Compositions for small molecule therapeutic agent compounds

Abstract

To provide compositions for small molecule therapeutic agents.SOLUTION: A composition is provided that includes an aqueous suspension comprising a therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g / L and (ii) is an organic base, and an organic acid that (i) has a water solubility at room temperature of 0.1-10 g / L, (ii) has a molar mass of less than 500 grams per mole, (iii) is present in a stoichiometric (molar) excess relative to the therapeutic agent, and (iv) maintains a pH of the suspension in its environment of use between 3.0 and 6.5 for a period of at least about 30 days.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 399,083, filed September 23, 2016, which is incorporated herein by reference.

[0002] The subject matter described herein relates to compositions and formulations for small molecule therapeutics and drug delivery devices including compositions and formulations for the controlled and sustained delivery of small molecule therapeutics.

Background Art

[0003] An important class of small molecule drugs exhibits poor water solubility at neutral pH. This property can be advantageous for oral absorption and tissue penetration, but it complicates the development of injectable or implantable sustained release systems that rely on passive diffusion as the primary drug release mechanism; for example, low solubility cannot generate a sufficient concentration gradient to cause appropriate efflux from a reservoir containing an aqueous suspension of the drug. Many insoluble drugs are weak organic bases (i.e., molecules containing functional groups such as at least one primary, secondary or tertiary amine, aniline or amidine), and their water solubility is improved by protonation (i.e., when converted to a salt). However, such salts are unstable and are prone to hydrolysis at a pH near or above the pKa of the protonated drug. Since the efflux of the drug from the formulation must be coupled with the influx of buffering species from the physiological fluid, this process makes it difficult for diffusion-mediated drug delivery systems by implants or depots. Compositions and devices are needed to address these and other complex factors associated with the sustained and controlled delivery of small molecule therapeutic agents that are weak organic bases.

Summary of the Invention

[0004] The aspects and embodiments described and illustrated below are intended to be exemplary and illustrative and not limiting of the scope.

[0005] In one aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility of less than about 20 g / L at room temperature and (ii) binds to a stoichiometric excess of an organic acid that maintains the pH of the suspension in its use environment at pH 3 to 6.5 for at least about 30 days, wherein the small molecule therapeutic agent (i) has a water solubility of less than 1 g / L at room temperature and (ii) is a weak base (i.e., has a conjugate acid with a pKa of 6 to 9).

[0006] In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility of 0.1 to 10 g / L at room temperature; (ii) has a molecular weight of less than 500 grams per mole; (iii) binds to a stoichiometric excess of an organic acid that maintains the pH of the suspension in its use environment at pH 3 to 6.5 for at least about 30 days, wherein the small molecule therapeutic agent (i) has a water solubility lower than 1 g / L at room temperature and (ii) is a weak base (i.e., has a conjugate acid with a pKa of 6 to 9).

[0007] In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility of less than 20 g / L at room temperature and (ii) binds to a stoichiometric excess of an organic acid that maintains the pH of the suspension in its use environment at a pH equal to or less than the pKa of the protonated drug for at least about 30 days, wherein the small molecule therapeutic agent (i) has a water solubility of less than 1 g / L at room temperature and (ii) becomes more soluble upon protonation.

[0008] In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility of 0.1 to 10 g / L at room temperature; (ii) has a molecular weight of less than 500 grams per mole; (iii) binds to a stoichiometric excess of an organic acid that maintains the pH of the suspension in its use environment at a pH equal to or less than the pKa of the protonated drug for at least about 30 days, wherein the small molecule therapeutic agent (i) has a water solubility of less than 1 g / L at room temperature and (ii) becomes more soluble upon protonation.

[0009] In one embodiment, the aqueous suspension is a heterogeneous mixture comprising a small molecule therapeutic agent and an organic acid, where the organic acid is sufficiently soluble to maintain the pH of the heterogeneous solution in its use environment at a value equal to or less than physiological pH (about 7.4) for a 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.

[0010] In one embodiment, the organic acid is present at an amount approximately equal to or exceeding its saturation concentration at the end of the period.

[0011] In another embodiment, the organic acid is present in a stoichiometric (molar concentration) amount in the range of about 105% to 1000% compared to the therapeutic agent, although it may be as much as 10,000%. In other embodiments, the organic acid on a molar basis is 110%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500% more than the amount of the therapeutic agent in the composition.

[0012] In another embodiment, the organic acid is crystalline and has a melting point above about 37°C.

[0013] In yet another embodiment, the small molecule therapeutic agent is an antipsychotic drug.

[0014] In other embodiments, the antipsychotic drug is risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole or asenapine.

[0015] In one embodiment, the aqueous suspension comprises, or is produced using, an organic acid suspended in a water-based solution such as an aqueous buffer solution.

[0016] In another embodiment, the aqueous suspension comprises, or is produced using, a salt previously formed from the therapeutic agent and the organic acid, where the acid is present in a stoichiometric (molar concentration) excess.

[0017] In another embodiment, the therapeutic agent and a stoichiometric (molar concentration) excess of an organic acid are thoroughly mixed by dissolving them in a polar organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, and the intermediate solution is concentrated to dryness.

[0018] In certain embodiments, the organic acid is an aromatic carboxylic acid. In certain embodiments, typical organic acids are organic acids having a carboxylic acid group bonded to an unsubstituted benzene ring or pyridine ring. In certain embodiments, the carboxylic acid is selected from the group consisting of benzoic acid, picolinic acid, nicotinic acid, and isonicotinic acid.

[0019] In another embodiment, the carboxylic acid is a carboxylic acid having a benzene ring and one electron-donating group. In another embodiment, the carboxylic acid has antioxidant properties.

[0020] In still 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-toluic acid, m-toluic acid, p-toluic acid, and salicylic acid.

[0021] 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 certain embodiments, and by way of example, the carboxylic acid is vanillic acid.

[0022] In still another embodiment, the carboxylic acid is a carboxylic acid having at least two carboxylic acid groups bonded to a benzene ring. In certain embodiments, and by way of example, the carboxylic acid is phthalic acid.

[0023] 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, quinolinic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid, and 8-quinolinecarboxylic acid.

[0024] In another embodiment, the carboxylic acid contains an aromatic ring having an electron-donating group selected from the group consisting of hydroxy, methoxy, amino, alkylamino, dialkylamino, and alkyl. 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.

[0025] In yet another embodiment, the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly bonded to a 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 diphenic acid.

[0026] In yet another embodiment, the carboxylic acid is a carboxylic acid having one additional electron-donating substituent in addition to the hydroxyl group of 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.

[0027] 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 to 4 saturated carbon atoms. In one embodiment, and by way of example, the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.

[0028] In another embodiment, the carboxylic acid is an aliphatic dicarboxylic acid having a carbon chain of 4 to 8 carbon atoms separating the 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), suberic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H) and sebacic acid (HO2C(CH2)8CO2H).

[0029] In another embodiment, the carboxylic acid is an unsaturated or polyunsaturated dicarboxylic acid containing 4 to 10 carbons. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of fumaric acid, trans,trans-muconic acid, cis,trans-muconic acid and cis,cis-muconic acid.

[0030] In other embodiments, the carboxylic acid is cis-cinnamic acid or trans-cinnamic acid. In yet other embodiments, the carboxylic acid is trans-cinnamic acid having one or two electron donating groups selected from hydroxy, methoxy, amino, alkylamino, dialkylamino or alkyl groups. In yet other embodiments, 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.

[0031] In one embodiment, the organic acid is a phenol or naphthol substituted with about 2 to 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.

[0032] In another embodiment, the organic acid is a 1,3-dicarbonyl compound containing an acidic (pKa < 8) CH bond. 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.

[0033] In yet another embodiment, the organic acid is an imide. In one embodiment, and by way of example, the imide is phthalimide or a substituted phthalimide. In another embodiment, the substituted phthalimide has at least one electron-withdrawing substituent.

[0034] In yet another embodiment, the organic acid is a hydroxamic acid. In one embodiment, and by way of example, the hydroxamic acid is an aromatic hydroxamic acid containing a hydroxamic 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 naphthalene ring, a quinoline ring, and a biphenyl ring. In yet another embodiment, the hydroxamic acid is benzohydroxamic acid. In yet another embodiment, the hydroxamic acid is a hydroxamic acid containing a hydroxamic functional group separated from the aromatic ring by a chain of 1 to 4 sp 3 hybrid carbon atoms.

[0035] In yet another embodiment, the aromatic ring is selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring.

[0036] In yet another embodiment, the hydroxamic acid is a dihydroxamic acid containing two or more hydroxamic acid functional groups directly bonded to a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, or a biphenyl ring system.

[0037] In other embodiments, the hydroxamic acid contains an aromatic ring having an electron-donating substituent selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, and alkyl groups.

[0038] In other embodiments, the hydroxamic acid is an aliphatic dihydroxamic acid containing 6 to 10 carbon atoms.

[0039] In one embodiment, the hydroxamic acid is suberohydroxamic acid.

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

[0041] 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.

[0042] In yet another embodiment, the hydroxy derivative of cinnamic acid is m-coumaric acid or p-coumaric acid.

[0043] In still further embodiments, p-coumaric acid is trans-p-coumaric acid.

[0044] In other embodiments, the methoxy derivative of cinnamic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

[0045] In still further embodiments, the amino derivative of benzoic acid is o-amino-benzoic acid (anthranilic acid) or 4-aminobenzoic acid (para-aminobenzoic acid; PABA).

[0046] In another embodiment, the methoxy derivative of benzoic acid is 4-methoxybenzoic acid (p-anisic acid), o-anisic acid, or m-anisic acid.

[0047] In certain embodiments, the composition is in a dry form. In other embodiments, the composition is in a dry form and is hydrated in situ when in its use environment.

[0048] In another aspect, a device is provided that includes the composition described herein. The device is designed for subcutaneous implantation in a mammal.

[0049] In another aspect, an implantable device is provided. The device includes a reservoir containing a formulation of a small molecule therapeutic agent that (i) provides a substantially zero-order release of the small molecule therapeutic agent in an amount to provide a therapeutic effect at a rate during a delivery period of at least about 30 days and (ii) includes an organic acid that (a) maintains the pH of the formulation when hydrated in its use environment having a pH of 3.0 to 6.5 during the delivery period, (b) is present in a stoichiometric (molar concentration) excess relative to the therapeutic agent, and (c) is present in an amount that is substantially equivalent to or greater than its saturation concentration in the formulation at the end of the delivery period when hydrated.

[0050] In another aspect, an implantable device is provided. The device includes a reservoir containing a formulation of a small molecule therapeutic agent that (i) provides a substantially zero-order release of the small molecule therapeutic agent in an amount to provide a therapeutic effect at a rate during a delivery period of at least about 30 days and (ii) includes an organic acid that (a) maintains the pH of the formulation when hydrated at a pKa equal to or less than that of the protonated drug during the delivery period, (b) is present in a stoichiometric (molar concentration) excess relative to the therapeutic agent, and (c) is present in an amount that is substantially equivalent to or greater than its saturation concentration in the formulation at the end of the delivery period when hydrated.

[0051] In certain embodiments, 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.

[0052] In another embodiment, the formulation hydrates in the presence of an aqueous solution to form an aqueous suspension. In certain embodiments, the aqueous solution is an in vivo fluid.

[0053] 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.

[0054] 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 of 0.1 - 10 g / L and a molar mass of less than 500 grams per mole at room temperature.

[0055] In another embodiment, the organic acid has a water solubility of less than about 20 g / L and a pKa of 3 - 6 at room temperature. In another embodiment, the organic acid has a water solubility of 0.1 - 10 g / L, a molar mass of less than 500 grams per mole and a pKa of 3 - 6 at room temperature.

[0056] In another embodiment, two or more organic acids, each having a water solubility of 0.1 - 10 g / L, a molar mass of less than 500 grams per mole and a pKa of 3 - 6 at room temperature, are used in combination.

[0057] In yet another embodiment, the organic acid has a melting point higher than about 37°C.

[0058] In another aspect, a method for sustained release, controlled release of a small molecule therapeutic agent is provided. The method includes providing a composition or device as described herein. In some embodiments, the method further includes administering the device, for example, by subcutaneous implantation.

[0059] In another aspect, a method for sustained release, controlled release of an antipsychotic drug is provided, including providing a composition or device as described herein. In some embodiments, the method further includes administering the device, for example, by subcutaneous implantation.

[0060] In another aspect, a method for maintenance therapy for treating schizophrenia or bipolar disorder is provided, which includes providing the compositions or devices described herein. In some embodiments, the method further includes administering the device, for example, by subcutaneous implantation.

[0061] In addition to the above exemplary aspects and embodiments, further aspects and embodiments will become apparent by reference to the drawings and by the tests described hereinafter.

[0062] Further embodiments, such as the methods, devices, and compositions of the present invention, will be apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and following descriptions, each and every feature described herein, and each and every combination of two or more of such features, are included within the scope of this specification, provided that the features included in such combinations are not mutually inconsistent. Further, any feature or combination of features may be specifically excluded from any embodiment of the present invention. In particular, further aspects and advantages of the present invention are described when considered in conjunction with the accompanying examples and drawings.

Brief Description of the Drawings

[0063]

Figure 1A - B

[0064]

Figure 1C - F

[0065]

Figure 1G - K

[0066]

Figure 2

[0067]

Figure 3A

[0068]

Figure 3B

[0069]

Figure 4

[0070]

Figure 5

[0071]

Figure 6

[0072]

Figure 7

[0073] Detailed Description I. Definition Various aspects are shown in more detail hereinafter. However, such aspects may be embodied in many different forms and should not be construed as limiting the embodiments described herein; rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope to those skilled in the art.

[0074] When a numerical range is provided, each value between the upper and lower limits of that range and any other indicated or intervening value within that range is intended to be encompassed within the disclosed scope. For example, if a range of 1 mg to 8 mg is indicated, then 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg, as well as ranges of values greater than or equal to 1 mg and less than or equal to 8 mg, are also clearly disclosed.

[0075] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the recitation of "a polymer" includes a single polymer and two or more identical or different polymers, and the recitation of "an excipient" includes a single excipient and two or more identical or different excipients, and so on.

[0076] The word "about", when positioned immediately before a value, means a range of plus or minus 10% of that value. For example, unless the context clearly dictates otherwise or is inconsistent with such an understanding, "about 50" means 45 to 55, and "about 25,000" means 22,500 to 27,500, and so on. For example, in a list of numerical values such as "about 49, about 50, about 55", "about 50" means a range that extends less than half the interval between the preceding and following values, for example, a value greater than 49.5 and less than 52.5. Further, the phrases "less than about (a value)" or "greater than about (a value)" should be understood in light of the definition of the term "about" provided herein.

[0077] The compositions of the present invention can include, consist essentially of, or consist of the disclosed components.

[0078] Unless otherwise specified, all percentages, parts, and ratios are based on the total weight of the composition, and all measurements are conducted at about 25 °C.

[0079] The phrase "pharmaceutically acceptable" as used herein refers to compounds, salts, compositions, dosage forms, etc. that are suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response or other problems or complications, within the scope of sound medical judgment, and that exhibit a reasonable benefit / risk ratio. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state government regulatory authority for use in mammals (e.g., animals), and more specifically in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias.

[0080] As used herein, the term "treating" is used to indicate a method of administering a small molecule that reduces the frequency of symptoms of a medical condition (e.g., schizophrenia, bipolar disorder) in a subject compared to a subject not given the compound or composition, or delays its onset. This can include reversing, reducing or arresting symptoms, clinical signs and the underlying pathology of the condition in a way that improves or stabilizes the subject's condition (e.g., controlling schizophrenia symptoms).

[0081] Any such group of individual members that may be claimed by a range or in any similar manner, including sub-ranges or combinations of sub-ranges within the group, and having the right to conditionally exclude or except, for any reason, can claim a scope that is less than the full scope of the invention. Further, a scope that is less than the full scope of the invention can be claimed by conditionally excluding or excepting any individual substituent, analog, compound, ligand, structure or group thereof or any member of the claimed group.

[0082] Throughout the present invention, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entirety are hereby incorporated by reference into the present disclosure to more fully describe the common general knowledge in the art known to those skilled in the art as of the date of the present disclosure. In the event of any conflict between the cited patents, patent applications, and publications and the present disclosure, the present disclosure shall control.

[0083] For convenience, the specific terms used herein, in the examples, and in the claims are summarized here. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0084] II. Formulation for improving the solubility of small molecule therapeutics In one aspect, a composition or formulation, wherein a small molecule therapeutic agent is solubilized by the use of a partially soluble organic acid, and the delivery of the therapeutic agent from a device or drug delivery platform is improved over a long period of time. In certain embodiments, the composition is an aqueous suspension or slurry. In another embodiment, the composition is a heterogeneous or non-uniform mixture or solution. In some embodiments, the solution or mixture can be an aqueous mixture or an aqueous heterogeneous mixture. In another embodiment, the composition is in a dry form (e.g., lyophilized, spray dried, dried, etc.). In these various embodiments, the composition has one or more of the following: (i) a water solubility of less than about 20 g / L or about 0.1 - 10 g / L at room temperature (e.g., about 25 °C); (ii) a molar mass of less than 500 grams per mole; (iii) being present in a stoichiometric (molar concentration) excess compared to the therapeutic agent; and (iv) maintaining a pH of the suspension (or solution) in the use environment that is approximately equal to or less than the pKa of the protonated therapeutic agent for a period of at least about 30 days, and includes a small molecule therapeutic agent that can function as a Bronsted base or a Lewis base and an organic acid. The composition may further comprise an aqueous liquid, such as water, a buffer, or an aqueous solvent mixture. In embodiments where the composition is in a dry form, the aqueous liquid hydrates the composition in situ in its use environment.

[0085] As described above, the formulations described herein provide the solubility of small molecule therapeutic agents to enable delivery during a duration. In certain embodiments, the duration is intended to be at least about 2 weeks to about 6 months. In another embodiment, the duration is intended to be at least about 2 weeks or at least about 3 weeks or at least about 4 weeks to about 6 months or about 4 months or about 3 months. In another embodiment, the duration is intended to be at least 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 another embodiment, the duration is intended to be at least about 6 months, or 9 months, or 12 months.

[0086] As described above, the formulations described herein partially improve the solubility of small molecule therapeutic agents by maintaining a specific pH of the formulation in its use environment over a period of time. In certain embodiments, the use environment is in vivo. For example, the formulation can be part of a drug delivery device implanted in vivo, and some examples of such devices are provided below. In another embodiment, the use environment is in vitro in a release medium maintained at about 37°C.

[0087] The components of the composition, namely the small molecule therapeutic agent and the organic acid, are described hereinafter.

[0088] A. Small molecule therapeutic In certain embodiments, the composition has a water solubility of less than 1.0 g / L at room temperature and (ii) comprises a small molecule therapeutic agent that is an organic base. In certain embodiments, the recitation of "small molecule" refers to a biologically active molecule having a molecular weight of 2,000 Daltons or less and is commonly used in the context of small molecule drugs (therapeutic agents) to distinguish them from protein, polypeptide, or peptide therapeutic agents. In another embodiment, the small molecule has a molecular weight of 1,000 Daltons or less or 500 Daltons or less. In other embodiments, the molecular weight of the small molecule is 10 - 2,000 Daltons, 10 - 1,000 Daltons, 10 - 500 Daltons, 50 - 2,000 Daltons, 50 - 1,000 Daltons, 50 - 500 Daltons, 100 - 2,000 Daltons, 100 - 1,000 Daltons, or 100 - 500 Daltons.

[0089] The small molecule therapeutic agents contemplated include, but are not limited to, weak organic bases (i.e., having a conjugate acid with a pKa of 6 - 9 or 5 - 9) and agents that are efficacious such that a 30 - 60 day dose can be included in a delivery device implanted in a human.

[0090] By way of example, therapeutic agents containing a primary, secondary, or tertiary amine, aniline or aniline derivative, or amidine functional group are contemplated as small molecule therapeutic agents that are organic bases. It is understood that therapeutic agents having a structure containing one or more of these functional groups are contemplated. Examples of aniline derivatives include analogs of aniline where the phenyl group is substituted with, for example, a methyl group (toluidine), a halogen such as chlorine (2 - chloroaniline, 3 - chloroaniline, 4 - chloroaniline), an amino group (4 - aminobenzoic acid or 2 - aminobenzoic acid or 3 - aminobenzoic acid), a nitro group (e.g., 2 -, 3 -, or 4 - nitroaniline), and many others.

[0091] In certain embodiments, the small molecule therapeutic agent is an antipsychotic drug that includes an atypical antipsychotic. In another embodiment, the small molecule therapeutic agent has activity for treating central nervous system disorders. Exemplary agents include, but are not limited to, risperidone, olanzapine, asenapine, aripiprazole, or brexpiprazole.

[0092] In one embodiment, the small molecule drug is i) poorly water soluble at physiological pH (about 7.4) and ii) functions as a Bronsted or Lewis base. As described below, in the presence of an aqueous liquid and an organic acid having i) a water solubility between 0.1 and 10 g / L at 25° C. or less than 20 g / L and ii) a stoichiometric excess that dissolves at least partially in the presence of the drug and a physiological buffer, the suspension or slurry is produced at a pH (in the aqueous fraction) that is approximately equal to or less than the pKa of the protonated drug.

[0093] B. Organic Acid

[0092] In addition to the small molecule therapeutic agent, the composition includes an organic acid or combination of organic acids. The organic acid has one or more of the following characteristics: (i) a water solubility of less than about 20 g / L between 0.1 and 10 g / L at room temperature; (ii) a molar mass of less than 500 grams per mole; (iii) present in a stoichiometric excess compared to the therapeutic agent; and (iv) maintains the pH of the suspension or solution in its use environment at approximately equal to or less than the pKa of the protonated small molecule therapeutic agent for a period of at least about 30 days. As described above, the composition enables the use of the composition in a drug delivery platform that improves the solubility of the small molecule therapeutic agent and provides for long-term sustained release. The excess (compared to the therapeutic agent on a stoichiometric basis) acid interferes with physiological buffer species that would otherwise cause hydrolysis of the pharmacologically active salt. Examples of organic acids for use in the composition are described below.

[0094] In the first embodiment, the organic acid is a carboxylic acid. Examples thereof include aromatic carboxylic acids in which a carboxylic acid group is directly bonded to an aromatic ring. For example, the aromatic carboxylic acid may have one carboxylic acid group bonded to an unsubstituted benzene or pyridine ring. Examples include benzoic acid, picolinic 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 having antioxidant properties. Specific examples include o-anisic acid, m-anisic acid, p-anisic acid, p-aminobenzoic acid (PABA), o-aminobenzoic acid (anthranilic acid), o-toluic acid, m-toluic acid, p-toluic acid and salicylic acid.

[0095] In yet another example, the aromatic carboxylic acid may have a single benzene ring and two electron-donating groups having antioxidant properties. A specific example is vanillic acid. In yet another example, the 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.

[0096] In another example, the aromatic carboxylic acid is a carboxylic acid containing one carboxylic acid group bonded to a naphthalene or quinoline ring. Examples include 1-naphthoic acid, 2-naphthoic acid, quinolinic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid and 8-quinolinecarboxylic acid. Further classification of this type of acid having one carboxylic acid group bonded to a naphthalene or quinoline ring includes acids containing further electron-donating groups such as hydroxy group, methoxy group, amino group, alkylamino group, dialkylamino group or alkyl group. Examples of acids of this classification 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.

[0097] In another typical embodiment, the carboxylic acid is a carboxylic acid containing an electron-donating substituent in addition to one carboxylic acid group bonded to a naphthalene or quinoline ring and a hydroxyl group in 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.

[0098] In another typical embodiment, the acid is a dicarboxylic acid or tricarboxylic acid having two or three carboxylic acid groups bonded to a naphthalene or quinoline ring. Examples include 1,4-naphthalenedicarboxylic acid and 2,6-naphthalenedicarboxylic acid.

[0099] In another typical embodiment, the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly bonded to a biphenyl ring system. Examples include 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid, and diphenic acid.

[0100] In another typical embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid functional group separated from a benzene, pyridine, naphthalene, or quinoline ring by one to four saturated carbon atom chains. Examples of acids in this embodiment include phenylacetic acid and 3-phenylpropionic acid.

[0101] In another typical embodiment, the carboxylic acid is an aliphatic dicarboxylic acid having 6 to 10 carbon atoms, such as adipic acid ((CH2)4(COOH)2), pimelic acid (HO2C(CH2)5CO2H), suberic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H), and sebacic acid (HO2C(CH2)8CO2H).

[0102] In another typical embodiment, the carboxylic acid is an unsaturated or polyunsaturated dicarboxylic acid containing 4 to 10 carbon atoms. Examples of acids in this embodiment include fumaric acid, trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid.

[0103] In another typical embodiment, the carboxylic acid is cis-cinnamic acid or trans-cinnamic acid. In certain embodiments, trans-cinnamic acid contains one or two electron-donating groups selected from a hydroxy group, a methoxy group, an amino group, an alkylamino group, a dialkylamino group, or an alkyl group. 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, p-methoxycinnamic acid, and ferulic acid.

[0104] In another embodiment, the organic acid is a phenol or naphthol substituted with about 2 to 5 electron-withdrawing groups selected from -F, -Cl, -Br, -I, -CN, -CHO (aldehyde), -COR (ketone), and NO2. An example includes 2,4-dinitrophenol.

[0105] In another embodiment, the organic acid is a 1,3-dicarbonyl compound containing an acidic (pKa < 8) CH bond. Examples include 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), cyanuric acid, or barbituric acid.

[0106] In another embodiment, the organic acid is an imide such as phthalimide. In certain embodiments, the phthalimide is a phthalimide substituted with at least one electron-withdrawing substituent.

[0107] In another embodiment, the organic acid is a hydroxamic acid. In some embodiments, the hydroxamic acid can be an aromatic hydroxamic acid containing one hydroxamic functional group directly bonded to an aromatic ring. The aromatic ring can be selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring. Examples include benzohydroxamic acid. The hydroxamic acid can also be a hydroxamic acid containing a hydroxamic functional group separated from the aromatic ring by a 1-4 sp 3 hybridized carbon atom chain. Dihydroxamic acids containing two or more hydroxamic functional groups directly bonded to a benzene, pyridine, naphthalene, quinoline, or biphenyl ring system are also contemplated. Further, substitution derivatives of the above hydroxamic acids containing electron donating substituents such as hydroxy groups, methoxy groups, amino groups, alkylamino groups, dialkylamino groups, or alkyl groups are contemplated. Aliphatic dihydroxamic acids containing 6-10 carbon atoms and unsaturated dihydroxamic acids containing 6-10 carbon atoms, such as suberohydroxamic acid, are also contemplated.

[0108] The organic acid for use in the compositions described herein preferably has a water solubility of 0.1-10 g / L at room temperature, or less than about 20 g / L. In another embodiment, the organic acid for use in the compositions described herein has a molar mass of less than 500 grams per mole. In another embodiment, the organic acid for use in the compositions described herein is non-polymeric or non-oligomeric. In another embodiment, the organic acid for use in the compositions described herein does not have a polymeric or oligomeric backbone and / or is not bonded 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 of about 3-6, more preferably about 3-5.5 or about 3.5-5.5. In other embodiments, the organic acid is crystalline and has a melting point above about 37 °C.

[0109] A composition containing an organic acid and a small molecule therapeutic agent in molar excess is produced by mixing the organic acid and the therapeutic agent together in a suitable solvent. In some embodiments, the solvent is an aqueous liquid such as a buffer or a water-organic solvent mixture. In preferred embodiments, the organic acid is present in an amount such that it remains at or above the saturation concentration of the organic acid in its use environment at the end of the delivery period.

[0110] The following organic acids listed in Table 1 were used to produce the composition and the pH value was measured.

Table 1

[0111] In embodiments where the composition is present within the reservoir of a drug delivery device, when placed in its use environment, the device is susceptible to the influence of the use environment. That is, the use environment and the composition within the device are fluidly connected via pores or porous membranes in the drug delivery device. The compositions described herein contain the organic acid in the form of a suspension or slurry that confers limited water solubility. The organic acid is present in the composition in an amount that exceeds its saturation concentration, and in another embodiment, the organic acid is present at, or above, the saturation concentration at the end of the delivery period. Thus, the composition maintains the desired pH of the suspension or heterogeneous solution between 3.0 and 6.5, preferably between 2.75 and 5.75, more preferably between 2.8 and 5.6, preferably between 2.9 and 5.6, preferably between 3.1 and 5.5, 3.2 and 5.5, 3.3 and 5.5, 3.4 and 5.5, 3.5 and 5.5, 3.1 and 5.4, 3.2 and 5.4, 3.3 and 5.4, 3.4 and 5.4, 3.5 and 5.4, 3.1 and 5.3, 3.2 and 5.3, 3.3 and 5.3, 3.4 and 5.3, 3.5 and 5.3, 3.1 and 5.2, 3.2 and 5.2, 3.3 and 5.2, 3.4 and 5.2, 3.5 and 5.2, 3.1 and 5.1, 3.2 and 5.1, 3.3 and 5.1, 3.4 and 5.1, 3.5 and 5.1, 3.1 and 5.0, 3.2 and 5.0, 3.3 and 5.0, 3.4 and 5.0, 3.5 and 5.0, 3.5 and 5.5 or 3.5 and 6.0.

[0112] In another embodiment, the organic acid is crystalline and has a melting point above about 37°C. Such organic acids remain in solid form in the in vivo use environment, providing a heterogeneous mixture or suspension of the organic acid in the composition during the delivery period.

[0113] In another embodiment, the molar excess of the 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%, 150% to 600%, 150% to 500%, 150% to 400%, 150% to 300%, 150% to 200%, 200% to 1000%, 200% to 900%, 200% to 800%, 200% to 700%, 200% to 600%, 200% to 500%, 200% to 400%, 200% to 300%, 150% to 10000% or 200% to 10000%.

[0114] Delivery device In another aspect, a drug delivery device for administration of the compositions or aqueous suspensions described herein is provided. The drug delivery device can be any implantable device based on, for example, diffusion, erosion or convection systems, such as diffusion systems, osmotic pumps, electro-diffusion systems, electro-osmotic pressure systems, electromechanical systems, etc. In certain embodiments, a controlled drug delivery device can be utilized for controlled, long-term delivery of the composition over a period of time. The term "controlled drug delivery device" means any device in which the release (e.g., rate, timing of release, administration period) of the drug or other desired substance contained in the device is (fully or in part) controlled or determined by the device itself, rather than by the use environment alone. Some non-limiting examples are described.

[0115] In one embodiment, the drug delivery device is a device having a housing member that defines a reservoir in which the above-described composition and / or aqueous suspension is retained. The housing member is of a size and shape appropriate for implantation into the body. For subcutaneous implantation using a cannula or trocar, a cylindrical shape is preferred. The outer diameter of the cylindrical housing component 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 initially exists in a dry form within the reservoir of the device. For example, an aqueous suspension containing a small molecule therapeutic agent and an organic acid is produced, and subsequently spray dried, pulverized, or lyophilized to provide a dry form of the aqueous suspension. Alternatively, the individual components in the 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 the 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 concentrated to yield a dry powder suitable for resuspension in an aqueous medium. The dry form of the composition is tableted or pelletized, introduced into the device, and can be hydrated in situ by subcutaneous implantation of the device containing the dried composition, or the composition can be hydrated at the time of subcutaneous implantation by a physician who introduces a liquid (e.g., physiological buffer, isotonic saline, phosphate buffered saline, or aqueous propylene glycol) into a reservoir or matrix containing the composition. The liquid can be provided as part of a kit containing the drug delivery device and a vial containing the hydration liquid.

[0116] Examples of drug delivery devices are provided in FIGS. 1A-1B. FIG. 1A shows a device 10 assembled and prepared for implantation into an anatomical compartment of a subject, such as subcutaneous or intraperitoneal. The device consists of a non-erosive housing member 12 that defines an internal compartment or reservoir 14. The compositions or formulations described herein are contained within the reservoir. The housing member 12 has first and second ends, 16, 18. As seen in FIG. 1B showing the device 10 in an unassembled form, the first end 16 is sealed with a liquid-tight end cap 20. The end cap 20 may optionally include a porous, semi-permeable or microporous septum 22. The second end 18 is fitted with a porous, semi-permeable or microporous septum 24.

[0117] FIGS. 1C-1K show end caps and end cap sub-assembly parts of a drug delivery device. The numbered components of the sub-assemblies shown in FIGS. 1C-1F are 1 = cap, 2 = porous membrane, 3 = seal, 4 = retention ring and 5 = drug device reservoir. The numbered components of the sub-assemblies shown in FIGS. 1G-1K are 1 = cap, 2 = porous membrane, 3 = seal, 4 = drug delivery device reservoir and 5 = retention ring.

[0118] The interior of the device contains a formulation comprising a small molecule drug that i) has poor water solubility at physiological pH (about 7.4) and ii) functions as a Bronsted or Lewis base. The drug has i) a water solubility of 0.1 to 10 g / L or less than 20 g / L at 25°C and ii) forms a suspension or slurry at a pH (in the aqueous fraction) that is approximately equal to or less than the pKa of the protonated drug when combined with a stoichiometric excess of an organic acid that dissolves at least partially in the presence of the drug and physiological buffer.

[0119] As used herein, the terms "porous membrane" and "porous partition" are intended to mean structural members having a plurality of pores in the nanometer or micrometer (μm) range, preferably in the range of 0.1 to 100 μm or 0.1 to 200 μm. The porous partition allows the passage of a therapeutic agent in soluble form from the formulation contained in the reservoir. The porous partition also allows the passage of an organic acid that is part of the formulation in soluble form. The porous partition in the preferred embodiment retains the therapeutic agent and / or the organic acid in an insoluble form. That is, the therapeutic agent and / or the organic acid in insoluble form do not pass through the pores of the porous partition. The drug delivery device is described in detail in U.S. Patent No. 2011 / 0106006, which is incorporated herein by reference.

[0120] Tests were conducted to evaluate the release rate and reaction order from a drug delivery device containing in the device reservoir a composition consisting of a small molecule therapeutic agent and an organic acid. 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 a model therapeutic agent because of its potency and insolubility in water as a neutral free base (volume of water per volume of drug > 10,000 at 20 - 25 °C). In the tests using risperidone, the drug was formulated with p-aminobenzoic acid (PABA) at an acid:drug ratio of 1:1, 1.5:1, or 2:1 (molar basis) to give a stoichiometric excess of organic acid in each formulation. The dry formulation was filled into the reservoir of the delivery device, hydrated, and incubated with diluted phosphate buffered saline. The release of risperidone was evaluated over a 30-day period, and the results are shown in Figure 2.

[0121] Figure 2 shows the cumulative release of risperidone, in milligrams (mg), from a drug delivery device containing a heterogeneous aqueous formulation consisting of risperidone and 4-aminobenzoic acid (PABA) at risperidone / PABA molar ratios of 1:1 (diamonds); 1:1.5 (squares); 1:2 (black circles), as a function of time (days). In a set of devices containing the 1:2 risperidone / PABA formulation, the membrane surface area decreased to about 50% (open circles). The addition of the organic acid, PABA, to the formulation increased the release rate of the therapeutic agent and also provided a more stable release rate, approaching zero-order kinetics during the delivery period. Devices containing compositions of 1.5:1 or 2:1 PABA / risperidone produced relatively similar release profiles relative to each other, on condition that the membrane surface area of the device was kept constant. A decrease to about 50% in the membrane surface area resulted in a corresponding decrease in the release rate for the system filled with the 2:1 PABA / risperidone formulation. Note that devices with a 1:2 risperidone / PABA molar ratio reach steady state in about 32 days, as the device releases all of the drug.

[0122] In summary, the controlled formulation (risperidone / PABA salt, without excess acid; diamonds) resulted in a slow release rate (i.e., non-linear release rate) that decreased over time from devices with the largest membrane surface area. Formulations containing an acid and drug in a molar ratio of 1.5:1 or 2:1 (squares and black circles, respectively) resulted in higher drug delivery rates compared to formulations containing a non-stoichiometric excess of organic acid. Devices containing the 2:1 organic acid / risperidone formulation and having about half the membrane surface area resulted in a release rate about half that of devices with 100% of the available surface area and the same formulation.

[0123] The results for a similar test using olanzapine (Example 2) are shown in Figure 3A in milligrams as a function of time (days) for the cumulative release of olanzapine from a drug delivery device containing a heterogeneous formulation consisting of olanzapine and 4-aminobenzoic acid (PABA, squares) or p-toluic acid (diamonds) at a molar ratio of olanzapine / organic acid 1:1.5 or containing no acid (circles) as a control in the device reservoir. Olanzapine is a base with poor water solubility. When formulated with a stoichiometric excess (1.5:1 molar ratio) of organic acid (PABA or p-toluic acid), increased and stable release rates are observed. The various organic acids result in substantially different release rates, which is thought to reflect formulation pH values (4.5 - 5.0) close to the reported pKa values of doubly protonated olanzapine (pKa1 = 5.0; pKa2 = 7.4).

[0124] Figure 3B shows the results for another study such as the test described in Example 2, presumably with a heterogeneous aqueous formulation consisting of olanzapine and 4-aminobenzoic acid (PABA, *) or p-toluic acid (triangles) at a molar concentration of olanzapine / organic acid 2:1 in the drug delivery device. The in vitro cumulative release of olanzapine from the drug delivery device is shown in Figure 3B in milligrams as a function of time (days), where the device containing olanzapine and PABA (*) released more rapidly than the device containing the formulation with p-toluic acid (triangles). As a control, the device containing no acid - i.e., containing only olanzapine (squares) - released the drug slowly during the 15-day test period.

[0125] In summary, during the test or treatment period, little olanzapine free base was released from the control device (circle) (total amount < 1 mg). Devices containing formulations with a drug to organic acid molar ratio of 1:1.5 or 1:2, with organic acid - PABA (square) or p - toluic acid (diamond), achieved a greater release rate than the control device, as well as a linear release rate. In the case of olanzapine, the various acid additives resulted in substantially different release rates; for example, PABA resulted in a faster release than p - toluic acid. Considering this data, one of ordinary skill in the art would understand that the release rate can be adjusted by the selection of the organic acid in the formulation and the molar ratio of the drug to the organic acid.

[0126] In certain embodiments, a formulation comprising a small molecule therapeutic agent and an organic acid, where the organic acid is present in stoichiometric amount or in stoichiometric excess, 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 the small molecule therapeutic agent that does not contain the organic acid or contains less than stoichiometric amount of the organic acid. In certain embodiments, the increased release rate is for a period of at least 14 days, at least 2 weeks, at least 30 days or at least 45 days or at least 60 days or at least 90 days or at least 180 days. In another embodiment, the increased release rate approaches a zero - order release rate during the period.

[0127] Another test was formulated such that the drug delivery device contained dry tablets of risperidone base and PABA (Example 3) or sebacic acid (Example 4) in the device reservoir, as described in Examples 3-4. Tablets consisting of risperidone base and organic acid in a weight ratio of 1.5:1 or 1:1 were produced by dissolving the drug and the organic acid together in a solvent, 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 the tablets were pressed. The tablets were filled into the drug delivery device. Immediately prior to in vivo implantation, each device was filled with sterile phosphate buffered saline (PBS) to hydrate the tablets. The devices were implanted, blood samples were obtained for pharmacokinetic (PK) analysis, and local safety was evaluated for 6 months. The results are shown in Figure 4 as the plasma concentration of risperidone in ng / mL as a function of time (days) for devices having aqueous formulations of risperidone and 4 - aminobenzoic acid (PABA, circles) and for devices having aqueous formulations of risperidone and sebacic acid (diamonds). For devices filled with risperidone and PABA (Figure 4, circles), the plasma levels of the active moiety of risperidone (risperidone and its active metabolite, 9 - OH risperidone) reached a peak in the first few days and then were located at a plasma level of about 50 ng / mL during the 6 - month implantation period. Mass balance analysis revealed that the devices explanted after 6 months released the drug at an average rate of 0.70 mg / day and contained an average of 108 mg of un - released risperidone. These findings indicate that the devices operated in vivo for an additional 154 days for a total operating period of 337 days. To extend the operating period, the device reservoir is sized and filled with sufficient drug and organic acid at the desired rate for the delivery period. For example, to create a 12 - month system, the length of the reservoir is increased by 10% from 40.0 mm to 44.0 mm. Thus, the dosing rate is increased by increasing the diameter of the device or by implanting more than one device per subject.

[0128] For the device filled with risperidone and sebacic acid (Figure 4, diamond), the plasma levels of the risperidone active moiety (risperidone and its active metabolite, 9-OH risperidone) reached a peak in the first few days and then reached a steady state maintaining a plasma level of 50 - 60 ng / mL for 6 months. Mass balance analysis revealed that the device removed after 6 months released the drug at an average rate of 0.80 mg / day and contained an average of 26 mg of un-released risperidone. These findings indicate that the device operated in vivo for an additional 32 days during the entire 7-month operating period.

[0129] Example 5 describes a test in which a composition containing various risperidone salts is prepared by dissolving a drug and a two-fold molar excess of an organic acid in methanol. The solvent was removed and the dried cake was further dried, pulverized and optionally tabletted. The dried drug salt was placed in the reservoir of a drug delivery device. The filled device was hydrated and allowed to stand at 37 °C in 100 mL of PBS. The release of risperidone was measured by collecting aliquots of the receiving buffer and analyzing for risperidone concentration. Figure 5 shows the cumulative in vitro release (expressed as the percentage of the total loaded drug released into the receiving medium) for various risperidone salts (PABA salt, squares; terephthalate salt, diamonds; sebacate salt, open diamonds; vanillate salt, triangles; hippurate salt, x; hydroxyphenylpropionate salt, open circles; urate salt, filled circles). As can be seen, the slopes of the curves are different, indicating different release rates. The terephthalic acid (diamonds) and uric acid (filled circles) addition salts resulted in poor release, achieving only 2.6% and 16% release, respectively, over 15 days. The risperidone salts of hippuric acid (x) and hydroxyphenylpropionic acid (open circles) achieved 94% and 92% release, respectively, after 15 days. The risperidone salts of sebacic acid (open diamonds), vanillic acid (triangles) and PABA (squares) resulted in an intermediate rate of risperidone release, with approximately 40 - 60% of the total drug amount released over about 15 days. Thus, in one embodiment, a composition of a therapeutic agent and an organic acid provides release of the therapeutic agent such that at least about 40%, 50% or 60% of the therapeutic agent is released in vitro over about 15 days. In another embodiment, a composition of a therapeutic agent and an organic acid provides release of the therapeutic agent such that less than about 30% or less than 40% of the therapeutic agent is released in vitro over about 15 days. In another embodiment, a composition of a therapeutic agent and an organic acid provides release of the therapeutic agent such that about 40 - 50% of the therapeutic agent is released in vitro over about 15 days.

[0130] The in vitro release rate of the risperidone salts described in Example 5 and shown in Figure 5 is related to the intrinsic aqueous solubility of the acid. The aqueous solubilities of the acids used in Example 5 and their respective risperidone release rates from the devices into the buffer (expressed as the cumulative percent of total risperidone released after incubation at 37 °C for 15 days) are listed in Table 2. These data are plotted in Figure 6. The highest risperidone release rate occurs when the drug is combined with an acid having an intrinsic aqueous solubility of about 1.0 - 6.0 mg / mL. Maximum release is seen for the risperidone salts of hippuric acid and 3-(4-hydroxyphenyl)propionic acid, which exhibit an aqueous solubility of about 2.5 - 4.0 mg / mL at about 25 °C. This data indicates that acids with an aqueous solubility of less than about 1 g / L do not maintain a sufficiently low pH within the device, while acids with a substantially higher aqueous solubility than 6 g / L are released from the device extremely rapidly and thus cannot maintain drug release over an extended period. [Table 2]

[0131] The in vitro release rate of the risperidone salts enumerated in Example 5 is 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 percent of total risperidone released after incubation at 37 °C for 15 days) are shown in Figure 7. The highest risperidone release rate occurs when the drug is combined with an acid having a pH at the saturated concentration of about 2.0 - 3.7. Maximum release is seen for the risperidone salts of hippuric acid and 3-(4-hydroxyphenyl)propionic acid, which exhibit pH values of 2.6 and 3.0, respectively. Thus, in certain embodiments, the composition comprises a therapeutic agent and an organic acid having a saturated pH in aqueous solution of about 2.0 - 3.7, or about 2.1 - 3.6, about 2.1 - 3.5, about 2.2 - 3.5, about 2.2 - 3.4, about 2.3 - 3.4, about 2.4 - 3.3, about 2.5 - 3.2, about 2.5 - 3.1, about 2.5 - 3.0, about 2.6 - 3.2, about 2.6 - 3.1, or about 2.6 - 3.0.

[0132] Other drug delivery devices are known in the art. The compositions described herein are useful for a variety of devices including devices that contain a drug reservoir for holding a small molecule therapeutic agent and an organic acid formulation, and devices having a substrate or matrix that can hold or can contain a formulation. Suitable controlled drug release devices of the present invention can generally provide delivery of a drug from the device to a selected site of a subject in a selected or other patterned amount and / or rate. The drug delivery device must be capable of containing an amount of formulation to provide a therapeutically effective amount of the small molecule during the treatment period. The delivery period varies depending on the therapeutic agent, the condition being treated, and the individual patient. In certain embodiments, the delivery period, also referred to herein as the duration, is intended to be a period of at least about 2 weeks to about 6 months. In another embodiment, the duration is intended to be a period of at least about 2 weeks or at least about 3 weeks or at least about 4 weeks to about 6 months or about 4 months or about 3 months. In another embodiment, the duration is intended to be 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 other embodiments, about 2 hours to about 72 hours, about 4 hours to about 36 hours, about 12 hours to about 24 hours, about 2 days to about 30 days, about 5 days to about 20 days, about 7 days or more, about 10 days or more, about 100 days or more; about 1 week to about 4 weeks, about 1 month to about 24 months, about 2 months to about 12 months, about 3 months to about 9 months, about 1 month or more, about 2 months or more, or about 6 months or more.

[0133] Accordingly, in another aspect, an implantable device is contemplated. The device includes a reservoir containing a formulation of a small molecule therapeutic agent, the reservoir including (i) an amount of the therapeutic agent to provide substantially zero-order release of the therapeutic agent in an amount to provide a therapeutic effect for a period of at least about 30 days, and (ii) an organic acid that (a) maintains the pH of the formulation when hydrated in a use environment having a pH of 3.0 to 6.0 during the delivery period, (b) is present in a stoichiometric (molar concentration) excess relative to the therapeutic agent, and (c) is present in an amount substantially equal to or greater than its saturation concentration in the formulation at the end of the delivery period when hydrated.

[0134] In another aspect, an implantable device is contemplated. The device comprises a reservoir comprising a formulation of a small molecule therapeutic agent that (i) provides substantially zero-order release of the therapeutic agent in an amount that provides a therapeutic effect for a period of at least about 30 days, and (ii) an organic acid that (a) maintains the pH of the formulation when hydrated in its use environment that is approximately equal to or less than the pKa of the protonated drug during the delivery period; (b) is present in a stoichiometric (molar concentration) excess relative to the therapeutic agent; and (c) is present in an amount approximately equal to or greater than its saturation concentration in the formulation at the end of the delivery period when hydrated.

[0135] In certain embodiments, the formulation comprising a stoichiometric excess of the organic acid is in a dry form. For example, the dry formulation can be present in the reservoir as a powder, tablet, or film. When used in vitro or in vivo, the device absorbs fluid from the surrounding environment to hydrate the dry formulation, thus forming in situ an aqueous suspension comprising particles of both the salt form of the therapeutic agent and the insoluble excess.

[0136] The drug delivery device can be implanted at any suitable implantation site using methods and devices known in the art. As described below, the implantation site is a site within the body of the subject into which the drug delivery device is introduced and positioned. The implantation site includes, but is not necessarily limited to, subdermal, subcutaneous, intramuscular, or other suitable sites within the body of the subject. Subcutaneous implantation sites are preferred for convenience in implantation and removal of the drug delivery device. Typical subcutaneous delivery sites include the subcutaneous regions of the arm, shoulder, neck, back, or leg. Sites within body cavities are also suitable implantation sites. Methods for implanting or otherwise attaching a drug delivery device for subcutaneous delivery of a drug are known in the art. In general, attachment of the drug delivery device is accomplished using methods and instruments known in the art and is performed under aseptic conditions using at least some local or general anesthesia administered to the subject.

[0137] Treatment method In other aspects, methods of treatment using the compositions and devices described herein are contemplated. In certain embodiments, methods for sustained and controlled delivery of central nervous system drugs are contemplated, and compositions described herein or delivery devices comprising such compositions are provided.

[0138] In another embodiment, methods for sustained and controlled delivery of antipsychotic drugs are contemplated, and compositions described herein or delivery devices comprising such compositions are provided.

[0139] In another embodiment, methods for maintaining therapeutic plasma levels of antipsychotic drugs and thereby delaying relapse in patients who have been previously dosed stably by at least four weeks are contemplated.

[0140] Based on the foregoing, the compositions described herein, which consist of small molecule therapeutic agents and organic acids, provide release of the therapeutic agent at a constant rate approaching zero order release rate over an extended period - at least about 14 days or at least about 30 days - and maintain a sufficient amount of the therapeutic agent relative to the therapeutic dose of the drug and (i) the concentration of the protonated therapeutic agent at or near its saturation concentration in the hydrated composition during the period and / or (ii) an amount of organic acid sufficient to maintain a concentration of the organic acid equal to or greater than its saturation concentration in the hydrated composition at the end of the delivery period. The drug at approximately saturated concentration is with respect to the aqueous phase of the composition. In some embodiments, the composition is retained within a drug delivery system (or device) and, when placed in the use environment (e.g., subcutaneous implantation site, e.g., plasma or interstitial fluid having a constant pH of about 7.4), provides a constant concentration gradient between the interior of the device, which facilitates a constant release rate (rate approaching zero order) of the therapeutic agent during that period, and the use environment.

Examples

[0141] III. Examples The following examples are illustrative and not intended to be limiting.

[0142] Example 1 Formulation containing risperidone as a small molecule therapeutic agent and an organic acid Risperidone and p-aminobenzoic acid (PABA) were formulated at an acid:drug ratio of 1:1, 1.5:1 or 2:1 (molar basis), tabletted with a lactose binder (13%), and filled into a delivery device equipped with a 0.1 micron polyvinylidene fluoride (DURAPORE®) membrane. In some devices, approximately 50% of the available membrane surface area was blocked to measure the effect of surface area on the release rate. All devices were filled under reduced pressure with phosphate buffer and transferred to a bottle containing the same volume (about 100 mL) of buffer. The sealed bottles were then incubated at 37 °C, aliquots (about 500 μL) of the receiving buffer were withdrawn at selected time points, and the released drug was quantified by high performance liquid chromatography (HPLC). The release of risperidone is shown in Figure 2.

[0143] Example 2 Formulation containing olanzapine organic acid as a small molecule therapeutic agent Olanzapine was formulated with p-aminobenzoic acid (PABA) or p-toluic acid at an acid:drug ratio of 1.5:1 (molar basis), tabletted with a lactose binder (13%), and filled into a delivery device equipped with a 0.1 micron polyvinylidene fluoride (DURAPORE®) membrane. All devices were filled under reduced pressure with phosphate buffer and transferred to a bottle containing the same volume (about 100 mL) of buffer. The sealed bottles were then incubated at 37 °C, aliquots (about 500 μL) of the receiving buffer were withdrawn at selected time points, and the released drug was quantified by high performance liquid chromatography (HPLC). The release of olanzapine is shown in Figure 3A.

[0144] Example 3 In vivo pharmacokinetics of a 12-month implantable device filled with a formulation containing risperidone and para-aminobenzoic acid Risperidone base (75.00 g, 0.1827 mol) was weighed and transferred to a 1.0 L medium bottle containing a stir bar. PABA (50.00 g, 0.3646 mol) was weighed and added to the bottle containing risperidone. Approximately 750 mL of methanol was then added. The bottle containing the formulation was sealed and mixed by a magnetic stirrer. The mixture was visually inspected for complete dissolution of the drug and acid, and the stir bar was removed. The solution was then directly filtered through a rotary evaporator (0.45 μ DURAPORE®) and subjected to a primary drying process under vacuum until most of the solvent had evaporated, and the start time and end time were recorded. After completion of the rotary (primary) drying, the vacuum was released, and the resulting foamy material was briefly reduced by hand before being subjected to secondary drying under high vacuum.

[0145] After secondary drying, all of the mixture was transferred to a glove box for grinding. The formulation was placed into a milling container equipped with a blade for grinding the dry material and milled using a blender base at 20,000 rpm. To prevent heating of the formulation, a custom polypropylene sleeve was used around the container together with dry ice. The mixture was milled for 5 cycles. The resulting powder was mixed with polyvinylpyrrolidone (PVP ~40K, Sigma Aldrich) as a 12 wt% binder and stearic acid (1% of the final powder weight, Sigma Aldrich) as a 1 wt% lubricant. Tablets were manufactured using a tablet press obtained from Vanguard Pharmaceutical Machinery (Spring, Texas) and a custom die set. The die used for tableting had a diameter that fit the inner diameter (4.30 mm) of the device reservoir.

[0146] The drug delivery device was manufactured from titanium measured at a length of 40.0 mm and has an internal reservoir. The cap portion assembly (Figs. 1C - 1K) included a DURAPORE® porous membrane (0.1 micron, Millipore Corp). The assembled cap was attached to the device reservoir and weighed together with another assembled cap to obtain the weight of the empty device. Each reservoir sub - assembly (reservoir + one cap) was manually filled with tablets, capped with the second cap sub - assembly and weighed again to obtain the filling weight of the tablets. The average filling weight of each device was 460 mg (equivalent to 230 mg of risperidone as the free base).

[0147] After weighing, the assembled devices were individually placed into 20 mL lyophilization vials. The vials were loosely capped with an igloo - type rubber septum and placed in a lyophilizer equipped with a stopper trace system. Before sealing, the airspace within each device and vial was evacuated to a vacuum pressure of < 1 torr for more than 30 minutes.

[0148] During the manufacturing process, efforts were made to maintain a low bioburden at the formulation, device assembly, and trocar assembly stages. Finally, terminal sterilization of both the filled devices and their implantation tools was performed using electron beam sterilization at a split dose of 25 kGy.

[0149] Immediately prior to in vivo implantation, each device was filled with sterile phosphate buffered saline (PBS) using a 20 mL syringe with a blunt fill needle. Through insertion of the needle through the rubber septum, the hydration solution was rapidly drawn into the vial and device by the vacuum within the vial without any manual force being applied to the plunger. After hydration, the needle was withdrawn from the septum and the device was left for approximately 10 minutes. Each device was then recovered from its vial, blotted with tissue to absorb any external liquid, and weighed. Using a custom implanting tool, it was implanted subcutaneously on one side of the animal's dorsal side, and the incision was closed with sutures or surgical adhesive. Whole blood samples were obtained for pharmacokinetic (PK) analysis, and local safety was evaluated for 6 months. The implants were well tolerated by all animals. For the first 6 months, the PK results are shown in Figure 4. Plasma levels of the risperidone active moiety (risperidone and its active metabolite 9-OH risperidone) reached a peak in the first few days and then reached a steady-state plasma level of 50 - 60 ng / mL during the 6-month implantation period. Mass balance analysis revealed that the devices explanted after 6 months released drug at an average rate of 0.70 mg / day and contained an average of 108 mg of un-released risperidone. These findings indicate that the devices operated in vivo for an additional 154 days, for a total operating period of 337 days. To extend the operating period, the device reservoir can be sized and filled with sufficient drug and organic acid at the desired rate for the delivery period. For example, to create a 12-month system, the length of the reservoir is increased by 10% from 40.0 mm to 44.0 mm. Thus, the dosing rate can be increased by increasing the diameter of the device or by implanting more than one device per subject.

[0150] Example 4 In Vivo Pharmacokinetics of a 7-Month Implantable Device Filled with a Formulation Containing Risperidone and Sebacic Acid Weighed risperidone base (75.00 g, 0.1827 mol) and transferred it to a 1.0 L media bottle containing a stir bar. Weighed sebacic acid (74.91 g, 0.3704 mol) and added it to the bottle containing risperidone. Then added approximately 75 mL of methanol. Sealed the bottle containing the formulation and mixed it with a magnetic stirrer. Visually inspected the mixture for complete dissolution of the drug and acid, and removed the stir bar. Dried, granulated, tabletted, filled the device reservoir, and finally sterilized the mixture as described in Example 3. The device reservoir size was 3.6 mm inner diameter and 5.21 mm outer diameter, with a length of 41.4 mm. Five devices were filled with tablets of an average of 400 mg (corresponding to 167 mg equivalent of risperidone base).

[0151] Each device was then recovered from its vial, wiped with tissue to absorb all external liquid, and weighed. Subcutaneously implanted on one side of the dorsal side of the animal using a custom implanting tool, and the incision was sutured or closed with a surgical adhesive. Obtained whole blood samples for pharmacokinetic (PK) analysis and evaluated local safety for 6 months. The implants were well tolerated by all animals. The PK results for the first 6 months are shown in Figure 4.

[0152] Example 5 In vitro release of risperidone from devices filled with various risperidone addition salts Manufactured various risperidone salts by dissolving the drug and a two-fold molar excess of the selected acid in methanol. Removed the solvent under reduced pressure. As described in Example 3, further dried, pulverized, (in some cases) tabletted, filled the reservoir, capped, and made into a vacuum vial. Hydrated the filled device and left it standing at 37 °C in 100 mL of PBS on an orbital rotor (50 rpm). Analyzed a portion of the receiving buffer for risperidone concentration (spectrophotometer or HPLC). Figure 5 represents the cumulative in vitro release (expressed as a percentage of the total filled drug released into the receiving medium) for various risperidone salts.

Claims

**Claim 1** (i) having a water solubility of less than 1.0 g / L at room temperature, (ii) a therapeutic agent that is an organic base, and (i) having a water solubility of 0.1 to 10 g / L at room temperature, (ii) having a molar mass of less than 500 grams per mole, (iii) being present in a stoichiometric (molar concentration) excess relative to the therapeutic agent, and (iv) an aqueous suspension comprising an organic acid that maintains the pH of the suspension in its use environment at pH 3.0 to 6.5 for a period of at least about 30 days. **Claim 2** The composition according to claim 1, wherein the saturated aqueous solution of the organic acid has a pH value that is approximately equal to or less than the pKa of the protonated therapeutic agent. **Claim 3** The composition according to claim 1 or 2, wherein at the end of the period, the organic acid is present in an amount approximately equal to or exceeding its saturated concentration. **Claim 4** The composition according to any one of claims 1 to 3, wherein the organic acid is present in a stoichiometric excess of 105% to 1000% relative to the therapeutic agent. **Claim 5** The composition according to any one of claims 1 to 4, wherein the organic acid is a crystal and has a melting point above about 37 °C. **Claim 6** The composition according to any one of claims 1 to 5, wherein the therapeutic agent is used for treating a disease of the central nervous system. **Claim 7** The composition according to claim 6, wherein the therapeutic agent is an antipsychotic drug. **Claim 8** The composition according to claim 6 or 7, wherein the therapeutic agent is risperidone, olanzapine, asenapine, aripiprazole or brexpiprazole. **Claim 9** The composition according to any one of claims 1 to 8, wherein the aqueous suspension comprises a buffer. **Claim 10** The composition according to claim 9, wherein the buffer is phosphate buffered saline. **Claim 11** The composition according to any one of claims 1 to 10, wherein the organic acid is an aromatic carboxylic acid. **Claim 12** The composition according to any one of claims 1 to 10, wherein the organic acid is a carboxylic acid having a water solubility of about 2 mg / mL to 8 mg / mL at a temperature of 25 °C to 37 °C. **Claim 13** The composition according to any one of claims 1 to 10, wherein the organic acid is a carboxylic acid having a pH of about 2.0 to 3.7 at a saturated concentration at a temperature of 25 °C to 37 °C. **Claim 14** The composition according to any one of claims 11 to 13, wherein the carboxylic acid is a carboxylic acid having a carboxylic acid group bonded to an unsubstituted benzene ring or pyridine ring. **Claim 15** The composition according to claim 14, selected from the group consisting of benzoic acid, picolinic acid, nicotinic acid and isonicotinic acid.

16. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having a benzene ring and one electron-donating group having antioxidant properties.

17. The composition according to claim 16, wherein 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-toluic acid, m-toluic acid, p-toluic acid and salicylic acid.

18. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having a benzene ring and two electron-donating groups having antioxidant properties.

19. The composition according to claim 18, wherein the carboxylic acid is vanillic acid.

20. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having at least two carboxylic acid groups bonded to the benzene ring.

21. The composition according to claim 20, wherein the carboxylic acid is phthalic acid.

22. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having a carboxylic acid group bonded to a naphthalene ring or a quinoline ring.

23. The composition according to claim 22, wherein the carboxylic acid is selected from the group consisting of 1-naphthoic acid, 2-naphthoic acid, quinolinic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid and 8-quinolinecarboxylic acid.

24. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having an electron-donating group selected from the group consisting of hydroxy, methoxy, amino, alkylamino, dialkylamino and alkyl.

25. The composition according to claim 24, wherein 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.

26. The composition according to claim 14, wherein the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly bonded to a biphenyl ring system.

27. The composition according to claim 26, wherein the carboxylic acid is selected from the group consisting of 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid and diphenic acid.

28. The composition according to claim 14, wherein the carboxylic acid has one additional electron-donating substituent in addition to the hydroxyl group of the carboxylic acid moiety.

29. The composition according to claim 28, 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.

30. The organic acid has 1 to 4 sp ３ The composition according to any one of claims 1 to 10, wherein the organic acid is an organic acid containing a carboxylic acid functional group separated from a benzene ring, a pyridine ring, a naphthalene ring or a quinoline ring by a chain of sp hybridized carbons.

31. The composition according to claim 30, wherein the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.

32. The composition according to any one of claims 1 to 10, wherein the organic acid is an aliphatic dicarboxylic acid having 4 to 8 carbon atoms between the carboxylic acid groups.

33. The carboxylic acid is adipic acid (CH ２ ) ４ (COOH) ２ ), pimelic acid (HO ２ C(CH ２ ) ５ CO ２ H), suberic acid (HO ２ C(CH ２ ) ６ CO ２ H), azelaic acid (HO ２ C(CH ２ ) ７ CO ２ H) and sebacic acid (HO ２ C(CH ２ ) ８ CO ２ H) and is selected from the group consisting of, the composition according to claim 32.

34. The composition according to any one of claims 1 to 10, wherein the organic acid is an unsaturated or polyunsaturated dicarboxylic acid containing 4 to 10 carbon atoms.

35. The composition according to claim 34, wherein the carboxylic acid is selected from the group consisting of fumaric acid, trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid.

36. The composition according to any one of claims 1 to 10, wherein the organic acid is cis-cinnamic acid or trans-cinnamic acid.

37. The composition according to claim 36, wherein the carboxylic acid is trans-cinnamic acid having one or two electron-donating groups selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, or an alkyl group.

38. The composition according to claim 37, wherein 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, and p-methoxycinnamic acid, and ferulic acid.

39. The composition according to any one of claims 1 to 10, wherein the organic acid is a 1,3-dicarbonyl compound containing an acidic (pKa < 8) CH bond.

40. The composition according to claim 39, wherein the organic acid is 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), cyanuric acid, or barbituric acid.

41. The composition according to any one of claims 1 to 10, wherein the organic acid is an imide.

42. The composition according to claim 41, wherein the imide is phthalimide or a substituted phthalimide.

43. The composition according to claim 42, wherein the substituted phthalimide has at least one electron-withdrawing substituent.

44. The composition according to any one of claims 1 to 10, wherein the organic acid is a hydroxamic acid.

45. The composition according to claim 44, wherein the hydroxamic acid is an aromatic hydroxamic acid containing one hydroxamic functional group directly bonded to an aromatic ring.

46. The composition according to claim 45, wherein the aromatic ring is selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring.

47. The composition according to claim 45 or 46, wherein the hydroxamic acid is benzhydroxamic acid.

48. The composition according to claim 44, wherein the hydroxamic acid is a hydroxamic acid containing at least one hydroxamic functional group separated from the aromatic ring by a chain of 1 to 4 saturated carbon atoms.

49. The composition according to claim 48, wherein the aromatic ring is selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring.

50. The composition according to claim 44, which is a dihydroxamic acid containing two or more hydroxamic acid functional groups directly bonded to a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, or a biphenyl ring system.

51. The composition according to any one of claims 44 to 50, wherein the hydroxamic acid is a hydroxamic acid substituted with an electron-donating substituent selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, and an alkyl group.

52. The composition according to claim 44, wherein the hydroxamic acid is an aliphatic dihydroxamic acid containing 6 to 10 carbon atoms.

53. The composition according to claim 52, wherein the hydroxamic acid is suberohydroxamic acid.

54. The composition according to claim 44, wherein the hydroxamic acid is an unsaturated dihydroxamic acid containing 6 to 10 carbon atoms.

55. The composition according to any one of claims 1 to 10, wherein the organic acid contains an aromatic ring and a carboxylic acid functional group.

56. The composition according to claim 55, 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.

57. The composition according to claim 56, wherein the hydroxy derivative of cinnamic acid is m-coumaric acid or p-coumaric acid.

58. The composition according to claim 57, wherein p-coumaric acid is trans-p-coumaric acid.

59. The composition according to claim 56, wherein the methoxy derivative of cinnamic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

60. The composition according to claim 56, wherein the amino derivative of benzoic acid is 2-aminobenzoic acid (anthranilic acid) or 4-aminobenzoic acid (para-aminobenzoic acid; PABA).

61. The composition according to claim 56, wherein the methoxy derivative of benzoic acid is 4-methoxybenzoic acid (p-anisic acid), o-anisic acid, or m-anisic acid.

62. The composition according to any one of claims 1 to 61, wherein the amount of the small molecule therapeutic agent is sufficient to provide treatment for at least 30 days.

63. The composition according to any one of claims 1 to 62, wherein the composition is in a dry form.

64. A device comprising the composition according to any one of claims 1 to 63, designed for subcutaneous implantation in a mammal.

65. (i) A small molecule therapeutic agent in an amount sufficient to provide a therapeutic effect for a period of at least about 30 days, (ii) an organic acid that maintains the pH of the formulation in its use environment at pH 3.0 to 6.5 when hydrated during the delivery period, and (iii) an implantable device comprising a reservoir containing a formulation of the small molecule therapeutic agent having a release rate that provides a therapeutic dose of the agent over the period.

66. The device according to claim 63, wherein the saturated aqueous solution of the organic acid has a pH value approximately equal to or less than the pKa of the protonated therapeutic agent.

67. The device according to claim 65, wherein the formulation is in a dry form.

68. The device according to claim 66, wherein the formulation is a powder, tablet, or film.

69. The device according to claim 66 or claim 68, wherein the formulation is hydrated in the presence of an aqueous solution to form an aqueous suspension.

70. The device according to any one of claims 65 to 69, wherein during the period, the small molecule therapeutic agent is released from the device at a rate that provides a therapeutically effective effect.

71. The device according to any one of claims 65 to 70, wherein the organic acid has a water solubility of 0.1 to 10 g / L and a pKa of 3 to 6.

72. The device according to any one of claims 65 to 71, wherein the organic acid has a melting point above about 37°C.

73. A method for sustained and controlled delivery of a small molecule therapeutic agent, comprising providing a composition according to any one of claims 1 to 64 or a device according to any one of claims 64 to 72.

74. A method for sustained and controlled delivery of a small molecule therapeutic agent used for treating a central nervous system disease, comprising providing a composition according to any one of claims 1 to 64 or a device according to any one of claims 64 to 72.

75. A method for treating a mental disorder, comprising providing a composition according to any one of claims 1 to 64 or a device according to any one of claims 64 to 72.

76. The method according to claim 75, for treating schizophrenia.

Images