Compositions for small molecule therapeutic agent compounds

Abstract

To provide compositions and formulations for small-molecule therapeutic agents, and drug-delivery devices comprising compositions and formulations for controlled, sustained delivery of small-molecule therapeutic agents.SOLUTION: Provided is a composition comprising a molar amount of 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 polyprotic acid in an amount that (i) is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens that exceeds the stoichiometric equivalent for the molar amount of therapeutic agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The subject matter described herein relates to compositions and formulations for small molecule therapeutic agents and drug delivery devices containing the compositions and formulations for the controlled, sustained delivery of small molecule therapeutic agents. [Background technology]

[0002] An important class of small molecule drugs exhibits poor aqueous solubility at neutral pH. While this property can be advantageous for tissue penetration by transmembrane diffusion, particularly for drugs targeting the central nervous system, it complicates the development of injectable or implantable sustained-delivery systems that rely on passive diffusion as the primary drug release mechanism. For example, hydrophobic drugs with extremely low solubility may be unable to generate a sufficient concentration gradient across a membrane, porous compartment, or other phase boundary to produce adequate 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, amidine, or guanidine; or nitrogen-containing heterocycles, e.g., pyridine, quinoline, imidazole, thiazole, triazole, or tetrazole), and their aqueous solubility is improved by protonation (i.e., when converted to a salt). Antipsychotics (e.g., risperidone, paliperidone, olanzapine, and haloperidol), antidepressants (e.g., citalopram, escitalopram, and buspirone), opioid agonists and antagonists (e.g., buprenorphine, naloxone, naltrexone, and 4-phenylpiperidines such as fentanyl and meperidine); antimigraine agents (e.g., rizatriptan, naratriptan, sumatriptan, and zolmitriptan); antiemetics (e.g., granisetron, ondansetron, and other serotonin receptor antagonists); Many drugs that target the central nervous system, including anticonvulsants (e.g., perampanel); dopaminergic antiparkinsonian agents (e.g., pramipexole, ropinirole, rotigotine, cabergoline, and bromocriptine); acetylcholinesterase inhibitors (e.g., rivastigmine and donepezil); skeletal muscle relaxants (e.g., tizanidine and cyclobenzaprine); nicotinic agonists or partial agonists (e.g., varenicline), and VMAT2 inhibitors (e.g., tetrabenazine and deutetrabenazine), belong to this category.Examples of hydrophobic basic drugs that target receptors, cells, or tissues outside the central nervous system include alpha blockers (e.g., prazosin), cardiac inotropes (e.g., dobutamine), antimalarials (e.g., primaquine and mefloquine), aromatase inhibitors (e.g., anastrozole and letrozole), antiestrogens (e.g., tamoxifen and raloxifene), phosphodiesterase inhibitors (e.g., vardenafil), and immunomodulators (e.g., fingolimod).

[0003] Although salts formed between such drugs and cationic acids may have improved aqueous solubility, they are unstable and susceptible to hydrolysis at pH levels near or above the pKa of the protonated drug, typically greater than 7. This process complicates diffusion-mediated drug delivery systems via implants or depots (i.e., delivery mechanisms without an active pump mechanism or complex semipermeable membrane structure to control release) because drug efflux from the formulation must be coupled with the influx of buffering species from physiological fluids. Furthermore, if the salt form of the drug is delivered through an implantable device, the composition must contain a sufficient volume of active agent to provide therapeutic benefit during the prescribed administration period; furthermore, the total formulation volume should be minimized to limit the size (i.e., degree of invasiveness) of the final implanted structure. 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, compositions are provided that include a molar amount of a small molecule therapeutic agent and a polyprotic acid or a combination of two or more monoprotic acids that (i) have an aqueous solubility of less than about 1 g / L at 25° C. and (ii) are weak bases (i.e., have conjugate acids with pKa between 6 and 9).

[0006] In another embodiment, the composition comprises a molar amount of a therapeutic agent and (i) an amount of an organic polyprotonic acid that is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0007] In another embodiment, the composition comprises a molar amount of a therapeutic agent and (i) an amount of inorganic polyprotonic acid that is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0008] In another embodiment, the composition comprises a molar amount of a therapeutic agent and a mixture of two or more acids comprising at least one organic polyprotonic acid in an amount that (i) is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0009] In another embodiment, the composition comprises a molar amount of a therapeutic agent and a mixture of two or more acids comprising at least one inorganic polyprotonic acid in an amount that (i) is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0010] In yet another embodiment, the composition comprises a molar amount of a therapeutic agent and a dendrimer capped with an acidic functional group, said dendrimer being (i) about 0.25 to 1.0 molar amount of the therapeutic agent, and (ii) in an amount that provides a total number of acid hydrogens in excess of the equistoichiometric molar amount of the therapeutic agent.

[0011] In yet another embodiment, the composition comprises a mixture of a molar amount of a therapeutic agent and an acidic excipient comprising a dendrimer capped with at least one acidic functional group, said dendrimer being (i) about 0.25 to 1.0 molar amount of the therapeutic agent, and (ii) in an amount that provides a total number of acid hydrogens in excess of the equistoichiometric molar amount of the therapeutic agent.

[0012] In yet another embodiment, the composition comprises a molar amount of a therapeutic agent and a mixture of two or more monoprotic acids, wherein each monoprotic acid in the mixture is in an amount equal to or less than the molar amount of the therapeutic agent, and wherein the two or more monoprotic acids provide a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0013] In some embodiments, the organic acid compound (i) has an aqueous solubility of less than about 20 g / L at room temperature, (ii) maintains a suspension pH in its use environment of between pH 3 and 6.5 for a period of at least about 30 days, and / or (iii) has a molecular weight of 500 grams per mole or less.

[0014] In some embodiments, the composition is an aqueous suspension comprising a molar amount of a small molecule therapeutic agent that (i) has a water solubility of less than about 1 g / L at 25° C. and (ii) is a weak base (i.e., has a conjugate acid with a pKa of 6-9), and a polyprotic acid compound in an amount that (i) is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0015] In some embodiments, the therapeutic agent becomes more soluble upon protonation.

[0016] In another embodiment, a composition is provided comprising an aqueous suspension. The aqueous suspension comprises: (i) a small molecule therapeutic agent having an aqueous solubility of less than about 1 g / L at 25° C. and (ii) a small molecule therapeutic agent that becomes more soluble upon protonation; and (i) a polyprotonic acid compound in an amount equal to or less than the molar amount of the therapeutic agent and (ii) providing a total number of acid hydrogens in excess of the stoichiometry equivalent to the molar amount of the therapeutic agent. In some embodiments, the polyprotonic acid compound is a mixture of organic acid compounds comprising at least one polyprotonic acid or at least one dendrimer.

[0017] In some embodiments, the aqueous suspension is a heterogeneous mixture containing a small molecule therapeutic agent and a polyprotic organic acid compound, wherein the organic acid compound is sufficiently dissolved 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 a controlled temperature, for example, 37°C.

[0018] In some embodiments, the aqueous suspension is a heterogeneous mixture comprising a small molecule therapeutic agent and a mixture of organic acids, including at least one polyprotic acid, wherein the organic acid is selected to dissolve at a rate that maintains the pH of the aqueous suspension (or heterogeneous mixture) in its use environment at or below physiological pH (about 7.4) for a predetermined 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 a controlled temperature, for example, 37°C.

[0019] In another embodiment, the organic acid compound is crystalline and has a melting point above about 37°C.

[0020] In some embodiments, the small molecule therapeutic agent is selected to be a typical or atypical antipsychotic agent such as risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, asenapine, lurasidone, cariprazine, or haloperidol.

[0021] In some embodiments, the small molecule therapeutic agent is an opioid agonist or antagonist (e.g., buprenorphine, naloxone, naltrexone, and 4-phenylpiperidines such as fentanyl and meperidine); antimigraine agents (e.g., rizatriptan, naratriptan, sumatriptan, and zolmitriptan); antiemetics (e.g., granisetron, ondansetron, and other serotonin receptor antagonists); anticonvulsants (e.g., perampanel); dopaminergic The therapeutic agent is selected from antiparkinsonian agents (e.g., pramipexole, ropinirole, cabergoline, and bromocriptine); acetylcholinesterase inhibitors (e.g., rivastigmine and donepezil); skeletal muscle relaxants (e.g., tizanidine and cyclobenzaprine); nicotinic agonists or partial agonists (e.g., varenicline); immunomodulators (e.g., fingolimod), and / or VMAT2 inhibitors (e.g., tetrabenazine and deutetrabenazine).

[0022] In another embodiment, the small molecule therapeutic agent is selected from opioid agonists and antagonists, anti-Parkinson's agents, anti-migraine agents, agents that act as skeletal muscle relaxants, anti-emetic agents, and / or immunomodulatory agents for treating multiple sclerosis. Other embodiments include any one or combination of the classes of therapeutic agents and / or therapeutic agents described herein.

[0023] In another embodiment, the therapeutic agent is an organic base structurally derived from a fatty acid, such as fingolimod.

[0024] In another embodiment, the therapeutic agent is a cardiac agent such as dobutamine.

[0025] In yet another embodiment, the therapeutic agent is an antihypertensive agent such as prazosin.

[0026] In some embodiments, the therapeutic agent is an antimalarial drug such as primaquine or mefloquine.

[0027] In yet another embodiment, the therapeutic agent is an aromatase inhibitor such as anastrozole or letrozole.

[0028] In some embodiments, the therapeutic agent is an anti-estrogen active agent such as tamoxifen or raloxifene.

[0029] In some embodiments, the therapeutic agent is a benzothiazole, such as riluzole.

[0030] In some embodiments, the therapeutic agent is an alpha blocker such as prazosin or terazosin or a beta blocker such as metoprolol or propranolol.

[0031] 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.

[0032] In another embodiment, the aqueous suspension comprises or is prepared with a salt formed between a molar amount of a therapeutic agent and at least one polyprotic acid, such that the polyprotic acid is (i) equal to or less than the molar amount of the therapeutic agent, and (ii) in an amount that provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent.

[0033] In another embodiment, a mixture of a therapeutic agent and at least one polyprotic acid or two or more monoprotic acids or at least one dendrimer is combined by dissolution in an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, followed by concentration of the intermediate solution to dryness, resulting in salt formation of the therapeutic agent.

[0034] In some embodiments, a therapeutic agent and a submolar amount of a polyprotic acid are combined by dissolution in an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, followed by concentration of the intermediate solution to dryness, resulting in the formation of a mixture of salts of the therapeutic agent.

[0035] In another embodiment, a therapeutic agent is mixed with (i) a mixture of organic acids comprising at least one polyprotic acid in an amount less than the molar amount of the therapeutic agent and (ii) an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, followed by concentration of the intermediate solution to dryness, resulting in the formation of a mixture of salts of the therapeutic agent.

[0036] In another embodiment, the therapeutic agent is mixed with (i) a mixture of organic acids comprising two or more monoprotic acids, wherein each monoprotic acid in the mixture is equal to or less than the molar amount of the therapeutic agent, and the two or more monoprotic acids are in an amount that provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent, and (ii) an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, followed by concentration of the intermediate solution to dryness, resulting in the formation of a mixture of salts of the therapeutic agent.

[0037] In some embodiments, the formulation includes an organic acid that is an aromatic carboxylic acid. In some embodiments, the typical organic acid is an organic acid having a carboxylic acid group attached to an unsubstituted benzene ring or a pyridine ring. In some embodiments, the carboxylic acid is selected from the group consisting of benzoic acid, picolinic acid, nicotinic acid, and isonicotinic acid.

[0038] In another embodiment, the formulation comprises a carboxylic acid having a benzene ring and one electron donating group. In another embodiment, the carboxylic acid has antioxidant properties.

[0039] In yet another embodiment, the formulation comprises a carboxylic acid 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.

[0040] In another embodiment, the formulation comprises a carboxylic acid having a benzene ring and two electron donating groups.In another embodiment, the carboxylic acid has antioxidant properties.In some embodiments, and by way of example, the carboxylic acid is vanillic acid.

[0041] In yet another embodiment, the formulation comprises a carboxylic acid having at least two carboxylic acid groups attached to a benzene ring. In one embodiment, and by way of example, the carboxylic acid is phthalic acid.

[0042] In yet another embodiment, the formulation includes a carboxylic acid having a carboxylic acid group attached to a naphthalene ring or a quinoline ring. In some embodiments, and by way of example, the carboxylic acid is selected from the group consisting of 1-naphthoic acid, 2-naphthoic acid, quinaldic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid, and 8-quinolinecarboxylic acid.

[0043] In another embodiment, the formulation comprises a carboxylic acid having an aromatic ring with an electron donating group selected from the group consisting of hydroxy, methoxy, amino, alkylamino, dialkylamino, and alkyl. In some embodiments, 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.

[0044] In yet another embodiment, the formulation comprises a carboxylic acid having one or two carboxylic acid groups directly attached to the biphenyl ring system. In some embodiments, 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.

[0045] In yet another embodiment, the formulation includes a carboxylic acid having one additional electron-donating substituent on the biphenylcarboxylic acid moiety. In certain embodiments, 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.

[0046] In yet another embodiment, the formulation comprises a carboxylic acid having a carboxylic acid functional group separated from a benzene, pyridine, naphthalene, quinoline, or coumarin ring by a chain of 1 to 4 saturated carbon atoms. In certain embodiments, and by way of example, the carboxylic acid is phenylacetic acid, 3-phenylpropionic acid, or 7-hydroxycoumarin-4-acetic acid.

[0047] In another embodiment, the formulation includes a carboxylic acid that is an aliphatic dicarboxylic acid having a 4-8 carbon chain separating the carboxylic acid groups. In some embodiments, 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).

[0048] In another embodiment, the formulation comprises a polymer, dendrimer, peptide, or protein. In one embodiment, the formulation does not comprise polylactic-glycolic acid polymers and copolymers, and in another embodiment, does not comprise polylactic-glycolic acid polymers and copolymers having a solubility of about 20 g / L or less and an isoelectric point of less than 7.

[0049] In another embodiment, the formulation includes a carboxylic acid that is an unsaturated or polyunsaturated dicarboxylic acid containing 4 to 10 carbons. In certain embodiments, 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.

[0050] In other embodiments, the formulation comprises a carboxylic acid that 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, the trans-cinnamic acid is selected from the group consisting of o-coumaric acid, m-coumaric acid, p-coumaric acid, o-methylcinnamic acid, m-methylcinnamic acid, p-methylcinnamic acid, o-methoxycinnamic acid, m-methoxycinnamic acid, p-methoxycinnamic acid, and ferulic acid.

[0051] In certain embodiments, the formulation includes an organic acid that is a phenol or naphthol substituted with about 2-5 electron-withdrawing groups selected from F, Cl, Br, I, CN, and NO. In certain embodiments, and by way of example, the organic acid is pentafluorophenol or 2,4-dinitrophenol.

[0052] In another embodiment, the formulation includes an organic acid that is a 1,3-dicarbonyl compound containing an acidic (pKa<8) C-H or N-H bond. In some embodiments, and by way of example, the organic acid includes 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), uric acid, cyanuric acid, or barbituric acid.

[0053] In yet another embodiment, the formulation includes an organic acid that is an imide. In some embodiments, and by way of example, the imide is a phthalimide or a substituted phthalimide. In another embodiment, the substituted phthalimide has at least one electron-withdrawing substituent.

[0054] In yet another embodiment, the formulation comprises an organic acid that is a hydroxamic acid. In some embodiments, and by way of example, the hydroxamic acid is an aromatic hydroxamic acid that includes a hydroxamic functional group directly attached to the aromatic ring. In some embodiments, 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 benzhydroxamic acid. In yet another embodiment, the hydroxamic acid is a ... 3 It is a hydroxamic acid that contains a hydroxamic functional group separated from an aromatic ring by a chain of hybridized carbon atoms.

[0055] In yet another embodiment, the formulation comprises a hydroxamic acid that is a dihydroxamic acid containing two or more hydroxamic acid functional groups directly attached to a benzene, pyridine, naphthalene, quinoline, coumarin, or biphenyl ring system.

[0056] 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.

[0057] In other embodiments, the hydroxamic acid is an aliphatic dihydroxamic acid containing from 6 to 10 carbon atoms.

[0058] In some embodiments, the hydroxamic acid is suberohydroxamic acid.

[0059] In other embodiments, the hydroxamic acid is an unsaturated dihydroxamic acid containing from 6 to 10 carbon atoms.

[0060] In another embodiment, the formulation comprises an aromatic carboxylic acid 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.

[0061] In yet another embodiment, the hydroxy derivative of cinnamic acid is m-coumaric acid or p-coumaric acid.

[0062] In still other embodiments, the p-coumaric acid is trans-p-coumaric acid.

[0063] In other embodiments, the methoxy derivative of cinnamic acid is p-methoxycinnamic acid or m-methoxycinnamic acid.

[0064] 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).

[0065] In another embodiment, the methoxy derivative of benzoic acid is 4-methoxybenzoic acid (p-anisic acid), o-anisic acid or m-anisic acid.

[0066] In one embodiment, the composition is in a dry form. In another embodiment, the composition is in a dry form and is hydrated in situ when in its use environment.

[0067] In another aspect, there is provided a device comprising the composition described herein, the device being designed for subcutaneous implantation in a mammal.

[0068] In another embodiment, an implantable device is provided that includes: (i) a reservoir containing a formulation of a small molecule therapeutic agent in an amount sufficient to provide substantially zero-order release of the small molecule therapeutic agent at a rate that provides a therapeutic effect over a delivery period of at least about 30 days; and (ii) an organic polyprotic acid that (a) maintains the pH of the formulation when hydrated in its use environment of pH 3.0 to 6.5 over the delivery period; (b) is present in less than or equal to 1 stoichiometric amount relative to the therapeutic agent, and / or (c) contains an excess of acidic functional groups relative to the therapeutic agent.

[0069] In another embodiment, an implantable device is provided that includes a reservoir containing (i) a small molecule therapeutic agent in an amount sufficient to provide substantially zero-order release of the small molecule therapeutic agent at a rate that provides a therapeutic effect over a delivery period of at least about 30 days, and (ii) a formulation of the small molecule therapeutic agent comprising a mixture of organic acids, including at least one organic polyprotic acid, that (a) maintains the pH of the formulation when hydrated in its use environment of pH 3.0 to 6.5 over the delivery period; (b) contains less than or equal to 1 stoichiometric amount of total acid molecules relative to the therapeutic agent, and / or (c) has a stoichiometric excess of acidic functional groups relative to the therapeutic agent.

[0070] In another embodiment, an implantable device is provided that includes a reservoir containing (i) a formulation of a small molecule therapeutic agent in an amount that provides substantially zero-order release of the small molecule therapeutic agent over a delivery period of at least about 30 days and at a rate that provides a therapeutic effect, and (ii) an organic polyprotic acid that (a) maintains a pH of the formulation when hydrated in its use environment that is less than or equal to the pKa of the protonated therapeutic agent; (b) is present in less than or equal to a stoichiometric amount relative to the therapeutic agent, and / or (c) has acidic functional groups in a stoichiometric excess relative to the therapeutic agent.

[0071] In another embodiment, an implantable device is provided that includes a reservoir containing a formulation of a small molecule therapeutic agent in an amount that provides substantially zero-order release of the small molecule therapeutic agent over a delivery period of at least about 30 days and at a rate that provides a therapeutic effect, and (ii) a mixture of organic acids that (a) maintain a pH of the formulation when hydrated in its use environment that is less than or equal to the pKa of the protonated therapeutic agent; (b) contain less than or equal to one stoichiometric amount of total acid molecules relative to the therapeutic agent, and / or (c) contain at least one organic polyprotic acid having a stoichiometric excess of acidic functional groups relative to the therapeutic agent.

[0072] In some 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.

[0073] In another embodiment, the formulation hydrates in the presence of an aqueous solution to form an aqueous suspension. In some embodiments, the aqueous solution is an in vivo fluid.

[0074] 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.

[0075] In yet another embodiment, the organic acid has a water solubility of less than about 20 g / L at 25° C. In yet another embodiment, the organic acid has a water solubility of 0.1 to 10 g / L at room temperature.

[0076] In another embodiment, the organic acid has an aqueous solubility of less than about 20 g / L and a pKa of 3 to 6 at 25° C. In another embodiment, the organic acid has an aqueous solubility of 0.1 to 10 g / L and a pKa of 3 to 6 at room temperature.

[0077] In another embodiment, two or more organic acids, each having a water solubility of 0.1 to 10 g / L at room temperature, a molar mass of less than 500 grams per mole, and a pKa of 3 to 6, are used in combination, one of which is a polyprotic acid.

[0078] In another embodiment, two or more monoprotic organic acids are present in the formulation, wherein each monoprotic acid in the formulation is in an amount equal to or less than the molar amount of the therapeutic agent, and wherein the two or more monoprotic acids provide a total number of acids in excess of equivalent stoichiometry to the molar amount of the therapeutic agent.

[0079] In yet another embodiment, dendrimers or star polymers capped with acidic functional groups are used, such as PAMAM dendrimers capped with carboxymethyl, 3-carbomethoxypyrrolidone, succinic acid, or glutaramic acid groups.

[0080] In yet another embodiment, the organic acid has a melting point greater than about 37°C.

[0081] In another aspect, methods are provided for sustained, controlled delivery of small molecule therapeutic agents. The methods include providing a composition or device described herein. In some embodiments, the methods further include administering the device, e.g., by subcutaneous implantation.

[0082] In another aspect, methods are provided for sustained, controlled delivery of antipsychotic medications, comprising providing a composition or device described herein. In some embodiments, the methods further comprise administering the device, e.g., by subcutaneous implantation.

[0083] In another aspect, a method for maintenance therapy for treating schizophrenia or bipolar disorder is provided, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, for example, by subcutaneous implantation.

[0084] In another aspect, provided is a method of providing maintenance therapy for treating drug addiction, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, e.g., by subcutaneous implantation.

[0085] In another aspect, provided is a method of providing maintenance therapy for treating Parkinson's disease or Alzheimer's disease, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, e.g., by subcutaneous implantation.

[0086] In another aspect, there is provided a method for providing maintenance therapy for treating epilepsy, multiple sclerosis, or amyotrophic lateral sclerosis, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, e.g., by subcutaneous implantation.

[0087] In another aspect, provided are methods of providing protection against malaria, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, e.g., by subcutaneous implantation.

[0088] In yet another aspect, methods are provided for treating osteoporosis, breast cancer, or infertility, comprising providing a composition or device described herein. In some embodiments, the method further comprises administering the device, e.g., by subcutaneous implantation.

[0089] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by examination of the following descriptions.

[0090] Further embodiments of the methods, devices, compositions, and the like of the present invention will be apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and following description, each and every feature described herein, and each and every combination of two or more such features, is included within the scope of the present invention, provided that the features included in such combinations are not mutually exclusive. Furthermore, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Further aspects and advantages of the present invention will be described, particularly when considered in conjunction with the accompanying examples and drawings. [Brief explanation of the drawings]

[0091] [Figure 1A] 1A is an illustration of a drug delivery device in assembled form (FIG. 1A). [Figure 1B] 1B is an illustration of a drug delivery device in its unassembled form (FIG. 1B).

[0092] [Figures 1C-1F]

[0023] Figure 1C shows a cross-sectional view (Figure 1C) and an exploded view (Figure 1D) of the assembled configuration, and shows portions of a first exemplary drug delivery device, showing the end cap assembly in an exploded view when assembled (Figure 1E). Figure 1F shows an exploded view of only the cap subassembly. The numbered components of the subassembly are 1 = cap, 2 = porous membrane, 3 = seal, 4 = retention ring, and 5 = drug device reservoir.

[0093] [Figure 1G-1K] Portions of a second exemplary drug delivery device are shown, showing the end cap subassembly (FIG. 1E) in cross-sectional and isometric views (FIG. 1H) in assembled form (FIG. 1G), and in an exploded view (FIG. 1I) when assembled. Figures 1J-1K show exploded views of the cap subassembly only. Numbered components of the subassembly are 1 = cap, 2 = porous membrane, 3 = seal, 4 = drug delivery device reservoir, and 5 = retention ring.

[0094] [Figure 2] Figure 1 shows the cumulative release of naltrexone (mg) as a function of time (days) from drug delivery devices containing a composition of naltrexone base and a composition with less than an equimolar amount of the polyprotic acid, suberic acid (crosses), or a composition of naltrexone base without the polyprotic acid (diamonds).

[0095] [Figure 3] One group of devices ("Group 1," diamonds) had approximately half the diffusion surface area of ​​the second group of devices ("Group 2," crosses). Figure 1 shows plasma levels of naltrexone (ng / mL) in rats as a function of time (days) after implantation of a drug delivery device containing naltrexone and sebacic acid (a diprotic acid) in a 1:0.6 molar ratio. Data are plotted with + / - 1 standard deviation as a measure of dispersion. DETAILED DESCRIPTION OF THE INVENTION

[0096] I. Definition Various aspects are set forth in more detail below. However, such aspects may be embodied in many different forms and should not be construed as limiting the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0097] When a range of numerical values ​​is provided, it is intended that each value between the upper and lower limits of that range, and any other stated or intervening value within that range, is encompassed within the disclosed scope. For example, if a range of 1 mg to 8 mg is stated, 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 ranges less than or equal to 8 mg, are also specifically disclosed.

[0098] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "polymer" includes a single polymer and two or more of the same or different polymers, reference to an "excipient" includes a single excipient and two or more of the same or different excipients, etc.

[0099] The word "about," when immediately preceding a value, means a range of plus or minus 10% of that value. For example, unless clearly indicated otherwise by context or contradictory to such an understanding, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. For example, in a list of values ​​such as "about 49, about 50, about 55," "about 50" means a range spanning less than half the interval between the preceding and following values, for example, a range from greater than 49.5 to less than 52.5. Furthermore, 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.

[0100] The compositions of the present invention may comprise, consist essentially of, or consist of the disclosed components.

[0101] Unless otherwise specified, all percentages, parts and ratios are based on the total weight of the composition and all measurements made are made at about 25°C.

[0102] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, salts, compositions, dosage forms, etc. that are—within the scope of sound medical judgment—suitable for use in contact with the tissues of humans and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state regulatory agency, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias, for use in mammals (e.g., animals), and more specifically, humans.

[0103] As used herein, the term "treating" refers to a method of administering a small molecule that reduces the frequency of or delays the onset of symptoms of a medical condition (e.g., schizophrenia, bipolar disorder) in a subject compared to a subject not receiving the compound or composition. This can include reversing, reducing, or halting the symptoms, clinical signs, and pathology underlying the symptoms in a manner that improves or stabilizes the subject's condition (e.g., controlling schizophrenic symptoms).

[0104] The term "polyprotic" is used herein to describe acids in reference to molecules containing multiple acidic functional groups or molecules having a single functional group that can react with one or more stoichiometric amounts of a strong base (e.g., sodium hydroxide) to form multiple salts. For example, the term "polyprotic" can refer to diprotic acids such as succinic acid, glutaric acid, adipic acid, etc., or triprotic acids such as citric acid, aconitic acid, phosphoric acid, etc.

[0105] A less than full scope of the invention may be claimed for any reason by including, and reserving the right to conditionally exclude or exclude, any individual member of any such group that may be claimed by range or in any similar manner, any sub-range or combination of sub-ranges within the group. Furthermore, a less than full scope of the invention may be claimed by conditionally excluding or excluding any individual substituent, analog, compound, ligand, structure, or group thereof, or any member of a claimed group.

[0106] Throughout this invention, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure to more fully describe the general state of the art as known to those skilled in the art at the date of this disclosure. In the event of any conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure will control.

[0107] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0108] II. Formulations for improving the solubility of small molecule therapeutic agents In some embodiments, the composition or formulation is a composition or formulation in which the small molecule therapeutic agent is solubilized by the use of an acid in which the small molecule therapeutic agent is partially soluble, thereby improving delivery of the therapeutic agent from a device or drug delivery platform for an extended period of time. In some embodiments, the composition is an aqueous suspension or slurry. In other embodiments, 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 other embodiments, the composition is in a dried form (e.g., lyophilized, spray-dried, dried, etc.).

[0109] In various of these embodiments, the composition comprises a small molecule therapeutic agent that acts as a Bronsted or Lewis base in combination with less than or equal to one equivalent of an organic polyprotic acid compound that (i) provides a stoichiometric excess of acidic functional groups relative to the therapeutic agent, (ii) has an aqueous solubility of 0.1 to 10 g / L; (iii) has a molecular weight of less than 500 grams per mole; and / or (iv) maintains a suspension pH in its use environment that is less than or equal to the pKa of the protonated drug for a period of at least about 30 days. In another embodiment, the composition comprises a small molecule therapeutic agent that functions as a Bronsted or Lewis base and two or more monoprotic acid compounds, wherein the two or more monoprotic acid compounds collectively provide a stoichiometric excess of acidic functional groups relative to the therapeutic agent. In certain embodiments, each monoprotic acid in the two or more monoprotic acid compounds is present in the formulation in an amount equal to or less than the molar amount of the therapeutic agent. In another embodiment, each monoprotic acid in the mixture is in an amount equal to or less than the molar amount of the therapeutic agent, wherein the two or more monoprotic acids provide a total number of acid hydrogens in excess of an equivalent stoichiometry for the molar amount of the therapeutic agent.

[0110] The composition may further comprise an aqueous liquid, such as water, a buffer, or a water-solvent mixture. In some embodiments, when the composition is in a dry form, the aqueous liquid hydrates the composition in situ in its use environment.

[0111] In other compositions and formulations, the compositions include: (i) the sum of all acid molecules combined with the therapeutic agent is less than or equal to the stoichiometric amount of the therapeutic agent; (ii) the total number of acidic functional groups exceeds the stoichiometric amount of the therapeutic agent present; (iii) 50% or more by weight of the acids added to the formulation have an aqueous solubility of less than about 20 g / L at room temperature; (iv) 50% or more by weight of the acids added to the formulation have a molecular weight of 500 grams per mole or less; and / or (v) a small molecule therapeutic agent capable of functioning as a Bronsted base or Lewis base combined with a mixture of organic acids including at least one organic polyprotonic acid compound such that the pH of the suspension in its use environment is maintained between 3 and 6.5 for a period of at least about 30 days. In another composition and formulation, the composition comprises a small molecule therapeutic agent capable of functioning as a Bronsted or Lewis base in combination with less than one equivalent of an inorganic polyprotic acid that (i) provides a stoichiometric excess of acidic hydrogen compared to the therapeutic agent (i.e., has a pKa of less than or equal to 12); (ii) has an aqueous solubility of 0.1 to 10 g / L; (iii) has a molecular weight of less than 500 grams per mole; and / or (iv) maintains a suspension pH in its use environment that is less than or equal to the pKa of the protonated drug for a period of at least about 30 days. The composition may further comprise an aqueous liquid, e.g., water, a buffer solution, or a water-solvent mixture. In some embodiments, when the composition is in a dry form, the aqueous liquid hydrates the composition in situ in its use environment.

[0112] In other compositions and formulations, the compositions include: (i) the mixture comprises at least one polyprotic acid; (ii) the total number of all acid molecules combined with the therapeutic agent is less than or equal to the stoichiometric amount of the therapeutic agent; (iii) the total number of acidic hydrogen atoms present exceeds the stoichiometric amount of the therapeutic agent; (iv) 50% or more by weight of the acids added to the formulation have an aqueous solubility of less than about 20 g / L at room temperature; (v) 50% or more by weight of the acids added to the formulation have a molecular weight of 500 grams per mole or less; and / or (v) a small molecule therapeutic agent capable of functioning as a Bronsted base or Lewis base combined with a mixture of organic and inorganic acid compounds such that the pH of the suspension in its use environment is maintained between about 3.0 and 6.5 for a period of at least about 30 days.

[0113] In other compositions and formulations, the composition includes a small molecule therapeutic agent capable of functioning as a Bronsted or Lewis base in combination with a dendrimer capped with acidic functional groups. The dendrimer is present in the composition at a stoichiometric ratio of less than or equal to 0.25 relative to the therapeutic agent. Furthermore, the dendrimer (i) provides a stoichiometric excess of acidic hydrogen relative to the therapeutic agent (i.e., has a pKa of less than or equal to 12) and (ii) maintains a suspension pH in its use environment that is less than or equal to the pKa of the protonated drug for a period of at least about 30 days. The composition may further include an aqueous liquid, such as water, a buffer, or a water-solvent mixture. In some embodiments, when the composition is in a dry form, the aqueous liquid hydrates the composition in situ in its use environment.

[0114] As described above, the formulations described herein provide solubility of the small molecule therapeutic agent to enable delivery over a sustained period. In certain embodiments, a sustained period is intended to be at least about 2 weeks to about 6 months. In other embodiments, a sustained period 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 other embodiments, a sustained period is intended to be 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, a sustained period is intended to be at least about 6 months, or 9 months, or 12 months.

[0115] As mentioned above, the formulations described herein improve the solubility of small molecule therapeutic agents in part by maintaining a specific pH of the formulation in its use environment for a certain period of time.In some embodiments, the use environment is in vivo.For example, the formulation can be part of a drug delivery device that is 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 that is maintained at about 37°C.

[0116] The components of the composition, namely the small molecule therapeutic agent and the organic acid compound (also referred to herein as "organic acid"), are described below.

[0117] 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.

[0118] 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.

[0119] For example, therapeutic agents containing primary, secondary, or tertiary amines; aniline, amidine, or guanidine; or nitrogen-containing heterocycles, such as pyridine, quinoline, imidazole, thiazole, triazole, or tetrazole 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.

[0120] In some embodiments, the small molecule therapeutic agent is an antipsychotic agent. In various embodiments, the antipsychotic agent is selected from risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, asenapine, cariprazine, lurasidone, or haloperidol.

[0121] In some embodiments, the small molecule therapeutic agent is an opioid agonist or antagonist, hi some embodiments, the opioid agonist or antagonist is selected from buprenorphine, naloxone, naltrexone, fentanyl, and meperidine.

[0122] In another embodiment, the small molecule therapeutic agent is an antimigraine drug. In some embodiments, the antimigraine drug is selected from rizatriptan and naratriptan.

[0123] In another embodiment, the small molecule therapeutic agent is an antiemetic drug. In some embodiments, the antiemetic drug is selected from ondansetron and granisetron.

[0124] In another embodiment, the small molecule therapeutic is an anticonvulsant, hi some embodiments, the anticonvulsant drug is peramanel.

[0125] In another embodiment, the small molecule therapeutic agent is an anti-Parkinson's agent, hi an embodiment, the anti-Parkinson's agent is selected from pramipexole, ropinirole, cabergoline, and bromocriptine.

[0126] In some embodiments, the small molecule therapeutic agent is a cholinesterase inhibitor. In some embodiments, the cholinesterase inhibitor is selected from rivastigmine and donepezil.

[0127] In some embodiments, the small molecule therapeutic is a skeletal muscle relaxant. In some embodiments, the skeletal muscle relaxant is tizanidine.

[0128] In some embodiments, the small molecule therapeutic is a nicotinic agonist or partial agonist. In some embodiments, the nicotinic agonist or partial agonist is varenicline.

[0129] In some embodiments, the small molecule is an alpha blocker. In some embodiments, the small molecule is an alpha blocker such as prazosin or terazosin. In some embodiments, the small molecule is a beta blocker such as metoprolol or propranolol.

[0130] In some embodiments, the small molecule is a benzothiazole, such as riluzole.

[0131] In some embodiments, the small molecule is an inotropic agent. In some embodiments, the inotropic agent is dobutamine.

[0132] In some embodiments, the small molecule is an antimalarial agent. In some embodiments, the antimalarial agent is primaquine.

[0133] In some embodiments, the small molecule is an immunomodulatory agent. In some embodiments, the immunomodulatory agent is fingolimod.

[0134] In some embodiments, the small molecule is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from anastrozole and letrozole.

[0135] In some embodiments, the small molecule is an anti-estrogen compound. In some embodiments, the anti-estrogen compound is selected from tamoxifen and raloxifene.

[0136] In certain embodiments, the small molecule drug i) is poorly water-soluble at physiological pH (about 7.4) and / or ii) functions as a Bronsted base or Lewis base. As described below, i) has an aqueous solubility of 0.1-10 g / L or 20 g / L or less at 25°C, and / or ii) in the presence of a therapeutic agent and a physiological buffer, at least partially dissolves less than one stoichiometric amount of a polyprotic acid or two or more monoprotic acids to form a suspension or slurry at a pH (in the aqueous fraction) about equal to or less than the pKa of the protonated therapeutic agent. In other embodiments, the trace stoichiometry of a single polyprotic acid can be replaced with a mixture of acids comprising at least one polyprotic acid in combination with a less-than-stoichiometric or equal-to-stoichiometric amount of a therapeutic agent.

[0137] In some embodiments, the drug is selected from the group consisting of buprenorphine, naloxone, naltrexone, fentanyl and meperidine; rizatriptan and naratriptan; ondansetron and granisetron; peramanel; pramipexole, ropinirole, cabergoline and bromocriptine; rivastigmine and donepezil; tizanidine; varenicline; prazosin; dobutamine; primaquine; fingolimod; anastrozole and letrozole; tamoxifen and raloxifene. In another embodiment, the drug is selected from the group consisting of buprenorphine, naloxone, naltrexone, fentanyl, meperidine, rizatriptan, naratriptan, ondansetron, granisetron, peramanel, pramipexole, ropinirole, cabergoline, bromocriptine, rivastigmine, donepezil, tizanidine, varenicline, prazosin, dobutamine, primaquine, fingolimod, anastrozole, letrozole, tamoxifen, and raloxifene.

[0138] B.Organic acid (organic acid compound) In addition to the small molecule therapeutic agent, the composition includes a polyprotic acid compound or a combination of organic acid compounds, e.g., a combination comprising at least one polyprotic acid or a combination of two or more monoprotic acid compounds. The polyprotic acid or combination of polyprotic and / or monoprotic acids has one or more of the following characteristics: (i) an aqueous solubility of 0.1 to 10 g / L or less than about 20 g / L at room temperature; (ii) is present in an amount less than or equal to one stoichiometric amount relative to the therapeutic agent; (iii) provides an excess of acidic hydrogen atoms relative to the therapeutic agent (having a pKa value less than or equal to 12); and / or (iv) maintains a pH of the suspension or solution in its use environment that is approximately equal to or less than the pKa of the protonated small molecule therapeutic agent for a period of at least about 30 days. Optionally, the polyprotic acid may be present in the mixture of acidic excipients such that (i) the total stoichiometric amount of the acid excipient molecules is less than or equal to the amount of the therapeutic agent; (ii) all of the acid excipients provide a stoichiometric excess of acidic hydrogen atoms relative to the therapeutic agent (having a pKa value of less than or equal to 12); and / or (iii) the composition maintains a suspension or solution pH in its use environment that is approximately equal to or less than the pKa of the protonated small molecule therapeutic agent for a period of less than about 30 days. Optionally, two or more monoprotic acid compounds form the mixture of acidic excipients such that (i) the total stoichiometric amount of the acid excipient molecules is less than or equal to the amount of the therapeutic agent; (ii) all of the acid excipients provide a stoichiometric excess of acidic hydrogen atoms relative to the therapeutic agent (having a pKa value of less than or equal to 12); and / or (iii) the composition maintains a suspension or solution pH in its use environment that is approximately equal to or less than the pKa of the protonated small molecule therapeutic agent for a period of less than about 30 days. As described above, the compositions improve the solubility of small molecule therapeutic agents, enabling their use in drug delivery platforms that provide extended sustained release. The excess acidic hydrogen (relative to the therapeutic agent) interferes with physiological buffering species that would otherwise cause hydrolysis of the pharmacologically active salt.

[0139] In a first embodiment, the organic acid is a carboxylic acid. Examples include aromatic carboxylic acids in which the carboxylic acid group is directly bonded to the 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 one electron-donating group with antioxidant properties. Specific examples include o-anisic acid, m-anisic acid, p-anisic acid, p-aminobenzoic acid (PABA), o-aminobenzoic acid (anthranilic acid), o-toluic acid, m-toluic acid, p-toluic acid, and salicylic acid.

[0140] In yet another example, the aromatic carboxylic acid may have a single benzene ring and two electron-donating groups with 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 attached to the benzene ring. A specific example is phthalic acid.

[0141] In another example, the aromatic carboxylic acid is a carboxylic acid containing one carboxylic acid group attached to a naphthalene, quinoline, or coumarin ring. Examples include 1-naphthoic acid, 2-naphthoic acid, quinaldic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid, and 8-quinolinecarboxylic acid. A further class of acids of this type, which have one carboxylic acid group attached to the naphthalene or quinoline ring, includes acids containing additional electron-donating groups, such as hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl groups. Examples of acids of this class include 6-hydroxy-2-naphthoic acid, 6-hydroxy-3-naphthoic acid, 8-hydroxy-2-quinolinecarboxylic acid, 8-hydroxy-7-quinolinecarboxylic acid, 7-hydroxycoumarin-3-carboxylic acid, and their respective isomers.

[0142] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having one carboxylic acid attached to the biphenyl ring with an electron-donating substituent, such as a hydroxyl group, on the carboxylic acid moiety. Examples include 4'-hydroxy-4-biphenylcarboxylic acid, 4'-hydroxy-2-biphenylcarboxylic acid, 4'-methyl-4-biphenylcarboxylic acid, 4'-methyl-2-biphenylcarboxylic acid, 4'-methoxy-4-biphenylcarboxylic acid, and 4'-methoxy-2-biphenylcarboxylic acid.

[0143] In another exemplary embodiment, the acid is a dicarboxylic or tricarboxylic acid having two or three carboxylic acid groups attached to the naphthalene or quinoline ring. Examples include 1,4-naphthalenedicarboxylic acid and 2,6-naphthalenedicarboxylic acid.

[0144] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having one or two carboxylic acid groups directly attached to the biphenyl ring system. Examples include 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid, and diphenic acid.

[0145] In another exemplary embodiment, the carboxylic acid is a carboxylic acid having a carboxylic acid functional group separated from the benzene, pyridine, naphthalene, quinoline, or coumarin ring by a saturated chain of 1 to 4 carbon atoms. Examples of acids in this embodiment include phenylacetic acid and 3-phenylpropionic acid. Such acids can also be modified with one or more electron-donating groups, such as hydroxy or methoxy, e.g., 7-hydroxycoumarin-4-carboxylic acid.

[0146] In another exemplary 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).

[0147] In another exemplary embodiment, the carboxylic acid is an unsaturated or polyunsaturated dicarboxylic acid containing 4 to 10 carbons. Exemplary acids in this embodiment include fumaric acid, trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid.

[0148] In another exemplary embodiment, the carboxylic acid is cis-cinnamic acid or trans-cinnamic acid. In some embodiments, the 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, and p-methoxycinnamic acid, and ferulic acid.

[0149] In another embodiment, the organic acid is a phenol or naphthol substituted with about 2-5 electron-withdrawing groups selected from -F, -Cl, -Br, -I, -CN, -CHO (aldehyde), -COR (ketone), and NO. Examples include 2,4-dinitrophenol.

[0150] In another embodiment, the organic acid is a 1,3-dicarbonyl compound containing an acidic (pKa<8) C-H bond. Examples include 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), cyanuric acid, or barbituric acid.

[0151] In another embodiment, the organic acid is an imide, such as phthalimide. In some embodiments, the phthalimide is a phthalimide substituted with at least one electron-withdrawing substituent.

[0152] 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, coumarin, 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 contemplated. Aliphatic dihydroxamic acids containing 6-10 carbon atoms, such as suberohydroxamic acid, and unsaturated dihydroxamic acids containing 6-10 carbon atoms are also contemplated.

[0153] Organic acids for use in the compositions described herein preferably have a water 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, the acid has a water 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 other embodiments, the organic acid is crystalline and has a melting point greater than about 37°C.

[0154] In other embodiments, the acid is an inorganic polyprotonic acid derived from phosphoric acid having a molecular weight of 500 grams per mole or less. Examples of such acids include phosphoric acid, pyrophosphoric acid, sodium dihydrogen phosphate, calcium dihydrogen phosphate, magnesium dihydrogen phosphate, disodium pyrophosphate, monocalcium pyrophosphate, and monomagnesium pyrophosphate.

[0155] In other embodiments, the acid is an organic polyprotonic acid derived from phosphoric acid having a molecular weight of 500 grams per mole or less. Examples of such acids include methylphosphonic acid, ethylphosphonic acid, propylphosphonic acid, butylphosphonic acid, pentylphosphonic acid, and hexylphosphonic acid.

[0156] In other embodiments, the acid is a dendrimer or star polymer having capped acidic functional groups. Examples of such capping groups include methyl carboxylic acid, succinic acid, and glutaric acid groups.

[0157] Compositions comprising less than or equal to one equivalent of a polyprotic acid and a small molecule therapeutic agent are prepared by combining the acid and the therapeutic agent in a suitable solvent. Compositions comprising less than or equal to one equivalent of one or more monoprotic acids and a small molecule therapeutic agent are prepared by combining the acid and the therapeutic agent in a suitable solvent. In some embodiments, the solvent is an aqueous liquid, such as a buffer or an aqueous-organic solvent mixture.

[0158] In some embodiments, the molar amount of the organic acid in the composition provides a total number of acid hydrogens that exceeds the stoichiometric amount relative to the molar amount of the therapeutic agent in the composition, wherein the organic acid is two or more monoprotic acids, or a monoprotic acid and a polyprotic acid.In some embodiments, the stoichiometric amount is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 45%, more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 90%, or more than 100%.In other embodiments, the organic acid in the formulation provides a total number of acid hydrogens that exceeds the stoichiometric amount equivalent to the molar amount of the therapeutic agent in the composition by 25%, 50%, 75%, or 100%.In other embodiments, the organic acid in the formulation provides a total number of acid hydrogens that exceeds the stoichiometric amount equivalent to the molar amount of the therapeutic agent in the composition by 2 times, 3 times, 4 times, or 5 times. In some of these embodiments, reference to an organic acid is understood to contemplate a single polyprotic acid, a combination of polyprotic acids (e.g., two diprotic acids, two triprotic acids, a diprotic acid and a triprotic acid), a combination of two monoprotic acids, and / or a combination of a monoprotic acid and a polyprotic acid.

[0159] In some embodiments, the molar amount of polyprotic acid in the composition provides a total number of acid hydrogens that exceeds the stoichiometric amount relative to the molar amount of therapeutic agent in the composition. In some embodiments, the stoichiometric amount is greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%. In other embodiments, the polyprotic acid in the formulation provides a total number of acid hydrogens that is 25%, 50%, 75%, or 100% greater than the stoichiometric amount relative to the molar amount of therapeutic agent in the composition. In other embodiments, the polyprotic acid in the formulation provides a total number of acid hydrogens that is 2-fold, 3-fold, 4-fold, or 5-fold greater than the stoichiometric amount relative to the molar amount of therapeutic agent in the composition. In some of these embodiments, reference to a polyprotic acid is understood to contemplate a single polyprotic acid, two or more polyprotic acids (e.g., two diprotic acids, two triprotic acids, a diprotic acid and a triprotic acid, two diprotic acids and a triprotic acid, etc.) In some embodiments, the composition does not include a monoprotic acid.

[0160] In embodiments in which the composition resides in a reservoir of a drug delivery device, the device is susceptible to the use environment when placed in that environment. That is, the use environment and the composition in the device are fluidly connected via pores or a porous membrane in the drug delivery device. The compositions described herein include suspensions or slurries containing a steady-state or equilibrium mixture of a therapeutic agent salt form in addition to a stoichiometric excess of acidic functional groups. In this manner, the compositions 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, more preferably 2.9 to 5.6, more 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. Maintain at 0.3, 3.2-5.3, 3.3-5.3, 3.4-5.3, 3.5-5.3, 3.1-5.2, 3.2-5.2, 3.3-5.2, 3.4-5.2, 3.5-5.2, 3.1-5.1, 3.2-5.1, 3.3-5.1, 3.4-5.1, 3.5-5.1, 3.1-5.0, 3.2-5.0, 3.3-5.0, 3.4-5.0, 3.5-5.0, 3.5-5.5 or 3.5-6.0.

[0161] Typical Delivery Devices 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.

[0162] In some embodiments, the drug delivery device has a housing member defining a reservoir in which the composition and / or aqueous suspension is held. 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 member is preferably in the range of 2 mm to 6 mm, and the length is in the range of about 10 mm to about 50 mm. In some embodiments, the composition or aqueous suspension is initially present in a dry form in the device's reservoir. For example, an aqueous suspension containing a small molecule therapeutic agent and one or more acidic excipients is prepared, followed by spray drying, milling, or freeze-drying to provide a dry form of the aqueous suspension. Alternatively, the individual components in dry form—e.g., a therapeutic agent as a dry solid and an organic acid as a dry solid—can be mixed in the correct proportions, followed by subsequent hydration to provide the desired aqueous suspension. 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 aqueous media. The dried form of the composition can be tableted or pelleted, incorporated into a device, and 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 introducing 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.

[0163] Examples of drug delivery devices are provided in Figures 1A-1B. Figure 1A shows device 10 assembled and prepared for implantation into an anatomical compartment of a subject, such as subcutaneously or intraperitoneally. The device consists of a non-erodible housing member 12 defining an internal compartment or reservoir 14. A composition or formulation described herein is contained within the reservoir. Housing member 12 has first and second ends, 16, 18. As seen in Figure 1B, which shows device 10 in its unassembled form, first end 16 is sealed with a fluid-tight end cap 20. End cap 20 may optionally include a porous or semi-permeable membrane or porous septum 22. Second end 18 is attached to a porous membrane, semi-permeable membrane, or porous septum 24.

[0164] Figures 1C-1K show the end cap and end cap subassembly parts of a drug delivery device. The numbered subassembly components shown in Figures 1C-1F are 1 = cap, 2 = porous membrane, 3 = seal, 4 = retention ring, and 5 = drug device reservoir. The numbered subassembly components shown in Figures 1G-1K are 1 = cap, 2 = porous membrane, 3 = seal, 4 = drug delivery device reservoir, and 5 = retention ring.

[0165] The interior of the device contains a formulation comprising a small molecule drug that i) is poorly water soluble at physiological pH (about 7.4) and / or ii) can function as a Bronsted base or Lewis base, when combined with i) a polyprotic acid in an amount that is (a) equal to or less than the molar amount of the therapeutic agent and (b) provides a total number of acid hydrogens in excess of the stoichiometric equivalent to the molar amount of the therapeutic agent, or ii) a mixture of organic acid excipients comprising a polyprotic acid or a mixture of two or more monoprotic acid excipients, wherein the organic acid excipients are present in an amount that is (a) equal to or less than the molar amount of the therapeutic agent and (b) provides a total number of acid hydrogens in excess of the stoichiometric equivalent to the molar amount of the therapeutic agent. In certain embodiments, the therapeutic agent i) has an aqueous solubility of less than or equal to 0.1-10 g / L or 20 g / L at 25°C, and / or ii) forms, at least in part, a suspension or slurry in the presence of the drug and a physiological buffer at a pH (in the aqueous fraction) that is less than or equal to the pKa of the protonated drug.

[0166] 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.

[0167] Testing was performed as described in Example 1, where drug delivery devices were prepared. The internal reservoirs of the devices were filled with a composition of naltrexone base, a submolar amount of diprotic acid suberic acid, polyvinylpyrrolidone, and stearic acid. For comparison, devices were prepared with formulations that did not contain suberic acid. In vitro release from the devices was measured and is shown in Figure 2. The cumulative release of naltrexone for devices containing the naltrexone:suberic acid formulation (marked with an x) released essentially all of the drug within the device over a one-week period at a rate that significantly exceeded the rate of devices filled with formulations that did not contain polyprotic acid.

[0168] In vivo testing was performed as described in Example 2. Solid formulations containing naltrexone base and sebacic acid (also known as an aliphatic, diprotic acid, decanedioic acid) in a 1:0.6 molar ratio of drug to organic acid were prepared, along with binders and tableting lubricants. The formulations were compressed into tablets inserted into a drug delivery device combined with a porous membrane. One group of devices ("Group 1") had approximately half the nucleic acid surface area of ​​a second group of devices ("Group 2"). Devices were implanted in rats, and blood samples and animal weights were obtained at various time points over a period of approximately 3 months. Plasma naltrexone concentrations were determined from the samples and normalized to individual animal weights. Body weight-normalized naltrexone plasma levels (ng / mL) for Group 1 (diamonds) and Group 2 (crosses) devices are shown in Figure 3. Both Group 1 and Group 2 devices released naltrexone at a relatively constant rate after an initial burst period of 1-2 weeks. After the release period, devices were collected from each animal and subjected to mass balance analysis to calculate the average drug release rate. Devices from Group 1 (with 25% diffusion surface area) eluted naltrexone at an average rate of 1.8 mg / day. Devices from Group 2 (with 50% diffusion surface area) eluted naltrexone at an average rate of approximately 3.1 mg / day.

[0169] Thus, in certain embodiments, formulations and devices for delivery of a therapeutic agent are provided. The therapeutic agent (i) has an aqueous solubility of less than 1.0 g / L at room temperature and (ii) is an organic base. The therapeutic agent is present in the formulation or device in an amount sufficient to provide a therapeutic effect during a delivery period of at least about 30 days or at least about 60 days. The formulation also includes (i) a polyprotic acid or (ii) a mixture of organic excipients comprising at least one polyprotic acid in an amount (a) equal to or less than the molar amount of the therapeutic agent and (b) providing a total amount of acid hydrogen in excess of the stoichiometric equivalent to the molar amount of the therapeutic agent. In certain embodiments, the organic acid excipient maintains the pH of the formulation when hydrated in its use environment of 3.0 to 11.5 or about 3.0 to 6.5.

[0170] In some embodiments, a formulation comprising a small molecule therapeutic agent (also referred to herein as a "drug" or "therapeutic agent") and a polyprotic acid or a mixture of acids comprising at least one polyprotic acid, with the organic acid present in a stoichiometric or excess amount, provides an increase in the release rate of the small molecule therapeutic agent of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 50% compared to a formulation without an acidic excipient. In some embodiments, the increased release rate is for a period of at least 14 days, at least 2 weeks, at least 30 days, at least 45 days, at least 60 days, at least 90 days, or at least 180 days. In other embodiments, the increased release rate approaches a zero-order release rate during that period.

[0171] Drug delivery devices other than those specifically described herein are merely exemplary and are known in the art. The compositions described herein are useful in a variety of devices, including devices containing a drug reservoir for holding a small molecule therapeutic agent and a polyprotic acid formulation, and devices having a substrate or matrix capable of holding or containing the formulation. Controlled drug release devices suitable for the present invention generally provide for delivery of a drug from the device to a selected site in a subject in a selected or otherwise 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 over a treatment period. The delivery period will vary 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 period, contemplates a period of at least about 2 weeks to about 6 months. In other embodiments, the duration period contemplates 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 other embodiments, a sustained period contemplates 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, a period of 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 is contemplated.

[0172] Thus, in another embodiment, an implantable device is contemplated. The device comprises (i) a therapeutic agent in an amount sufficient to provide a substantially zero-order release of the therapeutic agent in an amount sufficient to provide a therapeutic effect for a period of at least about 30 days; (ii) a polyprotic acid or a mixture of acids comprising at least one polyprotic acid; and (c) a reservoir containing a formulation of a small molecule therapeutic agent, wherein, when hydrated in its use environment, the pH of the formulation is maintained at a value of about 3.0 to 6.0 during the delivery period. In some embodiments, the formulation comprising the small molecule therapeutic agent and the protic acid is in a dry form. For example, the dry formulation may 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 an aqueous suspension of the therapeutic agent in situ. The suspension contains an equilibrium or steady-state mixture of the therapeutic agent as a mixture of salt forms. 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 a 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 a drug delivery device is accomplished 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.

[0173] Treatment method In other embodiments, methods of treatment using the compositions and devices described herein are contemplated. In some embodiments, methods for sustained or controlled delivery of a therapeutic agent are contemplated, and a composition or delivery device is provided that includes a formulation of a therapeutic agent and a polyprotic acid (or a mixture of acids containing at least one polyprotic acid) in a substoichiometric amount relative to the therapeutic agent. In some embodiments, the therapeutic agent is an antipsychotic drug used to treat bipolar disorder or schizophrenia. Exemplary drugs include risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, asenapine, cariprazine, lurasidone, and haloperidol. In some embodiments, the therapeutic agent is an opioid agonist or antagonist useful for pain relief. Exemplary drugs include buprenorphine, naloxone, naltrexone, fentanyl, or meperidine. In another embodiment, the therapeutic agent is an antimigraine drug such as rizatriptan or naratriptan. In other embodiments, the therapeutic agent is an anticonvulsant such as peramanel, an antiparkinsonian such as pramipexole, ropinirole, cabergoline or bromocriptine, a cholinesterase inhibitor such as rivastigmine or donepezil, a skeletal muscle relaxant such as tizanidine, a nicotinic agonist or partial agonist such as varenicline, an alpha-blocker such as prazosin, a beta-blocker such as metoprolol, a cardiac inotropic agent such as dobutamine, an antimalarial such as primaquine, an immunomodulatory agent such as fingolimod, an aromatase inhibitor such as anastrozole or letrozole, or an anti-estrogen compound such as tamoxifen or raloxifene.

[0174] In another embodiment, a method is contemplated for maintaining therapeutic plasma levels of a therapeutic agent described herein, thereby delaying relapse in a stable, previously medicated patient by at least about 4 weeks.

[0175] Based on the foregoing, the compositions described herein, comprising a small molecule therapeutic agent and a polyprotic acid, provide release of the therapeutic agent for an extended period of time—e.g., at least about 14, 21, 30, 60, 90, or 120 days—at an essentially constant rate that approaches an essentially zero-order release rate during that period. The compositions contain a sufficient amount of therapeutic agent for a therapeutic dose of the agent during that period, and an equimolar or less amount of polyprotic acid (or a mixture of acidic excipients containing at least one polyprotic acid, wherein each acidic compound in the excipient mixture is present in an amount equal to or less than the molar amount of the therapeutic agent, yet providing a total number of acid hydrogens in excess of the stoichiometric equivalent to the molar amount of the therapeutic agent) to maintain the concentration of the protonated therapeutic agent in the hydrated composition at or near saturation during that period. The near-saturation concentration of the protonated drug is relative to the aqueous phase of the composition, e.g., at room temperature or human body temperature. In some embodiments, the composition is retained within a drug delivery system (or device) that, when placed in a use environment (e.g., a subcutaneous implantation site, an in vivo environment such as plasma or interstitial fluid having a constant pH of about 7.4), provides an essentially constant concentration gradient between the interior of the device and its use environment, facilitating an essentially constant release rate (substantially zero-order kinetics) of the therapeutic agent over an extended period of time. [Example]

[0176] The following examples are aiding in nature and are not intended to be limiting.

[0177] Example 1 Formulations Comprising Naltrexone and Polyprotic Organic Acids as Small Molecule Therapeutics A composition of naltrexone base (62.2% by weight, approximately 280 mg / device), suberic acid (23.8% by weight; 0.75 molar amount relative to drug), polyvinylpyrrolidone (12% by weight), and stearic acid (2% by weight) was compressed into pellets. A comparative formulation of naltrexone base (86% by weight, approximately 385 mg / device), polyvinylpyrrolidone (12% by weight), and stearic acid (2% by weight) was also compressed into pellets and served as a control. The formulation was loaded into a delivery device equipped with a 0.1 micron polyvinylidene fluoride (DURAPORE®) membrane. The device was vacuum-filled with phosphate buffer and transferred to a 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). Naltrexone release is shown in Figure 2. Cumulative release of naltrexone (mg) for devices with a comparative formulation (n=3) (diamonds) and devices with a naltrexone:suberic acid formulation (n=2) (crosses) is plotted against time (days). Error bars reflect standard deviation for the control system and minimum / maximum values ​​for the active system. Compared to the control, devices loaded with a formulation consisting of drug and polyprotic acid released virtually all of the loaded drug over a one-week period at a rate significantly exceeding that of the control system.

[0178] Example 2 In vivo evaluation of a drug delivery device containing naltrexone and sebacic acid as small molecule therapeutic agents. A solid formulation containing naltrexone base and sebacic acid was prepared by mixing the drug and organic acid with polyvinylpyrrolidone (5% by weight) as a binder and stearic acid (2% by weight) as a lubricant in a molar ratio of 1:0.6. The mixture was compressed into tablets.

[0179] Drug delivery devices were assembled by first sealing one end of a cylindrical reservoir with a solid PEEK cap and then filling each resulting tube with the tablet. Each device contained approximately 450 mg of solid formulation, after which the second open end was sealed with a cap fitted with a 0.1 micron polyvinylidene fluoride (DURAPORE®) membrane. Two separate device versions were constructed by incorporating washers into the cap assembly to limit the diffusion surface area per device; one version had a diffusion surface area of ​​approximately 25% of the total membrane surface area, and the second version had a diffusion surface area of ​​approximately 50% of the total membrane surface area. All devices were terminally sterilized and vacuum-filled with sterile saline before implantation into male Sprague-Dawley rats (n=4). Over a period of approximately 3 months, blood samples and animal weights were obtained at the time points described in the protocol, and naltrexone plasma concentrations were determined by liquid chromatography / mass spectrometry. The results are shown in Figure 3. After the release period, devices were collected from each animal and subjected to mass balance analysis to calculate the average drug release rate. Group 1 devices (with 25% diffusion surface area) eluted naltrexone at an average rate of 1.8 mg / day. Group 2 devices (with 50% diffusion surface area) eluted naltrexone at an average rate of approximately 3.1 mg / day.

Claims

1. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and (i) an amount of organic polyprotonic acid equal to or less than the molar amount of the therapeutic agent, and (ii) an amount of organic polyprotonic acid that provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent. A composition comprising:

2. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and (i) an amount of inorganic polyprotonic acid equal to or less than the molar amount of the therapeutic agent, and (ii) an amount of inorganic polyprotonic acid that provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent. A composition comprising:

3. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and A mixture of two or more acids including at least one organic polyprotonic acid in an amount (i) equal to or less than the molar amount of the therapeutic agent, and (ii) providing a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent. A composition comprising:

4. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and A mixture of two or more acids including at least one inorganic polyprotonic acid in an amount (i) equal to or less than the molar amount of the therapeutic agent, and (ii) providing a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent. A composition comprising:

5. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and (i) a molar amount of about 0.25 to 1.0 of the therapeutic agent, and (ii) a dendrimer capped with acidic functional groups in an amount that provides a total number of acid hydrogens in excess of the equivalent stoichiometry relative to the molar amount of the therapeutic agent. A composition comprising:

6. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and (i) a mixture of about 0.25 to 1.0 molar amounts of a therapeutic agent and (ii) an acidic excipient comprising a dendrimer capped with at least one acidic functional group in an amount that provides a total number of acid hydrogens in excess of the equistoichiometric molar amount of the therapeutic agent. A composition comprising:

7. a molar amount of a therapeutic agent that (i) has an aqueous solubility of less than 1.0 g / L at room temperature, and (ii) is an organic base; and A mixture of two or more monoprotic acids, wherein each monoprotic acid in the mixture is in an amount equal to or less than the molar amount of the therapeutic agent, and wherein the two or more monoprotic acids provide a total number of acid hydrogens in excess of an equivalent stoichiometric amount relative to the molar amount of the therapeutic agent. A composition comprising:

8. The composition of any one of claims 1 to 7, comprising an organic acid that is crystalline and has a melting point above about 37°C.

9. 9. The composition of any one of claims 1 to 8, comprising an inorganic acid that is crystalline and has a melting point above about 37°C.

10. The composition according to any one of claims 1 to 9, wherein the polyprotonic acid or monoprotonic acid is an aliphatic polyprotonic acid or an aliphatic monoprotonic acid.

11. The composition of any one of claims 1 to 4, wherein the polyprotic acid is a diprotic aliphatic acid containing from 4 to 12 carbon atoms.

12. 5. The composition of claim 1, wherein the polyprotic acid is a triprotic aliphatic acid containing from 4 to 12 carbon atoms.

13. The composition according to any one of claims 1 to 4 and 12, wherein the polyprotonic acid is selected from succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid and sebacic acid.

14. The composition according to any one of claims 1 to 4, wherein the polyprotonic acid is an unsaturated diprotonic acid.

15. 15. The composition of any one of claims 1 to 4 and 14, wherein the polyprotic acid is selected from fumaric acid, glutaconic acid, traumatic acid, muconic acid, citraconic acid, mesaconic acid or itaconic acid.

16. The composition according to any one of claims 1 to 4, wherein the polyprotonic acid is a diprotonic acid having an aromatic ring.

17. 17. The composition of any one of claims 1 to 4 and 16, wherein the polyprotonic acid is phthalic acid, isophthalic acid, or terephthalic acid.

18. The composition according to any one of claims 1 to 4, wherein the polyprotonic acid is biphenyl 4,4'-dicarboxylic acid or a positional isomer thereof.

19. The composition of any one of claims 1 to 4, wherein the polyprotonic acid has two carboxylic acid groups attached to a naphthalene ring or a quinoline ring.

20. The composition of any one of claims 1 to 4, wherein the polyprotonic acid is an alkylphosphonic acid.

21. 21. The composition of claim 20, wherein the formulation comprises methylphosphonic acid, ethylphosphonic acid, propylphosphonic acid, butylphosphonic acid, pentylphosphonic acid, hexylphosphonic acid, heptylphosphonic acid, or octylphosphonic acid.

22. 5. The composition of claim 2 or 4, wherein the polyprotonic acid is an inorganic diprotonic acid.

23. 5. The composition of claim 2 or 4, wherein the polyprotonic acid is an inorganic triprotonic acid.

24. 5. The composition of claim 2 or 4, wherein the polyprotic acid is a tetraprotic acid.

25. 25. The composition of any one of claims 2, 4 and 24, wherein the polyprotonic acid is phosphoric acid.

26. 25. The composition of any one of claims 2, 4 and 24, wherein the polyprotonic acid comprises dihydrogen phosphate ions.

27. 27. The composition of any one of claims 2, 4, 24, 25 and 26, comprising a salt formed with pyrophosphate or a partially neutral pyrophosphate.

28. 7. The composition of claim 5 or 6, wherein the dendrimer is capped with a carboxymethyl group, a succinyl group, a glutaryl group, an adipyl group, a pimelyl group, a suberyl group, an azelayl group, a sebacyl group, or a phthalyl group.

29. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid having the carboxylic acid group attached to an unsubstituted benzene or pyridine ring.

30. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid selected from the group consisting of benzoic acid, picolinic acid, nicotinic acid and isonicotinic acid.

31. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid having one electron donating group that has antioxidant properties.

32. 32. The composition of claim 31, 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.

33. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid having a benzene ring and two electron donating groups with antioxidant properties.

34. 34. The composition of claim 33, wherein the carboxylic acid is vanillic acid.

35. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid selected from the group consisting of 1-naphthoic acid, 2-naphthoic acid, quinaldic acid, 3-quinolinecarboxylic acid, 4-quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7-quinolinecarboxylic acid and 8-quinolinecarboxylic acid.

36. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid 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.

37. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid selected from the group consisting of 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid and diphenic acid.

38. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a carboxylic acid 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.

39. Acid excipient mixture 1-4 sp ３ 7. The composition of any one of claims 3, 4 and 6, comprising an organic acid having a carboxylic acid functionality separated from a benzene ring, a pyridine ring, a naphthalene ring or a quinoline ring by a hybridized carbon chain.

40. 40. The composition of claim 39, wherein the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.

41. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises cis-cinnamic acid or trans-cinnamic acid.

42. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a trans-cinnamic acid 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.

43. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a 1,3-dicarbonyl compound containing an acidic CH or NH bond (pKa<8).

44. 44. The composition of claim 43, wherein the organic acid is 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), uric acid, cyanuric acid, or barbituric acid.

45. The composition of any one of claims 1 to 4, wherein the polyprotonic acid is an imide.

46. 46. ​​The composition of claim 45, wherein the imide is a phthalimide or a substituted phthalimide.

47. 48. The composition of claim 47, wherein the substituted phthalimide has at least one electron-withdrawing substituent.

48. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a hydroxamic acid.

49. 49. The composition of claim 48, wherein the hydroxamic acid is an aromatic hydroxamic acid containing one hydroxamic functional group directly attached to the aromatic ring.

50. 50. The composition of claim 49, 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.

51. 51. The composition of claim 49 or 50, wherein the hydroxamic acid is benzhydroxamic acid.

52. 49. The composition of claim 48, wherein the hydroxamic acid contains one hydroxamic functional group separated from an aromatic ring by a chain of 1 to 4 saturated carbon atoms.

53. 5. The composition of claim 1, wherein the polyprotonic acid is a polyhydroxamic acid containing two or more hydroxamic acid functional groups directly attached to a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, or a biphenyl ring system.

54. 54. The composition of claim 53, wherein the hydroxamic acid is substituted with an electron-donating substituent selected from the group consisting of hydroxy, methoxy, amino, alkylamino, dialkylamino, and alkyl groups.

55. The composition according to any one of claims 1 to 4, wherein the polyprotonic acid is an aliphatic polyhydroxamic acid containing from 6 to 10 carbon atoms.

56. 56. The composition of claim 55, wherein the hydroxamic acid is suberohydroxamic acid.

57. The composition according to any one of claims 1 to 4, wherein the polyprotonic acid contained in the formulation is an unsaturated polyhydroxamic acid containing from 6 to 10 carbon atoms.

58. The composition of any one of claims 5-6, wherein the dendrimer excipient is capped with multiple hydroxamic acid functional groups.

59. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises an amino derivative of benzoic acid, such as 2-amino-benzoic acid (anthranilic acid) or 4-aminobenzoic acid (para-aminobenzoic acid; PABA).

60. 7. The composition of any one of claims 3, 4 and 6, wherein the acid excipient mixture comprises a methoxy derivative of benzoic acid such as 4-methoxybenzoic acid (p-anisic acid), o-anisic acid or m-anisic acid.

61. 61. The composition of any one of claims 1 to 60, wherein the therapeutic agent is selected from the group consisting of risperidone, paliperidone, olanzapine, aripiprazole, brexpiprazole, asenapine, cariprazine, lurasidone, or haloperidol.

62. 62. The composition of any one of claims 1 to 61, wherein the therapeutic agent is selected from the group consisting of buprenorphine, naloxone, naltrexone, fentanyl, and meperidine.

63. 63. The composition of any one of claims 1 to 62, wherein the therapeutic agent is selected from the group consisting of rizatriptan and naratriptan.

64. 64. The composition of any one of claims 1 to 63, wherein the therapeutic agent is selected from the group consisting of ondansetron, granisetron, rivastigmine and donepezil.

65. 65. The composition of any one of claims 1 to 64, wherein the therapeutic agent is selected from the group consisting of perampanel, tizanidine, varenicline, prazosin, dobutamine, primaquine, fingolimod, anastrozole, letrozole, tamoxifen, and raloxifene.

66. 66. The composition of any one of claims 1 to 65, wherein the therapeutic agent is selected from the group consisting of pramipexole, ropinirole, cabergoline, and bromocriptine.

67. 67. The composition of any one of claims 1 to 66, wherein the amount of small molecule therapeutic agent is sufficient to provide treatment for at least 30 days.

68. The composition of any one of claims 1 to 67, wherein the composition is in a dry form.

69. 69. The composition of any one of claims 1 to 68, wherein the composition is in dry form, and wherein when hydrated to form a solution or suspension, the organic acid is present in an amount to maintain a pH of the composition in its environment of use of 3.0 to 11.5, or about 3.0 to 6.5, for a period of at least about 30 days.

70. 70. A device comprising the composition of any one of claims 1 to 69, designed for subcutaneous implantation in a mammal.

71. 71. A method for sustained, controlled delivery of a therapeutic agent comprising providing a composition according to any one of claims 1 to 69 or a device according to claim 70.

72. 62. A method for sustained subcutaneous delivery of a therapeutic dose of an antipsychotic agent comprising providing a composition according to any one of claims 1 to 61 or a device comprising a composition according to any one of claims 1 to 61 designed for subcutaneous implantation in a mammal.

73. 62. A method for sustained subcutaneous delivery of a therapeutic dose of an opioid agonist or antagonist selected from buprenorphine, naloxone, naltrexone, fentanyl and meperidine, comprising providing a composition of any one of claims 1 to 61 or a device comprising the composition of any one of claims 1 to 61 designed for subcutaneous implantation into a mammal.

74. 62. A method for sustained subcutaneous delivery of a therapeutic dose of a therapeutic agent comprising providing a composition of any one of claims 1 to 61 or a device comprising the composition of any one of claims 1 to 61 designed for subcutaneous implantation into a mammal.

75. 75. The method of claim 74, wherein the therapeutic agent is a skeletal muscle relaxant, an antimigraine drug, an anticonvulsant, an antiparkinsonian, or an acetylcholinesterase inhibitor.

76. 76. The method of claim 75, wherein the skeletal muscle relaxant is selected from tizanidine and cyclobenzaprine, the antimigraine drug is selected from rizatriptan and naratriptan, the acetylcholinesterase inhibitor is selected from rivastigmine and donepezil, the anticonvulsant is selected from pramipexole, ropinirole, cabergoline, bromocriptine and donepezil, and the anticonvulsant is peramanel.

77. 77. The method of any one of claims 71 to 76, wherein said providing comprises providing 1 to 4 devices.

78. 79. The method of claim 78, further comprising administering or instructing to administer 1 to 4 devices.

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