composition also includes an organic acid or a combination of organic acids. The organic acid is an organic acid having one or more of the following characteristics: (i) a water solubility at room temperature between 0.1 and 10 g / L or less than about 20 g / L; (ii) a molar mass less than 500 g / mol; (iii) a stoichiometric excess relative to the therapeutic agent; and (iv) maintaining the pH of a suspension or solution of about equal to or less than the pKa of the protonated small molecule therapeutic agent at a time of at least about 30 days in its use environment. As described above, the composition enhances the solubility of the small molecule therapeutic agent, enabling its use in a sustained-release drug delivery platform over an extended period. The excess acid (stoichiometric relative to the therapeutic agent) traps physiological buffers that would otherwise drive the hydrolysis of the pharmacologically active salt. Examples of organic acids used in the composition are now described.

[0100] In a first embodiment, the organic acid is a carboxylic acid. Examples include aromatic carboxylic acids in which the carboxylic acid group is directly bonded to an aromatic ring. For example, an aromatic carboxylic acid may have a carboxylic acid group bonded to an unsubstituted benzene ring or pyridine ring. Examples include benzoic acid, pyridinecarboxylic acid, nicotinic acid, or isonicotinic acid. In another example, the aromatic carboxylic acid is a carboxylic acid having a benzene ring and an electron-donating group with antioxidant properties. Specific examples include o-anisic acid, m-anisic acid, p-anisic acid, p-aminobenzoic acid (PABA), o-aminobenzoic acid (anthranilic acid), o-methylbenzoic acid, m-methylbenzoic acid, p-methylbenzoic acid, and salicylic acid.

[0101] In yet another example, an aromatic carboxylic acid is a carboxylic acid having a single benzene ring and two electron-donating groups with antioxidant properties. A specific example is vanillic acid. In still another example, an aromatic carboxylic acid is a carboxylic acid having two or more carboxylic acid groups bonded to a benzene ring. A specific example is phthalic acid.

[0102] In another example, an aromatic carboxylic acid is a carboxylic acid having a carboxylic acid group bonded to a naphthyl or quinoline ring. Examples include 1-naphthoic acid, 2-naphthoic acid, quinaldinic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid, and 8-quinolinecarboxylic acid. Another group of acids of this type having a carboxylic acid group bonded to a naphthyl or quinoline ring includes those containing additional electron-donating groups such as hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl groups. Examples of acids in this group include 6-hydroxy-2-naphthoic acid, 6-hydroxy-3-naphthoic acid, 8-hydroxy-2-quinolinecarboxylic acid, 8-hydroxy-7-quinolinecarboxylic acid, and their respective isomers.

[0103] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid group bonded to a naphthalene ring or a quinoline ring and an electron-donating substituent other than the hydroxyl group on the carboxylic acid moiety. Examples include 4'-hydroxy-4-biphenylcarboxylic acid, 4'-hydroxy-2-biphenylcarboxylic acid, 4'-methyl-4-biphenylcarboxylic acid, 4'-methyl-2-biphenylcarboxylic acid, 4'-methoxy-4-biphenylcarboxylic acid, and 4'-methoxy-2-biphenylcarboxylic acid.

[0104] In another exemplary embodiment, the acid is a dicarboxylic acid or a tricarboxylic acid having two or three carboxylic acid groups bonded to a naphthalene ring or a quinoline ring. Examples include 1,4-naphthalenedicarboxylic acid and 2,6-naphthalenedicarboxylic acid.

[0105] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly bonded to the biphenyl ring system. Examples include 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid, and biphenylcarboxylic acid.

[0106] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid functional group separated from a benzene ring, pyridine ring, naphthalene ring, or quinoline ring by a chain of 1-4 saturated carbon atoms. Examples of acids in this embodiment include phenylacetic acid and 3-phenylpropionic acid.

[0107] In another exemplary embodiment, the carboxylic acid is an aliphatic dicarboxylic acid having 6-10 carbon atoms, such as adipic acid ((CH2)4(COOH)2), pimelic acid (HO2C(CH2)5CO2H), octanoic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H), and sebacic acid (HO2C(CH2)8CO2H).

[0108] In another exemplary embodiment, the carboxylic acid is an unsaturated dicarboxylic acid or a polyunsaturated dicarboxylic acid containing 4-10 carbon atoms. Examples of acids in this embodiment include fumaric acid, trans-, trans-mucoconic acid, cis-, trans-mucoconic acid, and cis-, cis-mucoconic acid.

[0109] In another exemplary embodiment, the carboxylic acid is cis-cinnamic acid or trans-cinnamic acid. In one embodiment, trans-cinnamic acid has one or two electron-donating groups selected from hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl. Examples include o-coumaric acid, m-coumaric acid, p-coumaric acid, o-methylcinnamic acid, m-methylcinnamic acid, p-methylcinnamic acid, o-methoxycinnamic acid, m-methoxycinnamic acid, and p-methoxycinnamic acid, and ferulic acid.

[0110] In another embodiment, the organic acid is a phenol or naphthol substituted with about 2-5 electron-withdrawing groups selected from -F, -Cl, -Br, -I, -CN, -CHO (aldehyde), -COR (ketone), and NO2. Examples include 2,4-dinitrophenol.

[0111] In another embodiment, the organic acid is a 1,3-dicarbonyl compound containing an acidic CH bond (pKa < 8). Examples include 2,2-dimethyl-1,3-dioxane-4,6-dione (medrum acid), cyanuric acid, or barbituric acid.

[0112] In another embodiment, the organic acid is an imide such as phthalimide. In one embodiment, the phthalimide is substituted with at least one electron-withdrawing substituent.

[0113] In another embodiment, the organic acid is an isohydroxamic acid. In some embodiments, the isohydroxamic acid can be an aromatic isohydroxamic acid containing an isohydroxamic acid functional group directly bonded to an aromatic ring. The aromatic ring is selected from the group consisting of benzene rings, pyridine rings, naphthyl rings, quinoline rings, and biphenyl rings. Examples include phenoxyxamic acid. The isohydroxamic acid can also be an aromatic isohydroxamic acid containing 1-4 sp... 3 - Hydroxyxamic acids are those with a chain of hybridized carbon atoms separated from an aromatic ring by an isohydroxamic acid functional group. Diisohydroxamic acids containing two or more isohydroxamic acid functional groups directly bonded to a benzene ring, pyridine ring, naphthyl ring, quinoline ring, or biphenyl ring system are also anticipated. Furthermore, substituted derivatives of the above-mentioned isohydroxamic acids containing electron-donating substituents such as hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl groups are also anticipated. Moreover, aliphatic diisohydroxamic acids containing 6-10 carbon atoms, such as cork oxime acid, and unsaturated diisohydroxamic acids containing 6-10 carbon atoms are also anticipated.

[0114] The organic acid used in the compositions described herein preferably has a water solubility between 0.1 and 10 g / L at room temperature, or less than about 20 g / L. In another embodiment, the organic acid used in the compositions described herein has a molar mass of less than 500 g / mol. In another embodiment, the organic acid used in the compositions described herein is non-polymeric or non-oligomeric. In another embodiment, the organic acid used in the compositions described herein does not have a polymeric or oligomeric backbone and / or is not linked to a polymeric or oligomeric backbone. In another embodiment, the acid has a water solubility of less than about 20 g / L at room temperature and a pKa value between about 3 and 6, more preferably between about 3 and 5.5 or between about 3.5 and 5.5. In other embodiments, the organic acid is crystalline and has a melting temperature greater than about 37°C.

[0115] Compositions comprising a molar excess of an organic acid and a small molecule therapeutic agent are prepared by mixing the organic acid and the therapeutic agent together in a suitable solvent. In some embodiments, the solvent is an aqueous fluid, such as a buffer or a water-organic solvent mixture. In a preferred embodiment, the organic acid is present such that at the end of the delivery period, it remains in an amount equal to or higher than its saturation concentration in its use environment.

[0116] Compositions were prepared using the following organic acids listed in Table 1, and the pH values ​​were measured.

[0117] Table 1

[0118]

[0119] In embodiments where the composition resides within a reservoir of a drug delivery device, it should be understood that the device is open to the environment of use when placed in its operating environment. That is, the operating environment and the composition within the device are in fluid communication via pores or a porous membrane in the drug delivery device. Given their limited water solubility, the compositions described herein comprise organic acids in suspension or slurry form. The organic acid is present in the composition in an amount exceeding its saturation concentration, and according to another embodiment, at the end of the delivery period, the organic acid is present in the composition in an amount equal to or exceeding its saturation concentration. In this way, the composition maintains the desired pH of the suspension or heterogeneous solution between 3.0 and 6.5, preferably 2.75 to 5.75, more preferably 2.8 to 5.6, preferably 2.9 to 5.6, preferably 3.1 to 5.5, 3.2 to 5.5, 3.3 to 5.5, 3.4 to 5.5, 3.5 to 5.5, 3.1 to 5.4, 3.2 to 5.4, 3.3 to 5.4, 3.4 to 5.4, 3.5 to 5.4, 3.1 to 5.3, 3. 2-5.3, 3.3-5.3, 3.4-5.3, 3.5-5.3, 3.1-5.2, 3.2-5.2, 3.3-5.2, 3.4-5.2, 3.5-5.2, 3.1-5.1, 3.2-5.1, 3.3-5.1, 3.4-5.1, 3.5-5.1, 3.1-5.0, 3.2-5.0, 3.3-5.0, 3.4-5.0, 3.5-5.0, 3.5-5.5, or 3.5-6.0.

[0120] In another embodiment, the organic acid is crystalline and has a melting temperature greater than about 37°C. Such organic acids remain in solid form in the in vivo environment to provide a heterogeneous mixture or suspension of the organic acid in the composition during the delivery period.

[0121] In another embodiment, the molar excess of organic acid ranges from 101% to 900%, 101% to 800%, 101% to 700%, 101% to 600%, 101% to 500%, 101% to 400%, 101% to 300%, 101% to 200%, 150% to 1000%, 150% to 900%, 150% to 800%, 150% to 700%, and 150% to 60%. 0%, 150%-500%, 150%-400%, 150%-300%, 150%-200%, 200%-1000%, 200%-900%, 200%-800%, 200%-700%, 200%-600%, 200%-500%, 200%-400%, 200%-300%, 150%-10000%, or 200%-10000%.

[0122] Conveying device

[0123] On the other hand, a drug delivery device is provided for administering compositions or aqueous suspensions as described herein. The drug delivery device can be any implantable device based on, for example, diffusion systems, soluble systems, or convection systems, such as diffusion systems, osmotic pumps, electrodiffusion systems, electroosmotic systems, and electromechanical systems. In one embodiment, the controlled drug delivery device is used for the controlled, prolonged delivery of the composition for a period of time. The term "controlled drug delivery device" refers to any device in which the release (e.g., release rate, release time, dosing period) of the drug or other desired substance contained therein is controlled or determined by the device itself (wholly or partially) and not solely by the environment of use. Several non-limiting examples are described.

[0124] In one embodiment, the drug delivery device is a device having a housing member defining a reservoir in which the above-described composition and / or aqueous suspension is held. The size and shape of the housing member are adapted for implantation. For subcutaneous implantation using a cannula or needle, a cylindrical shape is preferred. The outer diameter of the cylindrical housing member is preferably in the range of 2 mm to 6 mm, and the length is in the range of about 10 mm to about 50 mm. In one embodiment, the composition or aqueous suspension is initially present in the reservoir of the device in a dry form. For example, an aqueous suspension comprising a small molecule therapeutic agent and an organic acid is prepared and subsequently spray-dried, milled, or lyophilized to provide an aqueous suspension in a dry form. Alternatively, the individual components in dry form, i.e., the therapeutic agent as a dry solid and the organic acid as a dry solid, are mixed in the correct proportions to provide the desired aqueous suspension upon subsequent hydration. Alternatively, the therapeutic agent and organic acid can be co-dissolved in a suitable organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, and then concentrated to obtain a dry powder suitable for resuspension in an aqueous medium. The dry form of the composition can be tableted or granulated, loaded into a device, and hydrated in situ during subcutaneous implantation of a device containing the dry composition. Alternatively, the composition can be hydrated by a clinician introducing a liquid (e.g., physiological buffer, isotonic saline, phosphate-buffered saline, or aqueous propylene glycol solution) into a reservoir or matrix containing the composition during subcutaneous implantation. The liquid can be provided as part of a kit including a drug delivery device and a vial containing the hydration solution.

[0125] Figure 1A-1B Examples of drug delivery devices provided in China. Figure 1AA device 10, assembled and ready for implantation into a subject, is shown, comprising an anatomical compartment, such as subcutaneous or in the peritoneal cavity. The device includes an insoluble shell member 12 defining an internal compartment or reservoir 14. The reservoir contains the composition or formulation described herein. The shell member 12 has first and second ends 16, 18. The first end 16 is sealed with a fluid-tight end cap 20, best seen in [reference needed]. Figure 1B The diagram shows the device 10 in its unassembled form. The end cap 20 may optionally include a porous membrane, a semi-permeable membrane, or a porous partition 22. A porous membrane, a semi-permeable membrane, or a porous partition 24 is mounted on the second end 18.

[0126] Figure 1C-1K An end cap and end cap assembly portion of an exemplary drug delivery device is shown. Figure 1C-1F The numbered elements of the sub-components shown are 1=cap, 2=porous membrane, 3=seal, 4=retaining ring, and 5=drug device reservoir. Figure 1G-1K The numbered elements of the sub-components shown are 1=cap, 2=porous membrane, 3=seal, 4=drug delivery device reservoir, and 5=retaining ring.

[0127] The device contains a formulation comprising i) a small molecule drug that is poorly water-soluble at physiological pH (~7.4) and ii) can be used as a Brønsted or Lewis base. When the drug is combined with a stoichiometric excess of an organic acid, a suspension or slurry is produced at a pH (in the aqueous portion) approximately equal to or less than the pKa of the protonated drug, wherein the organic acid i) has a solubility in water at 25°C between 0.1 and 10 g / L or less than or equal to 20 g / L, and ii) is at least partially soluble in the presence of the drug and a physiological buffer solution.

[0128] As used herein, the terms "porous membrane" and "porous separator" refer to a structural member having a plurality of pores in the nanometer or micrometer (μm) range, preferably in the range of 0.1-100 μm or 0.1-200 μm. A porous separator allows therapeutic agents from a formulation contained within a reservoir to pass through in their soluble form. A porous separator may also allow organic acids, which are part of the formulation, to pass through in their soluble form. In a preferred embodiment, the porous separator retains therapeutic agents and / or organic acids in insoluble form. That is, therapeutic agents and / or organic acids in insoluble form preferably do not pass through the pores of the porous separator. A drug delivery device is described in detail in US2011 / 0106006, which is incorporated herein by reference.

[0129] Studies were conducted to evaluate the release rate and kinetics of a drug delivery device containing a composition comprising a small molecule therapeutic agent and an organic acid in its reservoir. As described in Examples 1 and 2, compositions of risperidone with various organic acids and compositions of olanzapine with two different organic acids were prepared. Risperidone was selected as the model therapeutic agent due to its potency and insolubility in water as a neutral free base (>10,000 volumes of water per volume of drug at 20-25°C). In studies using risperidone, the drug was mixed with para-aminobenzoic acid (PABA) at an acid:drug ratio of 1:1, 1.5:1, or 2:1 (molar) to obtain a stoichiometric excess of organic acid in each formulation. The dried formulation was loaded into the reservoir of the delivery device, hydrated, and incubated in diluted phosphate-buffered saline. The release of risperidone was evaluated over a 30-day period, and the results are shown in… Figure 2 middle.

[0130] Figure 2 The cumulative release (in mg) of risperidone from a drug delivery device comprising a heterogeneous aqueous formulation containing risperidone and 4-aminobenzoic acid (PABA) as a function of time (in days) is shown, where the risperidone / PABA molar ratio is 1:1 (rhombus); 1:1.5 (square); 1:2 (solid circle). In a group of devices containing a 1:2 risperidone / PABA formulation, the membrane surface area is reduced by approximately 50% (hollow circle). Adding the organic acid PABA to the formulation increases the release rate of the therapeutic agent relative to the control formulation and also provides a more constant release rate with near-zero-order kinetics close to the delivery time. Devices containing 1.5:1 or 2:1 PABA / risperidone compositions produce relatively similar output profiles, provided the membrane surface area of ​​the device remains constant. For a system containing a 2:1 PABA / risperidone formulation, the approximately 50% reduction in membrane surface area results in a corresponding decrease in the output rate. Note that the device with a 1:2 risperidone / PABA molar ratio reached a plateau around day 32 as the device ran out of drug.

[0131] In summary, the control formulation (risperidone / PABA salt, without excess acid; rhomboid) produced a slow release rate (i.e., nonlinear release kinetics) decreasing over time from the device equipped with the maximum membrane surface area. Formulations comprising acid to drug in a 1.5:1 or 2:1 molar ratio (square and solid circles, respectively) produced higher drug release rates compared to formulations in which there was no stoichiometric excess of organic acid. A device comprising a 2:1 organic acid / risperidone formulation and approximately half the membrane surface area produced approximately half the output rate of a device equipped with 100% of the available surface area and the same formulation.

[0132] Results of a similar study using olanzapine (Example 2) are shown in Figure 3AIn this study, the cumulative release (in mg) of olanzapine from a drug delivery device was measured as a function of time (in days). The device reservoir of the drug delivery device contained a heterogeneous formulation of olanzapine and 4-aminobenzoic acid (PABA, square) or p-methylbenzoic acid (rhomboid), or without an acid as a control (circle), in a molar ratio of olanzapine to an organic acid of 1:1.5. Olanzapine is a poorly water-soluble base. Increased and constant release rates were observed when formulated with a stoichiometric excess (molar ratio of 1.5:1) of an organic acid (PABA or p-methylbenzoic acid). Different organic acids produced significantly different release rates, possibly reflecting the closeness of the formulation's pH (4.5–5.0) to the reported pKa values ​​of diprotonated olanzapine (pKa1 = 5.0; pKa2 = 7.4).

[0133] Except for drug delivery devices filled with heterogeneous aqueous formulations containing olanzapine and 4-aminobenzoic acid (PABA, *) or p-methylbenzoic acid (trigonic acid) in a molar ratio of 2:1, Figure 3B The results of another study as described in Example 2 are shown. The cumulative in vitro release (in mg) of olanzapine from the drug delivery device as a function of time (in days) is shown in the figure. Figure 3B In the study, the device containing olanzapine and PABA (* symbol) released the drug faster than the device containing p-methylbenzoic acid (triangle). As a control, the device without acid, i.e., containing only olanzapine, released the drug slowly over a 15-day test period (square).

[0134] In summary, during the study or treatment, very little olanzapine free base was released from the control device (circle) (total <1 mg). Devices containing formulations in which the molar ratio of drug to organic acid—PABA (square) or p-toluic acid (rhombus)—was 1:1.5 or 1:2 achieved higher release rates and linear release kinetics than the control device. In the case of olanzapine, different acid additives produced significantly different release rates; for example, PABA produced a faster release rate than p-toluic acid. Given this data, those skilled in the art can understand that the release rate can be adjusted by choosing the organic acid in the formulation and the molar ratio of drug to organic acid.

[0135] In one embodiment, a formulation comprising a small molecule therapeutic agent and an organic acid, wherein the organic acid is present in a stoichiometric or stoichiometric excess form, provides an increase in the release rate of the small molecule therapeutic agent of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% compared to a formulation of a small molecule therapeutic agent having no organic acid or having less than a stoichiometric amount of organic acid. In one embodiment, the increased release rate is for a time period of at least 14 days, at least 2 weeks, at least 30 days, at least 45 days, at least 60 days, at least 90 days, or at least 180 days. In another embodiment, the increased release rate is close to the zero-order kinetic release over that time period.

[0136] Another study is described in Examples 3-4, in which a drug delivery device was manufactured to include dried tablets containing risperidone base and PABA (Example 3) or sebacic acid (Example 4) in the device reservoir. Tablets comprising risperidone base and an organic acid in a 1.5:1 or 1:1 weight ratio were prepared by dissolving the drug and organic acid together in a solvent and drying to remove the solvent. The dried drug-organic acid mixture was pulverized, and the resulting powder was mixed with a binder (polyvinylpyrrolidone) and a lubricant (stearic acid) and compressed into tablets. The tablets were loaded into the drug delivery device. Immediately prior to implantation in vivo, each device was filled with sterile phosphate-buffered saline (PBS) to hydrate the tablets. The device was implanted, and blood samples were obtained for pharmacokinetic (PK) analysis and evaluation of local safety over 6 months. Results are shown in… Figure 4 In the context of devices containing risperidone and 4-aminobenzoic acid (PABA, round) and devices containing risperidone and sebacic acid (diamond), the plasma concentration of risperidone (in ng / mL) is expressed as a function of time (in days). Regarding devices filled with risperidone and PABA... Figure 4 The plasma levels of the active fraction of risperidone (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a steady-state plasma level of approximately 50 ng / mL during the six-month implantation period. Mass balance analysis showed that the device removed after six months released the drug at an average rate of 0.70 mg / day and contained an average of 108 mg of unreleased risperidone. These findings suggest that the device will operate in vivo for an additional 154 days, for a total operating time of 337 days. To extend the operating time, the size of the device reservoir can be determined and filled with sufficient drug and organic acids for the desired delivery time at the desired rate. For example, to create a 12-month system, the reservoir length was increased by 10% from 40.0 mm to 44.0 mm. Therefore, the dose rate can be scaled by increasing the diameter of the device or by implanting more than one device per subject.

[0137] Regarding the device for filling with risperidone and sebacic acid ( Figure 4The plasma levels of the active fraction of risperidone (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a stable level of 50-60 ng / mL for 6 months. Mass balance analysis showed that the device removed after six months released the drug at an average rate of 0.80 mg / day and contained an average of 26 mg of unreleased risperidone. These findings suggest that the device will operate in vivo for an additional 32 days, for a total operating time of 7 months.

[0138] Example 5 describes a study in which compositions comprising various risperidone salts were prepared by dissolving the drug and a two-molar excess of a selected organic acid in methanol. The solvent was removed, and the dried cake was further dried, pulverized, and in some cases tableted. The dried drug salts were placed in the reservoir of a drug delivery device. The loaded device was hydrated and placed in 100 mL of PBS at 37°C. Risperidone release was measured by taking aliquots of the receiving buffer and analyzing the risperidone concentration. Figure 5 The cumulative in vitro release (expressed as the percentage of total loaded drug released into the receiving medium) for various risperidone salts (PABA, square; terephthalate, rhombus; sebacic acid, hollow rhombus; vanillic acid, triangle; hippurate, x symbol; hydroxyphenylpropionate, hollow circle; urate, solid circle) is shown. It can be seen that the different slopes of the curves indicate different release rates. Terephthalic acid (rhombus) and urate (solid circle) addition salts produce insufficient output, achieving only 2.6% and 16% output at 15 days, respectively. Risperidone hippurate (x symbol) and hydroxyphenylpropionate (hollow circle) achieve 94% and 92% risperidone release, respectively, after 15 days. Risperidone sebacic acid (hollow rhombus), vanillic acid (triangle), and PABA salt (square) produce intermediate rates of risperidone release, releasing approximately 40-60% of the total loaded drug at approximately 15 days. Therefore, in one embodiment, the composition of the therapeutic agent and the organic acid provides the release of the therapeutic agent such that at least about 40%, 50%, or 60% is released in vitro after about 15 days. In another embodiment, the composition of the therapeutic agent and the organic acid provides the release of the therapeutic agent such that no more than about 30% or 40% is released in vitro after about 15 days. In yet another embodiment, the composition of the therapeutic agent and the organic acid provides the release of the therapeutic agent such that about 40-50% is released in vitro after about 15 days.

[0139] The description in Example 5 and Figure 5 The in vitro release rate of the risperidone salts shown is related to the inherent water solubility of the acid. The water solubility of the acids used in Example 5 and their respective risperidone release rates from the device to the buffer (expressed as the cumulative percentage of total risperidone released after incubation at 37°C for 15 days) are listed in Table 2. These data are plotted in... Figure 6The highest risperidone release rate was observed when the drug was combined with acids whose inherent water solubility was between approximately 1.0 and 6.0 mg / mL. Peak release was seen for risperidone hippurate and 3-(4-hydroxyphenyl)propionate, which exhibit water solubility between approximately 2.5 and 4.0 mg / mL at approximately 25 °C. These data suggest that acids with water solubility less than approximately 1 g / L cannot maintain a sufficiently low pH within the device, while acids with significantly higher water solubility than 6 g / L are released from the device too rapidly, thus failing to sustain drug delivery for extended periods.

[0140] Table 2

[0141]

[0142] *See Example 5 and Figure 5

[0143] The in vitro release rates of the risperidone salts listed in Example 5 were also partially related to the pH of the saturated aqueous solution of the acid. The pH at the saturated concentration of the acids used in Example 5 and their respective risperidone release rates (expressed as the cumulative percentage of total risperidone released after incubation at 37°C for 15 days) are shown in [the table / example]. Figure 7 The highest risperidone release occurs when the drug is combined with an acid that shows a pH between about 2.0 and 3.7 at saturation concentration. Peak release is seen for risperidone hippurate and 3-(4-hydroxyphenyl)propionate, showing pH values ​​of 2.6 and 3.0, respectively. Therefore, in one embodiment, the composition comprises a therapeutic agent and an organic acid, wherein the organic acid is saturated in aqueous solution at a pH between about 2.0 and 3.7, or between about 2.1 and 3.6, about 2.1 and 3.5, about 2.2 and 3.5, about 2.2 and 3.4, about 2.3 and 3.4, about 2.4 and 3.3, about 2.5 and 3.2, about 2.5 and 3.1, about 2.5 and 3.0, about 2.6 and 3.2, about 2.6 and 3.1, or about 2.6 and 3.0.

[0144] Other drug delivery devices are known in the art. The compositions described herein can be used in a variety of devices, including those comprising drug reservoirs for holding small molecule therapeutic agents and organic acid formulations, and those having a matrix or substrate capable of holding or containing the formulation. Controlled drug release devices suitable for the present invention can generally deliver a drug from the device to selected sites in a subject at a selected or additionally patterned amount and / or rate. The drug delivery device must be able to contain an amount of formulation to provide a therapeutically effective amount of small molecules during treatment. The delivery time will vary depending on the therapeutic agent, the condition being treated, and the individual patient. In one embodiment, the delivery time, also referred to herein as a duration of duration, means a period of time of at least about two weeks to about six months. In another embodiment, a duration of duration means a period of time of at least about two weeks, or at least about three weeks, or at least about four weeks to about six months, or about four months, or about three months. In yet another embodiment, a duration of duration means a period of time of at least about 15 days, or at least about 21 days, or at least about 30 days, or at least about 45 days, or at least about 60 days. In other implementations, the time period is from about 2 hours to about 72 hours, from about 4 hours to about 36 hours, from about 12 hours to about 24 hours, from about 2 days to about 30 days, from about 5 days to about 20 days, from about 7 days or more, from about 10 days or more, from about 100 days or more; from about 1 week to about 4 weeks, from about 1 month to about 24 months, from about 2 months to about 12 months, from about 3 months to about 9 months, from about 1 month or more, from about 2 months or more, or from about 6 months or more.

[0145] Therefore, on the other hand, an implantable device is anticipated. This device includes a reservoir containing a formulation comprising (i) a quantity of the therapeutic agent to provide approximately zero-order release of the therapeutic agent over a delivery period of at least about 30 days and at a rate that provides a therapeutic effect, and (ii) an organic acid that: (a) maintains the pH of the hydrated formulation in its use environment at a pH between 3.0 and 6.5 during the delivery period; (b) is present in stoichiometric (molar) excess relative to the therapeutic agent; and (c) is present at the end of the delivery period in an amount approximately equal to or greater than its saturation concentration in the hydrated formulation.

[0146] On the other hand, an implantable device is anticipated. This device includes a reservoir containing a formulation comprising (i) a quantity of the small molecule therapeutic agent to provide approximately zero-order release of the small molecule therapeutic agent over a delivery period of at least about 30 days and at a rate providing a therapeutic effect, and (ii) an organic acid that: (a) maintains the pH of the hydrated formulation at a level equal to or less than the pKa of the protonated drug in its use environment during the delivery period; (b) is present in stoichiometric (molar) excess relative to the therapeutic agent; and (c) is present at the end of the delivery period in an amount approximately equal to or greater than its saturation concentration in the hydrated formulation.

[0147] In one embodiment, the formulation comprising a small molecule therapeutic agent and a stoichiometric excess of an organic acid is in a dry form. For example, the dry formulation may exist as a powder, tablet, or film in a reservoir of the device. When used in vitro or in vivo, the device absorbs liquid from the surrounding environment to hydrate the dry formulation, thereby forming in situ an aqueous suspension containing particles of both the salt form of the therapeutic agent and the undissolved excess acid.

[0148] Drug delivery devices can be implanted at any suitable implantation site using methods and apparatus known in the art. As described below, an implantation site is the location within a subject's body where the drug delivery device will be introduced and positioned. Implantation sites include, but are not limited to, subdermal, subcutaneous, intramuscular, or other suitable sites within the subject's body. Subcutaneous implantation sites are preferred due to the ease of implantation and removal of the drug delivery device. Exemplary subcutaneous delivery sites include under the skin of the arm, shoulder, neck, back, or leg. Sites within body cavities are also suitable implantation sites. Methods for implanting or otherwise positioning drug delivery devices for subcutaneous drug delivery are known in the art. Typically, the placement of the drug delivery device will be accomplished using methods and tools known in the art and under aseptic conditions with at least some local or general anesthesia administered to the subject.

[0149] Treatment

[0150] In other respects, therapeutic methods using the compositions and devices described herein are contemplated. In one embodiment, a method for the continuous, controlled delivery of central nervous system drugs is contemplated, wherein a composition or a delivery device comprising a composition as described herein is provided.

[0151] In another embodiment, a method for the continuous, controlled delivery of antipsychotic drugs is contemplated, wherein a composition or a delivery device comprising a composition as described herein is provided.

[0152] In another implementation, the method intended for maintaining therapeutic plasma levels of the antipsychotic drug is intended to delay relapse in stable, previously treated patients for at least 4 weeks.

[0153] Based on the foregoing, the composition described herein, comprising a small molecule therapeutic agent and an organic acid, provides the release of the therapeutic agent at a constant rate close to zero-order release kinetics over an extended period of time—at least about 14 days or at least about 30 days. The composition comprises a sufficient amount of the therapeutic agent for a therapeutic dose over a period of time, and a certain amount of the organic acid to (i) maintain the concentration of the protonated therapeutic agent at or near its saturation concentration in the hydrated composition during the period of delivery and / or (ii) maintain the concentration of the organic acid at or above its saturation concentration in the hydrated composition at the end of the delivery period. The near-saturated concentration of the drug is relative to the aqueous phase of the composition. In some embodiments, the composition is held in a drug delivery system (or device), and when placed in the use environment (e.g., a subcutaneous implantation site, such as plasma or interstitial fluid with a constant pH of ~7.4), a constant concentration gradient is created between the device and its use environment, promoting a constant release rate of the therapeutic agent over time (near-zero-order kinetics).

[0154] III. Examples

[0155] The following examples are illustrative in nature and are by no means intended to be limiting.

[0156] Example 1

[0157] Including risperidone as a small molecule therapeutic agent and formulations of organic acids.

[0158] Risperidone was mixed with para-aminobenzoic acid (PABA) at an acid:drug ratio of 1:1, 1.5:1, or 2:1 (in moles), tableted with lactose binder (13%), and loaded into delivery devices equipped with 0.1-micron polyvinylidene fluoride (DURAPORE®) membranes. In some devices, approximately 50% of the available membrane surface area was blocked to measure the effect of surface area on the delivery rate. All devices were vacuum-filled with phosphate buffer and transferred to a container containing a specific volume (~100 mL) of the same buffer. The sealed container was then incubated at 37°C, and aliquots (~500 µL) of the receiving buffer were removed at selected time points to quantify the released drug by high-performance liquid chromatography (HPLC). Risperidone release is shown in... Figure 2 middle.

[0159] Example 2

[0160] Including olanzapine as a small molecule therapeutic agent and formulations of organic acids.

[0161] Olanzapine was mixed with para-aminobenzoic acid (PABA) or para-methylbenzoic acid at an acid:drug ratio of 1.5:1 (in moles), compressed into tablets with a lactose binder (13%), and loaded into a delivery device equipped with a 0.1-micron polyvinylidene fluoride (DURAPORE®) membrane. The device was vacuum-filled with phosphate buffer and transferred to a container containing a specific volume (~100 mL) of the same buffer. The sealed container was then incubated at 37°C, and aliquots (~500 µL) of the receiving buffer were removed at selected time points to quantify the released drug by high-performance liquid chromatography (HPLC). The release of olanzapine is shown in... Figure 3A middle.

[0162] Example 3

[0163] In vivo pharmacokinetics of a 12-month implantable device containing formulations including risperidone and para-aminobenzoic acid.

[0164] Weigh risperidone base (75.00 g, 0.1827 mol) and transfer it to a 1.0 L culture medium bottle containing a stir bar. Weigh PABA (50.00 g, 0.3646 mol) and add it to the bottle containing risperidone. Then add approximately 750 mL of methanol. Seal the bottle containing the formulation and mix using a magnetic stirrer. Visually inspect the mixture for complete dissolution of the drug and acid, and remove the stir bar. Then filter the solution directly (0.45 μL DURAPORE®) into a rotary evaporator and allow it to undergo a primary drying step under vacuum until most of the solvent has evaporated, recording the start and end times. After completing the rotary (primary) drying, release the vacuum and briefly reshape the resulting foam material by hand before a secondary drying under high vacuum.

[0165] After secondary drying, all mixtures were transferred to a glove box for pulverization. The formulation was then transferred to a grinding chamber equipped with blades for grinding the dried material and ground using a blender base at 20,000 rpm. To prevent overheating of the formulation, a custom-made polypropylene sleeve was used to surround the chamber with dry ice. The mixture was ground for 5 cycles. The resulting powder was mixed with 12% by weight of polyvinylpyrrolidone (PVP-40K, Sigma Aldrich) as a binder and 1% by weight of stearic acid (1% of the final powder mass, Sigma Aldrich) as a lubricant. Tablets were produced using a tableting machine and custom diesets from Vanguard Pharmaceutical Machinery (Spring, Texas). The dies used for tableting had a diameter (4.30 mm) that matched the inner diameter of the device reservoir.

[0166] The drug delivery device is made of titanium, measures 40.0 mm in length, and has an internal reservoir. The cap assembly (see 1C-1K) includes DURAPORE. ® Porous membrane (0.1 micrometer, Millipore Corp). The assembled cap was attached to the device reservoir and weighed with another assembled cap to obtain the weight of the empty device. Before sealing with the second cap assembly, each reservoir subassembly (reservoir + cap at one end) was manually loaded with tablets using tweezers and weighed again to obtain the tablet filling weight. The average filling weight of each device was 460 mg (equivalent to 230 mg of risperidone as free base).

[0167] After weighing, place the assembled apparatus into 20 mL lyophilization vials. Loosely cover the vials with igloo-style rubber septa and place them in a freeze dryer equipped with a stopper tray system. Before sealing, evacuate the air space inside each apparatus and vial to a vacuum pressure of <1 Torr for at least 30 minutes.

[0168] During the manufacturing process, efforts are made to maintain low bioburden during mixing, device assembly, and cannula assembly. Final, terminal sterilization of both the filling devices and their implantation tools is performed using fractionated electron beam sterilization at doses of 25 kGy.

[0169] Immediately prior to implantation, each device was backfilled with sterile phosphate-buffered saline (PBS) using a 20 mL syringe equipped with a blunt filling needle. As the needle was inserted through the rubber septum, the vacuum within the vial rapidly drew the hydration solution into the vial and device without any manual force applied to the plunger. After hydration, the needle was removed from the septum, and the device was left in place for approximately 10 minutes. Each device was then removed from its vial, wiped with a paper towel to absorb any external fluid, and weighed. Using a custom-made implanter tool, the device was subcutaneously implanted on one side from the dorsal to the midline, and the incision was closed with sutures or surgical adhesive. Whole blood samples were obtained for pharmacokinetic (PK) analysis and to evaluate local safety over 6 months. All animals tolerated the implant well. PK results for the first 6 months are shown in [image / description]. Figure 4Plasma levels of the active fraction of risperidone (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a steady-state plasma level of approximately 50 ng / mL throughout the six-month implantation period. Mass balance analysis showed that the device removed after six months released the drug at an average rate of 0.70 mg / day and contained an average of 108 mg of unreleased risperidone. These findings suggest that the device will operate in vivo for an additional 154 days, for a total operating time of 337 days. To extend the operating time, the size of the device reservoir can be determined and filled with sufficient drug and organic acids for the desired delivery time at the desired rate. For example, to create a 12-month system, the reservoir length was increased by 10% from 40.0 mm to 44.0 mm. Therefore, the dose rate can be scaled by increasing the diameter of the device or by implanting more than one device per subject.

[0170] Example 4

[0171] In vivo pharmacokinetics of a 7-month implantable device containing formulations including risperidone and sebacic acid

[0172] Risperidone (75.00 g, 0.1827 mol) was weighed and transferred to a 1.0 L culture medium bottle containing a stir bar. Sebacic acid (74.91 g, 0.3704 mol) was weighed and added to the bottle containing risperidone. Then, approximately 75 mL of methanol was added. The bottle containing the formulation was sealed and mixed using a magnetic stirrer. The mixture was visually inspected for complete dissolution of the drug and acid, and the stir bar was removed. The mixture was dried, granulated, tableted, loaded into a device reservoir as described in Example 3, and finally sterilized. The device reservoir dimensions were 41.4 mm in length, 3.6 mm in inner diameter, and 5.21 mm in outer diameter. Five devices were filled with an average of 400 mg of tablets (equivalent to 167 mg of risperidone).

[0173] The devices were then removed from their vials, wiped with a tissue to absorb any external fluid, and weighed. Using a custom-made implantation tool, the devices were subcutaneously implanted on one side of the animal, from the dorsal side to the midline, and the incision was closed with sutures or surgical adhesive. Whole blood samples were obtained for PK analysis, and local safety was evaluated over 6 months. All animals tolerated the implants well. PK results are shown below. Figure 4 middle.

[0174] Example 5

[0175] Risperidone is released from an in vitro device containing various risperidone addition salts.

[0176] Various salts of risperidone were prepared by dissolving the drug and a two-molar excess of the selected acid in methanol. The solvent was removed under reduced pressure. The dried cake was further dried, pulverized, tableted (in some cases), filled into a reservoir, capped, and vacuum-absorbed as described in Example 3. The loaded device was hydrated and placed in 100 mL of PBS at 37°C on a planetary rotator (50 rpm). The risperidone concentration in aliquots of the receiving buffer was analyzed (spectrophotometer or HPLC). Figure 5 The cumulative in vitro release of various risperidone salts is shown (expressed as a percentage of the total loaded drug released into the receiving medium).

Claims

1. A composition comprising: An aqueous heterogeneous mixture comprising a therapeutic agent and an organic acid, wherein the therapeutic agent is risperidone, olanzapine, palmide, asenapine, aripiprazole, or epipiprazole; wherein the organic acid is an antioxidant carboxylic acid having a benzene ring and an electron-donating group, an antioxidant carboxylic acid having a benzene ring and two electron-donating groups, or an aliphatic dicarboxylic acid having 4-8 carbon atoms between the carboxylic acid groups; and wherein the organic acid is present in stoichiometric excess relative to the therapeutic agent, the stoichiometry being in molar quantities, and wherein after a period of use at human temperature for at least 30 days, the pH of the aqueous heterogeneous mixture is between 3.0 and 6.5, and the amount of the organic acid is equal to or greater than its saturation concentration.

2. The composition according to claim 1, wherein the pH of the saturated aqueous solution of the organic acid is equal to or less than the pKa of the protonated therapeutic agent.

3. The composition according to claim 1, wherein the organic acid is present in an excess of 105% to 1000% relative to the stoichiometry of the therapeutic agent.

4. The composition according to claim 1, wherein the carboxylic acid is selected from the group consisting of benzoic acid, pyridinecarboxylic acid, nicotinic acid, and isonicotinic acid.

5. The composition according to claim 1, wherein the carboxylic acid is selected from the group consisting of o-anesic acid, m-anesic acid, p-anesic acid, p-aminobenzoic acid (PABA), o-aminobenzoic acid (aminoanesic acid), o-methylbenzoic acid, m-methylbenzoic acid, p-methylbenzoic acid and salicylic acid.

6. The composition according to claim 1, wherein the carboxylic acid is vanillic acid.

7. The composition according to claim 1, wherein the carboxylic acid is a carboxylic acid having at least two carboxylic acid groups bonded to a benzene ring.

8. The composition according to claim 7, wherein the carboxylic acid is phthalic acid.

9. The composition according to claim 1, wherein the carboxylic acid is a carboxylic acid having an electron-donating group selected from the group consisting of hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl groups.

10. The composition according to claim 1, wherein the carboxylic acid is a carboxylic acid having an additional electron-donating substituent other than the hydroxyl group on the carboxylic acid moiety.

11. The composition according to claim 10, wherein the carboxylic acid is selected from the group consisting of 4'-hydroxy-4-biphenylcarboxylic acid, 4'-hydroxy-2-biphenylcarboxylic acid, 4'-methyl-4-biphenylcarboxylic acid, 4'-methyl-2-biphenylcarboxylic acid, 4'-methoxy-4-biphenylcarboxylic acid, and 4'-methoxy-2-biphenylcarboxylic acid.

12. The composition according to claim 1, wherein the organic acid has 1-4 sp... 3 Organic acids with hybridized carbon chains and carboxylic acid functional groups separated from benzene rings.

13. The composition according to claim 12, wherein the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.

14. The composition according to claim 1, wherein the carboxylic acid is selected from the group consisting of adipic acid ((CH2)4(COOH)2), pimelic acid (HO2C(CH2)5CO2H), octanoic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H), and sebacic acid (HO2C(CH2)8CO2H).

15. The composition according to claim 1, wherein the organic acid is an unsaturated dicarboxylic acid or a polyunsaturated dicarboxylic acid containing 4-10 carbon atoms.

16. The composition according to claim 15, wherein the carboxylic acid is selected from the group consisting of fumaric acid, trans-, trans-mucoconic acid, cis-, trans-mucoconic acid, and cis-, cis-mucoconic acid.

17. The composition according to claim 1, wherein the organic acid is cis-cinnamic acid or trans-cinnamic acid.

18. The composition according to claim 17, wherein the carboxylic acid is a trans-cinnamic acid having one or two electron-donating groups selected from hydroxyl, methoxy, amino, alkylamino, dialkylamino, or alkyl.

19. The composition of claim 18, wherein the trans-cinnamic acid is selected from the group consisting of o-coumaric acid, m-coumaric acid, p-coumaric acid, o-methylcinnamic acid, m-methylcinnamic acid, p-methylcinnamic acid; o-methoxycinnamic acid, m-methoxycinnamic acid, p-methoxycinnamic acid, and ferulic acid.

20. The composition according to claim 1, wherein the carboxylic acid is selected from the group consisting of 3-phenylpropionic acid, cinnamic acid, hydroxy derivatives of cinnamic acid, methoxy derivatives of cinnamic acid, nicotinic acid, benzoic acid, amino derivatives of benzoic acid, methoxy derivatives of benzoic acid, and phthalic acid.

21. The composition according to claim 20, wherein the hydroxy derivative of cinnamic acid is mesocoumaric acid or p-coumaric acid.

22. The composition according to claim 21, wherein the p-coumaric acid is trans-p-coumaric acid.

23. The composition according to claim 20, wherein the methoxy derivative of the cinnamic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

24. The composition according to claim 20, wherein the amino derivative of said benzoic acid is 2-aminobenzoic acid (aminoanisic acid) or 4-aminobenzoic acid (p-aminobenzoic acid; PABA).

25. The composition of claim 20, wherein the methoxy derivative of said benzoic acid is 4-methoxybenzoic acid (p-anesic acid), o-anesic acid, or m-anesic acid.

26. The composition of claim 1, wherein the use environment is a subcutaneous implantation site, and the therapeutic agent is released from the aqueous heterogeneous mixture to the subcutaneous implantation site.

27. The composition of claim 26, wherein the composition provides a substantially constant release rate of the therapeutic agent over time at the subcutaneous implantation site.

28. The composition of claim 1, wherein the aqueous heterogeneous mixture comprises the therapeutic agent and particles of undissolved excess organic acid.

29. The composition according to claim 1, wherein the organic acid is the main acidic excipient in the composition.

30. The composition according to claim 1, wherein the use environment is an in vivo use environment.

31. An apparatus comprising: The composition according to any one of claims 1-30, wherein the device is configured for subcutaneous implantation in a mammal.

32. Use of the composition according to any one of claims 1-30 in the preparation of an apparatus for the continuous, controlled delivery of small molecule therapeutic agents.

33. Use of the composition according to any one of claims 1-30 in the preparation of a medicament for treating diseases of the central nervous system.

34. Use of the composition according to any one of claims 1-30 in the preparation of a medicament for treating mental illness.

35. The use according to claim 34, wherein the mental illness is schizophrenia.

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