Compositions for small molecule therapeutic compounds

Abstract

A composition is described that includes an aqueous suspension containing a small molecule therapeutic agent and an organic acid. The small molecule therapeutic agent is a base and has an aqueous solubility of less than about 1.0 g / L at room temperature. The organic acid has an aqueous solubility of 0.1 to 10 at room temperature, a molar mass of less than 500 grams per mole, and / or maintains a pH of the suspension in a use environment of 3.0 to 6.5. The organic acid improves the solubility of the small molecule therapeutic agent, and when present in a stoichiometric excess, the organic acid causes the release of the small molecule therapeutic agent into a buffered environment for an extended period of time, for example, 6 months to 1 year. Devices and methods of treatment that include the composition are also described.

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 therapeutic agents and drug delivery devices including compositions and formulations for the controlled, sustained delivery of small molecule therapeutic agents. [Background technology]

[0003] An important class of small molecule drugs exhibits poor aqueous solubility at neutral pH. While this property can be advantageous for oral absorption and tissue penetration, it complicates the development of injectable or implantable sustained-delivery systems that rely on passive diffusion as the primary drug release mechanism; for example, low solubility prevents the generation of a sufficient concentration gradient to generate adequate efflux from a reservoir containing an aqueous suspension of the drug. Many insoluble drugs are weak organic bases (i.e., molecules containing at least one functional group, such as a primary, secondary, or tertiary amine, aniline, or amidine), and their aqueous solubility is improved by protonation (i.e., when converted to a salt). However, such salts are unstable and susceptible to hydrolysis at pHs near or above the pKa of the protonated drug. This process complicates the development of implant- or depot-based diffusion-mediated drug delivery systems, as drug efflux from the formulation must be coupled with the influx of buffer species from physiological fluids. There is a need for compositions and devices that address these and other complex factors associated with the sustained and controlled delivery of small molecule therapeutics that are weak organic bases. Summary of the Invention

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

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

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

[0007] In another embodiment, a composition is provided comprising an aqueous suspension comprising a small molecule therapeutic agent (i) having an aqueous solubility of less than 1 g / L at room temperature and (ii) rendered more soluble upon protonation, combined with a stoichiometric excess of an organic acid that (i) has an aqueous solubility of less than 20 g / L at room temperature and (ii) maintains the pH of the suspension in its use environment at or below the pKa of the protonated drug for a period of at least about 30 days.

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

[0009] In some embodiments, the aqueous suspension is a heterogeneous mixture comprising a small molecule therapeutic agent and an organic acid, wherein the organic acid is sufficiently soluble to maintain the pH of the heterogeneous solution in its use environment at or below physiological pH (about 7.4) for a period of time. In some embodiments, the use environment is in vivo. In another embodiment, the use environment is in vitro with the release medium maintained at 37°C.

[0010] In some embodiments, the organic acid is present at the end of the period in an amount that is about equal to or greater than its saturation concentration.

[0011] In another embodiment, the organic acid is present in a stoichiometric (molar) amount ranging from about 105% to 1000% relative to the therapeutic agent, but may be as much as 10,000% greater. In other embodiments, the organic acid, on a molar basis, is 110%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the amount of 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 some embodiments, the aqueous suspension comprises or is prepared 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 prepared using a preformed salt of the therapeutic agent with an organic acid, where the acid is present in a stoichiometric (molar) 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, exemplary 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 yet 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 yet 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 comprises an aromatic ring bearing 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 from 6 to 10 carbon atoms.

[0039] In some embodiments, the hydroxamic acid is suberohydroxamic acid.

[0040] In other embodiments, the hydroxamic acid is an unsaturated dihydroxamic acid containing from 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 silicic acid is m-coumaric acid or p-coumaric acid.

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

[0044] In another embodiment, the methoxy derivative of silicic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

[0045] In still other 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 another embodiment, the composition is in a dry form and is hydrated in situ when in its use environment.

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

[0049] In another aspect, an implantable device is provided. The device comprises a reservoir containing a formulation of a small molecule therapeutic agent comprising (i) an amount of the small molecule therapeutic agent to provide substantially zero-order release of the small molecule therapeutic agent at a rate to provide a therapeutic effect over a delivery 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 at a pH of 3.0 - 6.5 during the delivery period; (b) is present in a stoichiometric (molar) 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.

[0050] In another aspect, an implantable device is provided. The device comprises a reservoir containing a formulation of a small molecule therapeutic agent comprising (i) an amount of the small molecule therapeutic agent to provide substantially zero-order release of the small molecule therapeutic agent at a rate to provide a therapeutic effect over a delivery period of at least about 30 days and (ii) 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 excess amount 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.

[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 at room temperature and a molar mass of less than 500 grams per mole.

[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 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 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 a composition or device described herein. In some embodiments, the method further includes administering the device, for example, by subcutaneous implantation.

[0061] In addition to the above typical aspects and embodiments, further aspects and embodiments will become apparent by reference to the drawings and 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 contradictory. 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]

FIG. 1A - B

[0064]

FIG. 1C - F

[0065]

FIG. 1G - K

[0066]

FIG. 2

[0067]

FIG. 3A

[0068]

FIG. 3B

[0069]

FIG. 4

[0070]

FIG. 5

[0071]

FIG. 6

[0072]

FIG. 7

[0073] Detailed Description I. Definitions 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 values within that range are intended to be encompassed within the disclosed range. 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, a recitation of "polymer" includes a single polymer and two or more identical or different polymers, and a recitation of "excipient" includes a single excipient and two or more identical or different excipients, and so forth.

[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 forth. 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 range greater than 49.5 and less than 52.5. Further, the phrases "less than about (value)" or "greater than about (value)" should be understood in light of the definition of the term "about" provided herein.

[0077] The compositions of the present invention can contain, 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 carried out 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 decreases the frequency of symptoms of a medical condition (e.g., schizophrenia, bipolar disorder) in a subject as compared to a subject not receiving the compound or composition, or delays the onset thereof. This can include reversing, reducing or arresting the symptoms, clinical signs and underlying pathology of the condition in a manner that improves or stabilizes the condition of the subject (e.g., controlling schizophrenia symptoms).

[0081] Any such group of individual members that may be claimed by a range or in some similar manner, including sub-ranges or combinations of sub-ranges within the group, and having the right to conditionally exclude or except any reason whatsoever, may claim a range that is less than the full scope of the invention. Further, a range that is less than the full scope of the invention may 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. Formulations 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 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 include 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 solubility of small molecule therapeutics to enable delivery during a duration. In certain embodiments, the duration is intended to be at least about two weeks to about six months. In another embodiment, the duration is intended to be at least about two weeks or at least about three weeks or at least about four weeks to about six months or about four months or about three months. In another embodiment, the 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 six months, or nine months, or twelve months.

[0086] As described above, the formulations described herein partially improve the solubility of small molecule therapeutics 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 and the organic acid, are described hereinafter.

[0088] A. Small molecule therapeutics In some embodiments, the composition comprises a small molecule therapeutic agent that has an aqueous solubility of less than 1.0 g / L at room temperature and (ii) is an organic base. In some embodiments, the term "small molecule" refers to a biologically active molecule having a molecular weight of 2,000 daltons or less, and is generally used in the context of small molecule drugs (therapeutics) to distinguish them from protein, polypeptide, or peptide therapeutics. In other embodiments, 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] Contemplated small molecule therapeutic agents include, but are not limited to, agents that are weak organic bases (i.e., have a conjugate acid with a pKa of 6-9 or 5-9) and are potent such that a 30-60 day dose can be contained in a delivery device implanted in a human.

[0090] For example, therapeutic agents containing primary, secondary, or tertiary amine, aniline or aniline derivative, or amidine functional groups are contemplated as small molecule therapeutic agents that are organic bases. It is understood that therapeutic agents having structures containing one or more of these functional groups are contemplated. Examples of aniline derivatives include analogs of aniline in which the phenyl group is replaced with, for example, a methyl group (toluididine), a halogen atom 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 some embodiments, the small molecule therapeutic agent is an antipsychotic drug, including an atypical antipsychotic. In other embodiments, the small molecule therapeutic agent has activity in treating diseases of the central nervous system. Exemplary agents include, but are not limited to, risperidone, olanzapine, asenapine, aripiprazole, or brexpiprazole.

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

[0093] B.Organic acid 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) an aqueous solubility of between 0.1 and 10 g / L and less than about 20 g / L at room temperature; (ii) a molar mass of less than 500 grams per mole; (iii) a stoichiometric excess relative to the therapeutic agent; and (iv) maintains the pH of the suspension or solution in its use environment at or below the pKa of the protonated small molecule therapeutic agent for a period of at least about 30 days. As described above, the composition improves the solubility of the small molecule therapeutic agent, enabling the composition to be used in drug delivery platforms that provide extended sustained release. The excess acid (on a stoichiometric basis relative to the therapeutic agent) interferes with physiological buffering 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 groups, methoxy groups, amino groups, alkylamino groups, dialkylamino groups or alkyl groups. 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 the 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 the 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 the 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 the benzene, pyridine, naphthalene, or quinoline ring by a saturated carbon atom chain of 1 to 4 carbon atoms. 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 attached to the aromatic ring. 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. An example includes benzhydroxamic acid. Hydroxamic acids can also be aromatic hydroxamic acids containing 1 to 4 sp 3 The hydroxamic acid may be a hydroxamic acid containing a hydroxamic functional group separated from the aromatic ring by a hybridized carbon atom chain. Dihydroxamic acids containing two or more hydroxamic functional groups directly attached to a benzene, pyridine, naphthalene, quinoline, or biphenyl ring system are also contemplated. Additionally, substituted derivatives of the above hydroxamic acids containing electron-donating substituents such as hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl groups are also contemplated. Aliphatic dihydroxamic acids containing 6 to 10 carbon atoms, such as suberohydroxamic acid, and unsaturated dihydroxamic acids containing 6 to 10 carbon atoms are also contemplated.

[0108] Organic acids for use in the compositions described herein preferably have an aqueous solubility of 0.1 to 10 g / L, or less than about 20 g / L, at room temperature. In another embodiment, organic acids for use in the compositions described herein have a molar mass of less than 500 grams per mole. In another embodiment, organic acids for use in the compositions described herein are non-polymeric or non-oligomeric. In another embodiment, organic acids for use in the compositions described herein do not have a polymeric or oligomeric backbone and / or are not attached to a polymeric or oligomeric backbone. In another embodiment, the acid has an aqueous solubility of less than about 20 g / L at room temperature and a pKa value of about 3 to 6, more preferably about 3 to 5.5 or about 3.5 to 5.5. In another embodiment, the organic acid is crystalline and has a melting point above about 37°C.

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

[0110] Compositions were prepared using the following organic acids listed in Table 1, and the pH values were measured. [Table 1]

[0111] In embodiments in which the composition is present in a reservoir of a drug delivery device, the device is susceptible to the use environment when placed in the use environment. That is, the use environment and the composition in the device are fluidly connected through pores or a porous membrane in the drug delivery device. The compositions described herein include an organic acid in the form of a suspension or slurry that provides limited aqueous solubility. The organic acid is present in the composition in an amount greater than 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 can be used to achieve a desired pH of the suspension or heterogeneous solution of 3.0 to 6.5, preferably 2.75 to 5.75, more preferably 2.8 to 5.6, preferably 2.9 to 5.6, preferably 3.1 to 5.5, 3.2 to 5.5, 3.3 to 5.5, 3.4 to 5.5, 3.5 to 5.5, 3.1 to 5.4, 3.2 to 5.4, 3.3 to 5.4, 3.4 to 5.4, 3.5 to 5.4, 3.1 to 5.3 ... Maintain between 2-5.3, 3.3-5.3, 3.4-5.3, 3.5-5.3, 3.1-5.2, 3.2-5.2, 3.3-5.2, 3.4-5.2, 3.5-5.2, 3.1-5.1, 3.2-5.1, 3.3-5.1, 3.4-5.1, 3.5-5.1, 3.1-5.0, 3.2-5.0, 3.3-5.0, 3.4-5.0, 3.5-5.0, 3.5-5.5 or 3.5-6.0.

[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 delivery.

[0113] In another embodiment, the molar excess of the organic acid is between 101% and 900%, between 101% and 800%, between 101% and 700%, between 101% and 600%, between 101% and 500%, between 101% and 400%, between 101% and 300%, between 101% and 200%, between 150% and 1000%, between 150% and 900%, between 150% and 800%, between 150% and 700%, between 150% and 600%, between 150% and 500%, between 150% and 400%, between 150% and 300%, between 150% and 200%. Ranging from 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 is provided for administering the compositions or aqueous suspensions described herein. The drug delivery device may be, for example, any implantable device based on diffusion, erosion, or convection systems, such as diffusion systems, osmotic pumps, electrodiffusion systems, electroosmotic systems, electromechanical systems, etc. In some embodiments, a controlled drug delivery device may be utilized for controlled, long-term delivery of a composition over a period of time. The term "controlled drug delivery device" is intended to encompass any device in which the release (e.g., rate, timing of release, duration of administration) of a drug or other desired substance contained in the device is controlled or determined (fully or in part) by the device itself, rather than solely by the environment of use. Some non-limiting examples are described below.

[0115] In one embodiment, the drug delivery device is a device having a housing member that defines a reservoir in which the above composition and / or aqueous suspension is retained. The housing member is of a size and shape suitable 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, milled, 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 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., a 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 as 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-erodible 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, which shows 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 0.1-10 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 a physiological buffer.

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

[0120] Studies were conducted to evaluate the release rate and order of kinetics from drug delivery devices containing compositions consisting of a small molecule therapeutic agent and an organic acid in the device reservoir. As described in Examples 1 and 2, compositions of risperidone with various organic acids and olanzapine with two different organic acids were prepared. Risperidone was selected as a model therapeutic agent due to its potency in water as a neutral free base and its insolubility (>10,000 volumes of water per volume of drug at 20-25°C). In studies with risperidone, the drug was formulated with p-aminobenzoic acid (PABA) at acid:drug ratios of 1:1, 1.5:1, or 2:1 (molar basis) to provide a stoichiometric excess of the organic acid in each formulation. The dried formulations were loaded into the reservoir of the delivery device, hydrated, and incubated with diluted phosphate-buffered saline. Risperidone release 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 PABA / risperidone compositions of 1.5:1 or 2:1 resulted in relatively similar release profiles relative to each other, provided 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, no excess acid; diamonds) resulted in a slow release rate (i.e., non-linear release rate) that decreased with time from devices with the largest membrane surface area. Formulations containing acid and drug at molar ratios 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% 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 in the device reservoir 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 acid-free (circles) as a control. Olanzapine is a base with poor water solubility. Increased and stable release rates are observed when formulated with a stoichiometric excess (1.5:1 molar ratio) of organic acid (PABA or p-toluic acid). 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 filled 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 (* mark) released more rapidly than the device containing the formulation with p-toluic acid (triangles). As a control, the acid-free - i.e., the device 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 and an organic acid - PABA (square) or p - toluic acid (diamond) in a molar ratio of 1:1.5 or 1:2 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, wherein 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] Additional studies in which drug delivery devices were formulated to contain dried tablets of risperidone base and PABA (Example 3) or sebacic acid (Example 4) within the device reservoir are described in Examples 3-4. Tablets consisting of risperidone base and organic acid in a 1.5:1 or 1:1 weight ratio were prepared by dissolving the drug and organic acid together in a solvent and drying to remove the solvent. The dried drug-organic acid mixture was milled, and the resulting powder was mixed with a binder (polyvinylpyrrolidone) and a lubricant (stearic acid) and pressed into tablets. The tablets were loaded into drug delivery devices. 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. Results are shown in Figure 4 for the plasma concentrations of risperidone in ng / mL as a function of time (days) for devices containing an aqueous formulation of risperidone and 4-aminobenzoic acid (PABA, circles) and for devices containing an aqueous formulation of risperidone and sebacic acid (diamonds). For devices loaded with risperidone and PABA (Figure 4, circles), plasma levels of the risperidone active moiety (risperidone and its active metabolite, 9-OH risperidone) peaked within the first few days and then remained at a plasma level of approximately 50 ng / mL for the 6-month implant period. Mass balance analysis revealed that 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 unreleased risperidone. These findings indicate that the device operated for an additional 154 days in vivo, for a total operating period of 337 days. To extend the operating period, the device reservoirs were sized and filled with sufficient drug and organic acid for the desired delivery period. For example, to create a 12-month system, the reservoir length is extended by 10% from 40.0 mm to 44.0 mm. Thus, the administration rate can be increased by increasing the diameter of the device or by implanting more than one device per subject.

[0128] For the risperidone and sebacic acid-loaded devices (Figure 4, diamonds), plasma levels of the risperidone active moiety (risperidone and its active metabolite, 9-OH risperidone) peaked within the first few days and then reached a steady state, maintaining plasma levels of 50–60 ng / mL for 6 months. Mass balance analysis revealed that devices explanted after 6 months released the drug at an average rate of 0.80 mg / day and contained an average of 26 mg of unreleased risperidone. These findings indicate that the device operated for an additional 32 days in vivo, for a total operating period of 7 months.

[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 is removed and the dried cake is further dried, pulverized, and optionally tabletted. The dried drug salt is placed in the reservoir of a drug delivery device. The filled device is 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 the 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, diamonds; sebacate, open diamonds; vanillate, triangles; hippurate, x; hydroxyphenylpropionate, open circles; urate, 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 certain embodiments, 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 rates of risperidone salts described in Example 5 and shown in Figure 5 are 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 device into buffer (expressed as cumulative percent of total risperidone released after 15 days of incubation at 37°C) are listed in Table 2. These data are plotted in Figure 6. The highest risperidone release rates occur when the drug is combined with an acid having an intrinsic aqueous solubility of approximately 1.0 to 6.0 mg / mL. Maximum release is observed for risperidone salts of hippuric acid and 3-(4-hydroxyphenyl)propionic acid, which exhibit aqueous solubilities of approximately 2.5 to 4.0 mg / mL at approximately 25°C. This data indicates that acids with aqueous solubilities less than approximately 1 g / L do not maintain a sufficiently low pH within the device, while acids with aqueous solubilities substantially greater than 6 g / L release from the device too rapidly and therefore fail to sustain drug release over an extended period of time. [Table 2]

[0131] The in vitro release rates of the risperidone salts listed in Example 5 are also related in part to the pH of the saturated aqueous solution of the acid. The pH at saturation of the acids used in Example 5 and their respective risperidone release rates (expressed as cumulative percent of total risperidone released after 15 days of incubation at 37°C) are shown in Figure 7. The highest risperidone release rates occur when the drug is combined with an acid exhibiting a pH at saturation of approximately 2.0 to 3.7. Maximum release is observed for risperidone salts of hippuric acid and 3-(4-hydroxyphenyl)propionic acid, which exhibit pH values of 2.6 and 3.0, respectively. Thus, in some embodiments, the composition comprises a therapeutic agent and an organic acid having a saturated pH in aqueous solution of about 2.0 to 3.7, or about 2.1 to 3.6, about 2.1 to 3.5, about 2.2 to 3.5, about 2.2 to 3.4, about 2.3 to 3.4, about 2.4 to 3.3, about 2.5 to 3.2, about 2.5 to 3.1, about 2.5 to 3.0, about 2.6 to 3.2, about 2.6 to 3.1, or about 2.6 to 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 for the present invention can generally provide delivery of a drug from the device to a selected site in a subject at a selected or other patterned amount and / or rate. The drug delivery device must be capable of containing an amount of formulation sufficient 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 sufficient to provide 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 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 embodiment, an implantable device is contemplated, comprising: (i) a therapeutic agent in an amount to provide 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) a formulation of a small molecule therapeutic agent comprising an organic acid that (a) maintains a pH of the formulation when hydrated in its use environment that is about equal to or less than the pKa of the protonated drug during the delivery period; (b) is present in a stoichiometric (molar) excess amount relative to the therapeutic agent; and (c) is present when hydrated in an amount about equal to or greater than its saturation concentration in the formulation at the end of the delivery period.

[0135] In some embodiments, the formulation containing a stoichiometric excess of an organic acid is in a dry form. For example, the dry formulation can be in a 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 an aqueous suspension in situ containing both particles of the salt form of the therapeutic agent and an excess amount of insoluble particles.

[0136] The drug delivery device can be implanted at any suitable implantation site using methods and devices known in the art. As described below, an implantation site is a site within a subject's body where the drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to, subdermal, subcutaneous, intramuscular, or other suitable sites within a subject's body. Subcutaneous implantation sites are preferred due to the convenience of implanting and removing the drug delivery device. Typical subcutaneous delivery sites include subcutaneously in the arm, shoulder, neck, back, or leg. Sites within body cavities are also suitable implantation sites. Methods for implanting or otherwise attaching drug delivery devices for subcutaneous delivery of drugs are known in the art. Generally, attachment of the drug delivery device is achieved using methods and tools known in the art and is performed under sterile conditions with 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 a composition described herein or a delivery device comprising such a composition is provided.

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

[0139] In another embodiment, methods for maintaining therapeutic plasma levels of an antipsychotic drug and thereby delaying relapse in a stable previously dosed patient by at least four weeks are contemplated.

[0140] Based on the foregoing, the compositions described herein comprising a small molecule therapeutic agent and an organic acid 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 - during which the composition maintains a sufficient amount of the therapeutic agent relative to the therapeutic dose of the drug, and an amount of the organic acid sufficient to maintain (i) the concentration of the protonated therapeutic agent at or near its saturation concentration in the hydrated composition during the period and / or (ii) 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 substantially 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., a 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 (a rate close to zero order rate) 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 Formulations containing risperidone and organic acids as small molecule therapeutic agents. p-Aminobenzoic acid (PABA) and risperidone were blended at acid:drug ratios of 1:1, 1.5:1, or 2:1 (molar basis), compressed with lactose binder (13%), and loaded into delivery devices with 0.1 micron polyvinylidene fluoride (DURAPORE®) membranes. In some devices, approximately 50% of the available membrane surface area was blocked to measure the effect of surface area on release rate. All devices were vacuum-filled with phosphate buffer and transferred to bottles containing an equal volume (approximately 100 mL) of buffer. The sealed bottles were then incubated at 37°C, and aliquots (approximately 500 μL) of receiving buffer were withdrawn at selected time points, and the released drug was quantified by high-performance liquid chromatography (HPLC). Risperidone release is shown in Figure 2.

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

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

[0145] After secondary drying, all the mixture was transferred to a glove box for grinding. The formulation was placed in a milling container equipped with a blade for grinding the dry substance 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 approximately 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 a second cap portion assembly and weighed again to obtain the filled weight of the tablets. The average filled 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 into a freeze - dryer equipped with a stopper trace system. Prior to sealing, the void space 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 implanting instruments was performed using electron beam sterilization at a divided 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 equipped 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 standing 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 instrument, 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. 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 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 device 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 extended 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, tableted, 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 averaging 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 of the animal using a custom implanting tool, and the incision was sutured or closed with a 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. 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, the dried cake was further dried, pulverized, (in some cases) tableted, filled into the reservoir, capped, and made into a vacuum vial. Hydrated the filled device and placed it statically in 100 mL of PBS at 37 °C 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

1. A composition for subcutaneous use by being loaded into a drug delivery device comprising a porous partition having a plurality of pores having a diameter of 0.1 to 100 microns, A composition comprising an aqueous heterogeneous mixture comprising a therapeutic agent and an organic acid, the therapeutic agent is paliperidone, risperidone, olanzapine, asenapine, aripiprazole, or brexpiprazole; the organic acid (i) has an aqueous solubility of 0.1 to 10 g / L at 25° C., (ii) has a molar mass of less than 500 grams per mole, and (iii) is present in a stoichiometric (molar) excess amount compared to the therapeutic agent, wherein the organic 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, hippuric acid, vanillic acid, and salicylic acid; the organic acid is present in a 105% to 1000% stoichiometric excess relative to the therapeutic agent; The aqueous heterogeneous mixture (i) has a pH of 3.0 to 6.5 in a subcutaneous use environment at human body temperature for a period of at least 30 days, and (ii) has an amount of organic acid that is about equal to or greater than a saturation concentration in the subcutaneous use environment.

2. 10. The composition of claim 1, wherein a saturated aqueous solution of the organic acid has a pH value about equal to or less than the pKa of the protonated therapeutic agent.

3. 3. The composition of claim 1, wherein the organic acid is present in a 105% to 500% stoichiometric excess compared to the therapeutic agent.

4. The composition of any one of claims 1 to 3, wherein the aqueous heterogeneous mixture comprises a buffer.

5. 2. The composition of claim 1, wherein the organic acid is a carboxylic acid having a carboxylic acid group attached to an unsubstituted benzene or pyridine ring.

6. 2. The composition of claim 1, wherein the organic 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.

7. The composition of claim 1 , wherein the organic acid is vanillic acid.

8. 2. The composition of claim 1, wherein the organic acid is 2-aminobenzoic acid (anthranilic acid) or 4-aminobenzoic acid (para-aminobenzoic acid; PABA).

9. 2. The composition of claim 1, wherein the organic acid is 4-methoxybenzoic acid (p-anisic acid), o-anisic acid, or m-anisic acid.

10. The composition of any one of claims 1 to 9, wherein the amount of the therapeutic agent is sufficient to provide treatment for at least 30 days.

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