COMPOSITIONS FOR SMALL MOLECULE THERAPEUTIC AGENT COMPOUNDS

This application claims the benefit of U.S. Application No. 62/636,122, filed Feb. 27, 2018, incorporated by reference herein.

The subject matter described herein relates to compositions and formulations for a small molecule therapeutic agent, and to drug delivery devices comprising the compositions and formulations for controlled, sustained delivery of the small molecule therapeutic agent.

Important classes of small molecule drugs exhibit poor water solubility at neutral pH. Although this property may favor tissue penetration by transmembrane diffusion, particularly for drugs that target the central nervous system, it complicates the development of injectable or implantable sustained delivery systems which rely on passive diffusion as the primary drug release mechanism. For example, a hydrophobic drug with greatly reduced water solubility may not be able to create a concentration gradient across a membrane or porous partition sufficient to drive adequate efflux from a reservoir containing an aqueous suspension of the drug. Many insoluble drugs are weak organic bases (i.e., molecules that include at least one functional group such as a primary, secondary, or tertiary amine; aniline, amidine, or guanidine; or a nitrogen-bearing heterocyclic ring such as pyridine, quinoline, imidazole, thiazole, triazole, or tetrazole), and their water solubility improves upon protonation; i.e., when they are converted into a salt. Many drugs that target the central nervous system fall into this category, including 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); 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); nicotine agonists or partial agonists (e.g., varenicline) and VMAT2 inhibitors (e.g., tetrabenazine and deutetrabenazine). Examples of hydrophobic base drugs that target receptors, cells, or tissues outside of the central nervous system include alpha blockers (e.g., prazosin), cardiac inotropic agents (e.g., dobutamine), antimalarials (e.g., primaquine and mefloquine), aromatase inhibitors (e.g., anastrazole and letrozole), antiestrogens (e.g., tamoxifen and raloxifene), phosphodiesterase inhibitors (e.g., vardenafil), and immunomodulators (e.g., fingolimod).

Although salts formed between such drugs and a canonical acid may have improved solubility in water, they are unstable and susceptible to hydrolysis at pH values approaching or exceeding the pKa of the protonated drug, which is typically greater than 7. This process complicates diffusion-mediated drug delivery through an implant or depot (i.e., a delivery mechanism that lacks an active pumping mechanism or a complicated semi-permeable membrane architecture to regulate release), since efflux of drug from the formulation must be coupled to a constant influx of buffering species from physiological fluids. Compositions and devices that address these, and other, complications related to sustained and controlled delivery of small molecule therapeutic agents that are weak organic bases, are needed.

The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

In one aspect, a composition, comprising a small molecule therapeutic agent that (i) has a water solubility at 25° C. of less than about 1 g/L and (ii) is a weak base (i.e., possessing a conjugate acid with a pKa between 6 and 9), combined with a stoichiometric excess of an organic acid compound that (i) has a water solubility at room temperature of less than about 20 g/L, (ii) maintains a pH of the suspension in its environment of use of between 3-6.5 for a period of at least about 30 days, and (iii) has a molecular weight less than or equal to 500 grams per mole.

In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility at 25° C. of less than about 1 g/L and (ii) is a weak base (i.e., possessing a conjugate acid with a pKa between 5 and 9), combined with a stoichiometric excess of an organic acid compound that (i) has a water solubility at room temperature between 0.1 and 10 g/L; (ii) has a molecular weight less than 500 grams per mole; and (iii) maintains a pH of the suspension in its environment of use of between 3-6.5 for a period of at least about 30 days.

In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility at 25° C. of less than about 1 g/L and (ii) becomes more soluble upon protonation, combined with a stoichiometric excess of an organic acid compound that (i) has a water solubility at room temperature of less than about 20 g/L and (ii) maintains a pH of the suspension in its environment of use that is equal to or below the pKa of the protonated drug for a period of at least about 30 days.

In another aspect, a composition comprising an aqueous suspension is provided. The aqueous suspension comprises a small molecule therapeutic agent that (i) has a water solubility at 25° C. of less than about 1 g/L and (ii) becomes more soluble upon protonation, combined with a stoichiometric excess of an organic acid compound that (i) has a water solubility between 0.1 and 10 g/L; (ii) has a molecular weight less than 500 grams per mole; and (iii) maintains a pH of the suspension in its environment of use that is equal to or below the pKa of the protonated drug for a period of at least about 30 days.

In one embodiment, the aqueous suspension is a heterogeneous mixture comprising the small molecule therapeutic agent and the organic acid compound, where the organic acid compound sufficiently dissolves to maintain the pH of the heterogeneous solution in its environment of use at a value equal to or less than physiological pH (˜7.4) for the stated period. In one embodiment, the environment of use is in vivo. In another embodiment, the environment of use is in vitro in a release medium maintained at a controlled temperature, e.g., 37° C.

In one embodiment, the organic acid compound is present in an amount approximately equal to or above its saturation concentration at the end of the period.

In another embodiment, the organic acid compound is present in a stoichiometric (molar) amount ranging from about 105% to 1000% relative to the therapeutic agent, but as much as 10,000%. In other embodiment, the organic acid on a molar basis is 110%, 125%, 150%, 175% 200%, 250%, 300%, 350%, 400%, 450%, 500% more than the molar amount of therapeutic agent in the composition.

In another embodiment, the organic acid compound is crystalline and has a melting temperature of more than about 37° C.

In another embodiment, the organic acid compound is not a polymer or is a non-polymeric compound.

In one embodiment, the small molecule therapeutic agent is selected from 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); anticonvulsants (e.g., perampanel); dopaminergic antiparkinsonian agents (e.g., pramipexole, ropinirole, cabergoline, and bromocriptine); acetylcholinesterase inhibitors (e.g., rivastigmine and donepezil); skeletal muscle relaxants (e.g., tizanidine and cyclobenzaprine); nicotine agonists or partial agonists (e.g., varenicline); immunomodulating agents (e.g., fingolimod), and/or VMAT2 inhibitors (e.g., tetrabenazine and deutetrabenazine).

In another embodiment, the small molecule therapeutic agent is selected from opioid agonists and antagonists, anti-Parkinsonian agents, anti-migraine agents, agents that act as skeletal muscle relaxants, anti-emetics, and/or immunomodulators for treating Multiple sclerosis. Other embodiments include any one or any combination of classes of therapeutic agents and/or the therapeutic agents discloses herein.

In yet another embodiment, the small molecule therapeutic agent is not an antipsychotic medication. In other embodiments, the antipsychotic medication is not risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, or asenapine. In another embodiment, the small molecule therapeutic agent is not is not risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, or asenapine. In one embodiment, the therapeutic agent is haloperidol. In another embodiment, the therapeutic agent is not haloperidol.

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

In another embodiment, the therapeutic agent is a cardiac inotropic agent such as dobutamine.

In yet another embodiment, the therapeutic agent is an anti-hypertensive drug such as prazosin.

In one embodiment, the therapeutic agent is an anti-malarial drug such as primaquine or mefloquine.

In yet another embodiment, the therapeutic agent is an aromatase inhibitor such as anastrazole or letrozole.

In one embodiment, the therapeutic agent has antiestrogen activity, such as tamoxifen or raloxifene.

In one embodiment, the aqueous suspension comprises, or is manufactured with, an organic acid suspended into a water-based solution, such as an aqueous buffered solution.

In another embodiment, the aqueous suspension comprises, or is manufactured with, a pre-made salt formed between the therapeutic agent and the organic acid, where the acid is present in stoichiometric (molar) excess.

In another embodiment, the therapeutic agent and a stoichiometric (molar) excess of the organic acid are mixed by dissolution into 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.

In one embodiment, the organic acid is an aromatic carboxylic acid. Exemplary acids, in one embodiment, are those having a carboxylic acid group bound to an unsubstituted benzene or pyridine ring. In one embodiment, the carboxylic acid is selected from the group consisting of benzoic acid, nicotinic acid, nicotinic acid, and isonicotinic acid.

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

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

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

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

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

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

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

In yet another embodiment, the carboxylic acid is one having one additional electron donating substituent on the biphenyl carboxylic acid moiety. In one embodiment, and by way of example, the carboxylic acid is selected from the group consisting of 4′-hydroxy-4-biphenylcarboxylic acid, 4′-hydroxy-2-biphenylcarboxylic acid, 4′-methyl-4-biphenylcarboxylic acid, 4′-methyl-2-biphenylcarboxylic acid, 4′-methoxy-4-biphenylcarboxylic acid, and 4′-methoxy-2-biphenylcarboxylic acid.

In still another embodiment, the carboxylic acid is one having a carboxylic acid functional group separated from a benzene, pyridine, naphthalene, quinoline, or coumarin ring by a chain of 1-4 saturated carbon atoms. In one embodiment, and by way of example, the carboxylic acid is phenylacetic acid, 3-phenylpropionic acid, or 7-hydroxycoumarin-4-acetic acid.

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

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

In other embodiments, the carboxylic acid is a cis-cinnamic acid or a trans-cinnamic acid. In still other embodiments, the carboxylic acid is a trans-cinnamic acid with 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.

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

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

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

In yet another embodiment, the organic acid is a hydroxamic acid. In one embodiment, and by way of example, the hydroxamic acid is an aromatic hydroxamic acid containing one hydroxamic functional group bonded directly to an aromatic ring. In one embodiment, the aromatic ringis selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring. In still another embodiment, the hydroxamic acid is benzhydroxamic acid. In yet another embodiment, the hydroxamic acid is one containing a hydroxamic functional group separated from an aromatic ring by a chain of 1-4 sp³-hybridized carbon atoms.

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

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

In other embodiments, the hydroxamic acid contains an aromatic ring that bears an electron donating substituent selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, and alkyl groups.

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

The hydroxamic acid is, in one embodiment, suberohydroxamic acid.

The hydroxamic acid is, in other embodiments, an unsaturated dihydroxamic acid containing 6-10 carbon atoms.

In another embodiment, the aromatic carboxylic acid is selected from the group consisting of 3-phenylpropionic acid, cinnamic acid, a hydroxy-derivative of cinnamic acid, a methoxy derivative of cinnamic acid, nicotinic acid, benzoic acid, an amino-derivative of benzoic acid, a methoxy derivative of benzoic acid, and phthalic acid.

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

In yet other embodiments, the p-coumaric acid is trans-p-coumaric acid.

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

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).

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

In one embodiment, the composition is in a dry form. In another embodiment, the composition is in dry form and hydrates in situ when in its environment of use.

In another aspect, a device comprising a composition as described herein is provided. The device is configured for subcutaneous implantation into a mammal.

In another aspect, an implantable device is provided. The device comprises a reservoir comprising a formulation of a small molecule therapeutic agent, the formulation comprising (i) an amount of the small molecule therapeutic agent to provide substantially zero-order release of the small molecule therapeutic agent for a delivery period of at least about 30 days and at a rate that provides a therapeutic effect and (ii) an organic acid that (a) maintains a pH of the formulation when hydrated in its environment of use of between 3.0-6.5 for the delivery period; (b) is present in stoichiometric (molar) excess, relative to the therapeutic agent, and (c) is present at the end of the delivery period in an amount approximately equal to or above its saturation concentration in the formulation when hydrated.

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

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

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

In another embodiment, the small molecule therapeutic agent is released from the device at a rate that provides a therapeutic effect for the period.

In still another embodiment, the organic acid has a water solubility at 25° C. of less than about 20 g/L. In still another embodiment, the organic acid has a water solubility at room temperature between 0.1 and 10 g/L and a molar mass less than 500 grams per mole.

In another embodiment, the organic acid has a water solubility at 25° C. of less than about 20 g/L and a pKa between 3 and 6. In another embodiment, the organic acid has a water solubility at room temperature between 0.1 and 10 g/L, a molar mass less than 500 grams per mole, and a pKa between 3 and 6.

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

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

In another aspect, a method for sustained, controlled delivery of a small molecule therapeutic is provided. The method comprises providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method for sustained, controlled delivery of an antipsychotic drug is provided, where the method comprises providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method to provide maintenance therapy to treat schizophrenia or bipolar disorder is provided, where the method comprises providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method to provide maintenance therapy to treat drug addiction is provided, where the method comprises providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method to provide maintenance therapy to treat Parkinson's disease or Alzheimer's disease is provided, where the method comprises providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method to provide maintenance therapy to treat epilepsy, multiple sclerosis, or amyotrophic lateral sclerosis is provided, where the method providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In another aspect, a method to provide prophylaxis against malaria is provided, where the method providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

In yet another aspect, a method to treat osteoporosis, breast cancer, or infertility is provided, where the method providing a composition or a device as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

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

Additional embodiments of the present methods, devices and compositions, and the like, will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.

Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to 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.

Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 mg to 8 mg is stated, it is intended that 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg are also explicitly disclosed, as well as the range of values greater than or equal to 1 mg and the range of values less than or equal to 8 mg.

The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes a single polymer as well as two or more of the same or different polymers, reference to an “excipient” includes a single excipient as well as two or more of the same or different excipients, and the like.

The word “about” when immediately preceding a numerical value means a range of plus or minus 10% of that value, e.g., “about 50” means 45 to 55, “about 25,000” means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein.

The compositions of the present disclosure can comprise, consist essentially of, or consist of, the components disclosed.

All percentages, parts and ratios are based upon the total weight of the compositions and all measurements made are at about 25° C., unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are—within the scope of sound medical judgment—suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some aspects, “pharmaceutically acceptable” means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g., animals), and more particularly, in humans.

The term “treating” is used herein in reference to methods of administration of a small molecule which reduces the frequency of, or delays the onset of, symptoms of a medical condition (e.g., schizophrenia, bi-polar disorder) in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition (e.g., controlling schizophrenia symptoms).

By reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason.

Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

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

In one aspect, a composition or formulation in which a small molecule therapeutic agent is solubilized through the use of partially soluble organic acids to improve delivery of the therapeutic agent from a device or drug delivery platform for a sustained period of time. In one embodiment, the composition is an aqueous suspension or slurry. In another embodiment, the composition is a heterogeneous or nonuniform mixture or solution. The solution or mixture can be, in some embodiments, an aqueous mixture or an aqueous heterogeneous mixture. In another embodiment, the composition is in dry form (e.g., lyophilized, spray dried, desiccated, etc.). In these various embodiments, the composition comprises a small molecule therapeutic agent that can function as a Bronsted or Lewis base and an organic acid that has one or more of the following: (i) a water solubility at room temperature (e.g., approximately 25° C.) of less than about 20 g/L or of between about 0.1 to 10 g/L; (ii) a molar mass less than 500 grams per mole; (iii) is present in a stoichiometric (molar) excess relative to the therapeutic agent; and (iv) maintains a pH of the suspension (or solution) in its environment of use approximately equal to or less than the pKa of the protonated therapeutic agent for a period of at least about 30 days. The composition may additionally comprise an aqueous fluid, for example water, buffer or a water-solvent mixture. In embodiments where the composition is in dry form, the aqueous fluid hydrates the composition in situ in its environment of use.

As noted above, the formulations described herein provide solubility of the small molecule therapeutic agent in order to permit delivery for a sustained period. In one embodiment, a sustained period of time intends a period of at least about two weeks to about six months. In another embodiment, a sustained period of time intends a period of at least about two weeks, or at least about three weeks, or at least about four weeks to about six months, or to about four months, or to about three months. In another embodiment, a sustained period of time intends 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 another embodiment, the sustained period of time intends a period of at least about six months, or nine months, or twelve months.

Also as noted above, the formulations described herein enhance the solubility of the small molecule therapeutic in part by maintaining a particular pH range of the formulation in its environment of use for the stated period of time. In one embodiment, the environment of use is in vivo. For example, the formulation may be part of a drug delivery device that is implanted in vivo and several examples of such devices are provided below. In another embodiment, the environment of use is in vitro in a release medium maintained at about 37° C.

The components of the composition, namely the small molecule therapeutic agent and the organic acid compound (also referred to herein as an ‘organic acid’), are now described.

In one embodiment, the compositions comprise a small molecule therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base. Reference to “small molecule”, in one embodiment, is to a biologically active molecule that has a molecular weight of less than or equal to 2,000 Daltons, and is generally used in the context of a small molecule drug (therapeutic agent) as distinguished from a protein, polypeptide or peptide therapeutic agent. In another embodiment, the small molecule has a molecular weight of less than or equal 1,000 Daltons or less than or equal to 500 Daltons. In other embodiments, the molecular weight of the small molecule is between 10-2000 Daltons, 10-1000 Daltons, 10-500 Daltons, 50-2000 Daltons, 50-1000 Daltons, 50-500 Daltons, 100-2000 Daltons, 100-1000 Daltons, or 100-500 Daltons.

Small molecule therapeutic agents contemplated include, but are not limited to, agents that are weak organic bases (i.e., possessing conjugate acids with pKas between 6 and 9 or between 5 and 9) and a potency such that a 30-60 day dose can be contained in a delivery device implanted into a human.

By way of example, therapeutic agents that include a primary, secondary, or tertiary amine; aniline, amidine, or guanidine; or a nitrogen-bearing heterocyclic ring such as pyridine, quinoline, imidazole, thiazole, triazole, or tetrazole functional group are contemplated as small molecule therapeutic agents that are organic bases. It will be appreciated that therapeutic agents having a structure containing more than one of these functional groups are contemplated. Examples of aniline derivatives include analogues of aniline where the phenyl group is substituted with, for example, a methyl group (toluidine), a halogen such as chlorine (2-chloroaniline, 3-chloroaniline, 4-chloroaniline), an amino group (4- aminobenzoic acid, or 2-aminobenzoic acid, or 3-aminobenzoic acid), a nitro group (e.g., 2-, 3-, or 4-nitroaniline), and many others.

In one embodiment, the small molecule therapeutic agent is an opioid agonist or antagonist. In an embodiment, the opioid agonist or antagonist is selected from buprenorphine, naloxone, naltrexone, fentanyl, and meperidine.

In another embodiment, the small molecule therapeutic is an antimigraine drug. In an embodiment, the antimigraine drug is selected from rizatriptan and naratriptan.

In another embodiment, the small molecule therapeutic is an antiemetic drug. In an embodiment, the antiemetic drug is selected from ondansetron and granisetron.

In another embodiment, the small molecule therapeutic is an anticonvulsant. In an embodiment, the anticonvulsant drug is peramanel.

In another embodiment, the small molecule therapeutic is an anti-Parkinsonian agent. In an embodiment, the anti-Parkinsonian agent is selected from pramipexole, ropinirole, cabergoline, and bromocriptine.

In one embodiment, the small molecule therapeutic is a cholinesterase inhibitor. In an embodiment, the cholinesterase inhibitor is selected from such as rivastigmine and donepezil.

In one embodiment, the small molecule therapeutic is a skeletal muscle relaxant In an embodiment, the skeletal muscle relaxant is tizanidine.

In one embodiment, the small molecule therapeutic is a nicotine agonist or partial agonist. In an embodiment, the nicotine agonist or partial agonist is varenicline.

In one embodiment, the small molecule is an alpha-blocker. In an embodiment, the alpha-blocker is prazosin.

In one embodiment, the small molecule is a cardiac inotropic agent. In an embodiment, the cardiac inotropic agent is dobutamine.

In one embodiment, the small molecule is an antimalarial agent. In an embodiment, the antimalarial agent is primaquine.

In one embodiment, the small molecule is an immunomodulatory agent. In an embodiment, the immunomodulatory agent is fingolimod.

In one embodiment, the small molecule is an aromatase inhibitor. In an embodiment, the aromatase inhibitor is selected from anastrazole and letrozole.

In one embodiment, the small molecule is an antiestrogen compound. In an embodiment, the antiestrogen compound is selected from tamoxifen and raloxifene.

In another embodiment, the small molecule therapeutic agent has activity to treat a disease of the central nervous system. Exemplary agents include, but are not limited to, risperidone, olanzapine, asenapine, aripiprazole, brexpiprazole, or haloperidol. Yet, in one embodiment, the therapeutic agent is not risperidone, olanzapine, asenapine, aripiprazole, and/or brexpiprazole. In another embodiment, the therapeutic agent is not an antipsychotic drug. In one embodiment, the therapeutic agent is not risperidone, olanzapine, asenapine, aripiprazole, brexpiprazole, and/or haloperidol.

In one embodiment, the small molecule drug is i) poorly water soluble at physiological pH (˜7.4) and/or ii) functions as a Bronsted or Lewis base. In one embodiment, the drug is i) poorly water soluble at physiological pH (˜7.4) and/or ii) functions as a Bronsted or Lewis base, and is not an antipsychotic drug and/or is not risperidone, olanzapine, asenapine, aripiprazole, brexpiprazole, and/or haloperidol. As will be described below, in the presence of an aqueous fluid and a stoichometric excess of an organic acid that i) has a solubility in water between 0.1 and 10 g/L or less than or equal to 20 g/L at 25° C., and/or ii) dissolves at least partially in the presence of the drug and a physiological buffer, a suspension or slurry is produced with a pH (within the aqueous fraction) approximately equal to or less than the pKa of the protonated drug.

In one embodiment, the drug is selected from the groups 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; anastrazole 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, anastrazole, letrozole, tamoxifen, raloxifene.

The composition, in addition to a small molecule therapeutic agent, comprises an organic acid compound or combination of organic acid compounds. The organic acid compound (also referred to simply as an ‘organic acid’) is one that has one or more of the following features: (i) a water solubility at room temperature of between 0.1 and 10 g/L or of less than about 20 g/L; (ii) a molar mass less than 500 grams per mole; (iii) is present in stoichiometric excess relative to the therapeutic agent; and (iv) maintains a pH of the suspension or solution in its environment of use approximately equal to or less than the pKa of the protonated small molecule therapeutic agent for a period of at least about 30 days. As described above, the compositions enhance the solubility of the small molecule therapeutic agent, permitting use of the composition in a drug delivery platform that provides sustained release for an extended period of time. Excess acid (on a stoichiometric basis, relative to the therapeutic agent) intercepts physiological buffering species that would otherwise drive hydrolysis of the pharmacologically active salt. Examples of organic acids for use in the compositions are now described.

In a first embodiment, the organic acid is a carboxylic acid. Examples include aromatic carboxylic acids where a carboxylic acid group is bonded directly to an aromatic ring. For example, the aromatic carboxylic acid can have one carboxylic acid group bound 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 one 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.

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

In another example, the aromatic carboxylic acid is one having one carboxylic acid group bonded 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 grouping of acids of this type, with one carboxylic acid group bonded to a naphthalene or quinoline ring, include those containing an additional electron-donating group, such as a hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl group. Examples of acids in this grouping 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 isomers of each.

In another exemplary embodiment, the carboxylic acid is one having one carboxylic acid group bonded to a 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.

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

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

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

In another exemplary embodiment, the carboxylic acid is an aliphatic dicarboxylic acid with 6-10 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).

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

In another exemplary embodiment, the carboxylic acid is a cis- or trans-cinnamic acid. In one embodiment, the trans-cinnamic acid has one or two electron-donating groups selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl groups. 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.

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

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

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

In another embodiment, the organic acid is a hydroxamic acid. The hydroxamic acid may be, in some embodiments, an aromatic hydroxamic acid containing one hydroxamic functional group bonded directly to an 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. Examples include benzhydroxamic acid. The hydroxamic acid can also be one containing a hydroxamic functional group separated from an aromatic ring by a chain of 1-4 spa-hybridized carbon atoms. Dihydroxamic acids containing two or more hydroxamic acid functional groups bonded directly to a benzene, pyridine, naphthalene, quinoline, coumarin, or biphenyl ring system are also contemplated. In addition, substituted derivatives of the hydroxamic acids described above that contain electron donating substituents such as hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl groups are contemplated. Also contemplated are aliphatic dihydroxamic acids containing 6-10 carbon atoms, such as suberohydroxamic acid, and unsaturated dihydroxamic acids containing 6-10 carbon atoms.

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

The organic acid, in one embodiment, is not a polymer or is ‘non-polymeric.’

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

Compositions were prepared with the following organic acids listed in Table 1, and pH values were measured.

In embodiments where the composition is within a reservoir of a drug delivery device, it will be appreciated that the device when placed in its environment of use is open to the environment of use. That is, the environment of use and the composition in the device are in fluid communication via the pore or porous membrane in the drug delivery device. The compositions described herein include the organic acid in the form of a suspension or slurry, given its limited water solubility. The organic acid is present in the composition in an amount above its saturation concentration, and in accord with another embodiment, the organic acid is present in the composition at the end of the delivery period in an amount at or above its saturation concentration. In this way, the composition maintains the desired pH of the suspension or heterogeneous solution of between 3.0-6.5, preferably 2.75-5.75, more preferably 2.8-5.6, preferably 2.9-5.6, preferably 3.1-5.5, 3.2-5.5, 3.3-5.5, 3.4-5.5, 3.5-5.5, 3.1-5.4, 3.2-5.4, 3.3-5.4, 3.4-5.4, 3.5-5.4, 3.1-5.3, 3.2-5.3, 3.3-5.3, 3.4-5.3, 3.5-5.3, 3.1-5.2, 3.2-5.2, 3.3-5.2, 3.4-5.2, 3.5-5.2, 3.1-5.1, 3.2-5.1, 3.3-5.1, 3.4-5.1, 3.5-5.1, 3.1-5.0, 3.2-5.0, 3.3-5.0, 3.4-5.0, 3.5-5.0, 3.5-5.5 or 3.5-6.0.

In another embodiment, the organic acid is crystalline and has a melting temperature of more than about 37° C. Such organic acids remain in solid form in an in vivo environment of use to provide a heterogeneous mixture or suspension of the organic acid in the composition for the period of delivery time.

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

In another aspect, a drug delivery device for administration of a composition or aqueous suspension as described herein is provided. The drug delivery device can be any implantable device, based on, for example, diffusive, erodible or convective systems, e.g., diffusional systems, osmotic pumps, electro-diffusion systems, electro-osmosis systems, electromechanical systems, and the like. In one embodiment, a controlled drug delivery device is utilized, for controlled, extended delivery of the composition for a period of time, The term “controlled drug delivery device” is meant to encompass any device wherein the release (e.g., rate, timing of release, dosing period) of drug or other desired substance contained therein is controlled by or determined by the device itself (wholly or in part) and not solely the environment of use. Several non-limiting examples are described.

In one embodiment, the drug delivery device is one having a housing member that defines a reservoir in which the compositions and/or the aqueous suspensions described above are retained. The housing member is of a size and shape that is suitable for implantation into the body. A cylindrical shape is preferable for subcutaneous implantation using a cannula or trocar. The outer diameter of a cylindrically shaped housing member would preferably be in the range of 2 mm to 6 mm and the length in the range of about 10 mm to about 50 mm. The composition or aqueous suspension, in one embodiment, is initially present in a dry form within the reservoir of the device. For example, the aqueous suspension comprising the small molecule therapeutic agent and the organic acid is prepared and subsequently spray dried, milled or lyophilized to provide a dried form of the aqueous suspension. Alternatively, the individual components in dried form—i.e., the therapeutic agent as a dry solid and the organic acid as a dry solid—are mixed in the correct proportions to provide upon later hydration the desired aqueous suspension. Alternatively, the therapeutic agent and the organic acid may be co-dissolved within a suitable organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, acetone, 2-butanone, or ethyl acetate, followed by concentration to yield a dried powder suitable for resuspension into an aqueous medium. The dried form of the composition can be tableted or pelleted, loaded in the device and hydrated in situ upon subcutaneous implantation of a device containing the dried composition, or the composition can be hydrated at the time of subcutaneous implantation by a clinician introducing a liquid (e.g. a physiological buffer, isotonic saline, phosphate buffered saline, or aqueous propylene glycol) to a reservoir or matrix containing the composition. The liquid can be provided as part of a kit comprising the drug delivery device and a vial comprising a hydration liquid.

An example of a drug delivery device is provided in FIGS. 1A-1B. FIG. 1A illustrates a device 10, assembled and ready for implantation, in an anatomical compartment of a subject, such as under the skin or in the peritoneal cavity. The device is comprised of a non-erodible housing member 12 that defines an internal compartment or reservoir 14. Contained within the reservoir is a composition or formulation as described herein. Housing member 12 has first and second ends, 16, 18. First end 16 is sealed with a fluid-tight end-cap 20, seen best in FIG. 1B that illustrates device 10 in its unassembled form. End cap 20 may optionally comprise a porous membrane or semi-permeable membrane or porous partition 22. Second end 18 is fitted with a porous membrane, semi-permeable membrane, or porous partition 24.

FIGS. 1C-1K illustrate the end caps and end cap subassembly portions of the exemplary drug delivery devices. The numbered elements of the subassembly illustrated in FIGS. 1C-1F are 1=cap, 2=porous membrane, 3=seal, 4=retention ring, and 5=drug device reservoir. The numbered elements of the subassembly illustrated in FIGS. 1G-1K are 1=cap, 2=porous membrane, 3=seal, 4=drug delivery device reservoir, and 5=retention ring.

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

As used herein, the terms “porous membrane” and “porous partition” intend a structural member that has 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 permits passage of the therapeutic agent in its soluble form from the formulation contained within the reservoir. The porous partition can also permit passage of the organic acid that is part of the formulation in its soluble form. The porous partition in a preferred embodiment retains the therapeutic agent and/or the organic acid in their insoluble forms. That is, the therapeutic agent and/or the organic acid in insoluble form preferably do not pass through the pores of the porous partition. The drug delivery device is described in detail in U.S. 2011/0106006, which is incorporated by reference herein.

Studies were conducted to evaluate the release rate and kinetic order of release from drug delivery devices containing in the device reservoir compositions comprised of a small molecule therapeutic agent and an organic acid. As described in Examples 1 and 2, compositions of risperidone with various organic acids and of olanzapine with two different organic acids were prepared. As described in Example 6, a composition of tizanidine with a single acid was also prepared. Example 7 describes additional formulations of tizanidine with a 2-fold molar excess of p-aminobenzoic acid (PABA), vanillic acid, suberic acid, mandelic acid, p-coumeric acid, or benzoic acid, or a 2.-5 molar excess of sorbic acid, or a 3-fold molar excess of nicotinic acid, suberic acid or homophthalic acid. In Example 8, naltrexone salts were prepared using a two-fold molar excess of anisic acid, sebacic acid, sorbic acid or p-aminobenzoic acid. Other studies were conducted using as exemplary therapeutic agents buprenorphine, buspirone, rotigotine, escitalopram, ondansetron, vardenafil, and rivastigmine. Each of the examples and the resulting data are discussed in turn.

With regard to Examples 1 and 2, risperidone was initially selected as a model therapeutic agent due to its potency and insolubility in water as a neutral free base (>10000 volumes of water per volume of drug at 20-25° C.). In the study with risperidone, the drug was compounded with p-aminobenzoic acid (PABA) at acid:drug ratios of 1:1, 1.5:1, or 2:1 (molar basis) to compare formulations with or without a stoichiometric excess of organic acid relative to the drug. The dry formulations were loaded into the reservoir of delivery devices, hydrated, and incubated within dilute phosphate buffered saline. Release of risperidone was evaluated over a 30 day period and results are shown in FIG. 2. FIG. 2 shows cumulative release of risperidone, in mg, as a function of time, in days, from drug delivery devices comprising a heterogeneous aqueous formulation comprised of risperidone and 4-aminobenzoic acid (PABA) at risperidone/PABA molar ratios of 1:1 (diamonds); 1:1.5 (squares); 1:2 (closed circles). In one set of devices containing a 1:2 risperidone/PABA formulation, the membrane surface area was reduced by about 50% (open circles). The addition of the organic acid, PABA, to the formulation increased the release rate of therapeutic agent and also provided a more constant rate of release, approaching zero-order kinetics for the delivery period, relative to the control formulations. Devices containing a composition with a molar excess of the organic acid, e.g., of 1.5:1 or 2:1 PABA/risperidone, generated relatively similar output profiles to each other, provided that the membrane surface area of the device was held constant. A reduction in membrane surface area by approximately 50% produced a corresponding reduction in output rate for systems loaded with the 1:2 risperidone/PABA formulation. Note that the device with the 1:2 risperidone/PABA molar ratio plateaus at about day 32 as the drug is depleted from the device.

With continued reference to FIG. 2, the formulation with an equimolar ratio of risperidone/PABA salt (1:1; diamonds) produced a slow release rate that decreased over time (i.e., non-linear release kinetics) from devices equipped with a maximal membrane surface area. Formulations comprising an excess of the organic acid, e.g., 1:1.5 or 1:2 mole ratio of drug to organic acid (squares, closed circles, respectively) produced a higher rate of drug release relative to the formulation with organic acid not in stoichiometric excess. Devices comprising a 1:2 risperidone/organic acid formulation and approximately half of the membrane surface area produced approximately half of the output rate of devices equipped with 100% of the available surface area and the same formulation.

Results for another study (Example 2) with olanzapine are shown in FIG. 3A, where the cumulative release of olanzapine, in mg, as a function of time, in days, from drug delivery devices containing in the device reservoir a heterogeneous formulation comprised of olanzapine and 4-aminobenzoic acid (PABA, squares) or p-toluic acid (diamonds) at a molar ratio of olanzapine/organic acid 1:1.5, or with no acid as a control (olanzapine free base, circles). Olanzapine is a poorly water soluble base. When formulated with a stoichiometric excess (e.g., mole ratio of 1.5:1) of an organic acid (PABA or p-toluic acid), an increased release rate and constant rate of release were observed. The different organic acids produced different release rates, likely a reflection of the proximity of the formulation pH values (4.5-5.0) to the reported pKa value of doubly protonated olanzapine (pKa1=5.0; pKa2=7.4).

FIG. 3B shows results for another study like that described in Example 2, expect that the drug delivery devices were filled with a heterogeneous aqueous formulation comprised of olanzapine and 4-aminobenzoic acid (PABA, *) or p-toluic acid (triangles) at a molar ratio of olanzapine/organic acid 1:2. The in vitro cumulative release of olanzapine, in mg, as a function of time, in days, from drug delivery devices is shown in FIG. 3B, where devices comprising olanzapine and PABA (* symbols) released more rapidly than devices comprising a formulation with p-toluic acid (triangles). Devices with no acid—i.e., with olanzapine base, as a control released drug slowly over the 15 day test period (squares).

In summary, little olanzapine free base (<1 mg total) was released from control devices (circles) over the study or treatment period. Devices containing formulations with a 1:1.5 or 1:2 molar ratio of drug to organic acid—PABA (squares) or p-toluic acid (diamonds)—achieved a release rate greater than the control devices, as well as linear release kinetics. In the case of olanzapine, different acid additives produced substantially different release rates; for instance, PABA generated a faster release rate than p-toluic acid. In view of this data, a skilled artisan can appreciate that the release rate can be tailored by selection of the organic acid in the formulation, as well as the molar ratio of drug to organic acid.

Another study is described in Examples 3-4 where drug delivery devices were manufactured to comprise in the device reservoir a dry tablet of risperidone base and PABA (Example 3) or sebacic acid (Example 4). In Example 3, a formulation comprised of risperidone base and PABA in a 1.5:1 mass ratio (corresponding to a 1:2 mole ratio of drug to acid) was prepared by dissolving the drug and acid together in a solvent and drying the mixture to yield a uniform solid. In Example 4, a formulation comprised of risperidone base and sebacic acid in a 1:1 mass ratio (also corresponding to a 1:2 ratio of drug to acid) were prepared by dissolving the drug and organic acid together in a solvent and drying the mixture to yield a uniform solid. In both examples, the solid intermediates were pulverized and the resulting powders were mixed with a binding agent (polyvinylpyrrolidone) and a lubricant (stearic acid) before being pressed into tablets. The tablets were loaded into a drug delivery device. Immediately before implantation in vivo each device was filled with sterile phosphate-buffered saline (PBS) to hydrate the tablet. The devices were implanted, and blood samples were obtained for pharmacokinetic (PK) analysis and local safety was assessed for six months. Results are shown in FIG. 4, where the plasma concentration of risperidone, in ng/mL, as a function of time, in days, for the devices with an aqueous formulation of risperidone and 4-aminobenzoic acid (PABA, circles) and for the devices with an aqueous formulation of risperidone and sebacic acid (diamonds). With regard to the devices filled with risperidone and PABA (FIG. 4, circles), plasma levels of risperidone active moiety (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a steady state plasma level of about 50 ng/mL for the six-month implantation period. Mass balance analysis revealed that devices removed after six months released drug at an average rate of 0.70 mg/day and contained an average of 108 mg of unreleased risperidone. These findings indicate that the devices would have operated for another 154 days in vivo for a total operating period of 337 days. To extend the time period of operation the device reservoir can be sized and filled with drug and organic acid sufficient for the period of delivery at a desired rate. For example, to create a 12-month system the reservoir length is increased by 10% from 40.0 mm to 44.0 mm. Accordingly, the dose rate is scaled by increasing the diameter of the device, or by implanting more than one device per subject.

With regard to the devices filled with risperidone and sebacic acid (FIG. 4, diamonds), plasma levels of risperidone active moiety (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a steady state maintaining a plasma level of 50-60 ng/mL for 6 months. Mass balance analysis revealed that devices removed after 6 months released drug at an average rate of 0.80 mg/day and contained an average of 26 mg of unreleased risperidone. These findings indicate that the devices would have operated in vivo for another 32 days for a total operating period of 7 months.

Example 5 describes a study where compositions comprised of various risperidone salts were prepared by dissolving the drug and a two-fold molar excess of a selected organic acid in methanol. The solvent was removed and the dried cake was further dried, pulverized, and in some cases tableted. The dried drug salt was placed into reservoirs of drug delivery devices. The loaded devices were hydrated and placed in a fixed volume of buffered saline as the receiving medium at a controlled temperature. Release of risperidone was measured by taking aliquots of the receiving medium at time intervals and analyzing for risperidone concentration. FIG. 5 presents the cumulative in vitro release (expressed as the percent of total loaded drug released into a receiving medium) for various risperidone salts (PABA, squares; terephthalic, diamonds; sebacic, open diamonds; vanillate, triangles; hippurate, x symbols; hydroxyphenylpropionate, open circles; urate, solid circles). As can be seen, the slopes of the curves are different indicating different rates of release. Risperidone salts of terephthalic acid (diamonds) and uric acid (solid circles) produced output achieving only 2.6% and 16% output in 15 days. The risperidone salts of hippuric acid (x symbols) and hydroxyphenyl propionic acid (open circles) achieved release of risperidone, respectively, of 94% and 92% after 15 days. The risperidone salts of sebacic acid (open diamonds), vanillic acid (triangles) and PABA (squares) produced intermediate rates of risperidone release, with between about 40-60% of the total loaded drug amount released in about 15 days.

Accordingly, in one embodiment, the composition of therapeutic agent and organic acid provides release of the therapeutic agent such that at least about 40%, 50%, or 60%, is released in vitro in about 15 days. In another embodiment, the composition of therapeutic agent and organic acid provides release of the therapeutic agent such that no more than about 30% or 40% is released in vitro in about 15 days. In another embodiment, the composition of therapeutic agent and organic acid provides release of the therapeutic agent such that between about 40-50% is released in vitro in about 15 days.

The rates of in vitro release of the risperidone salts described in Example 5 and shown in FIG. 5 are related to the intrinsic water solubility of the acid. The water solubility of the acids used in Example 5 and their respective risperidone release rates into buffer from a device (expressed as the cumulative percent total risperidone released following 15 days incubation at 37° C.) are listed in Table 2. These data are plotted in FIG. 6. The highest risperidone release rate occurs when the drug is combined with an acid with an intrinsic water solubility between about 1.0 to 6.0 mg/mL. The peak release is seen for risperidone salts of hippuric acid and 3-(4-hydroxyphenyl)propionic acid which exhibit water solubilities of between about 2.5 to 4.0 mg/mL at approximately 25° C. This data suggests that acids that have water solubilities less than about 1 g/L do not maintain a sufficiently low pH within the device, whereas acids with water solubilities substantially greater than 6 g/L are released from the device too rapidly, and therefore cannot sustain output of the drug over prolonged periods of time.

The rates of in vitro release of the risperidone salts listed in Example 5 are also related in part to the pH of a saturated aqueous solution of the acid. The pH at saturating concentrations of the acids used in Example 5 and their respective risperidone release rates (expressed as the cumulative percent total risperidone released following 15 days incubation at 37° C.) are shown in FIG. 7. The highest risperidone release occurs when the drug is combined with an acid which exhibits a pH at a saturating concentration (excluding the drug) between about 2.0 and 3.7. The peak release is seen for risperidone salts of hippuric acid and 3-(4-hydroxyphenyl) propionic acid which exhibit pH values of 2.6 and 3.0, respectively.

Accordingly, in one embodiment, the composition is comprised of a therapeutic agent and an organic acid with a pH at saturation in an aqueous solution of between about 2.0-3.7, or between about 2.1-3.6, between about 2.1-3.5, between about 2.2-3.5 between about 2.2-3.4, between about 2.3-3.4, between about 2.4-3.3, between about 2.5-3.2, between about 2.5-3.1, between about 2.5-3.0, between about 2.6-3.2, between about 2.6-3.1, or between about 2.6-3.0.

Example 6 details another study conducted with tizanidine, a hydrophobic, basic drug used as a muscle relaxant. Tizanidine is another example of a potent drug that is a hydrophobic base. A test formulation was prepared by compounding tizanidine as a free base with PABA in a 1:2 mole ratio. Devices were built to include this formulation or a control powder consisting only of tizanidine base to function as a control. The devices were tested in vitro, as set forth in Example 6, and the results from the devices comprising formulations of acid addition salts of tizanidine are shown in FIG. 8. The cumulative release of tizanidine, in mg, is plotted as a function of time, in days, from drug delivery devices containing in the device reservoir a heterogeneous formulation comprised of tizanidine and 4-aminobenzoic acid (PABA, squares) in a 1:2 mole ratio, or tizanidine free base (control, diamonds). After 28 days, approximately 90% of the drug was released from PABA systems, whereas approximately 10% of the drug was released from control systems. The release kinetics were highly linear as evident from the data analysis in FIG. 8.

Devices comprising various salt forms of tizanidine were further studied as described in Example 7. Formulations of tizanidine were prepared by dissolving in a suitable solvent the base form of the drug and a 2-fold molar excess of p-aminobenzoic acid (PABA), vanillic acid, suberic acid, mandelic acid, p-coumeric acid, or benzoic acid, or a 2.-5 molar excess of sorbic acid, or a 3-fold molar excess of nicotinic acid, suberic acid or homophthalic acid. The tizanadine salts were placed into drug delivery devices and the release of tizanadine was measured in vitro and, for the tizanidine suberate formulation, in vivo. Results are shown in FIGS. 9A-9B.

FIG. 9A shows the cumulative in vitro release of tizanidine (in mg) as a function of time, in days, for the tizanadine-p-aminobenzoate, tizanadine vanillate, tizanadine suberate, tizanadine mandelate, tizanadine p-coumerate, tizanadine benzoate, tizanadine nicotinate, tizanadine sorbate and tizanadine homophthalate. In all of these examples, the active devices eluted tizanidine for a prolonged period at a rate exceeding that of the device with tinzanidie base (control). Data in FIG. 9B demonstrates that tinzanadine is release for an extended period of time of at least one month or at least about two months from devices comprising tinazandine suberate.

In another study, salts of naltrexone were prepared and tested in vitro and in vivo. As described in Example 8, naltrexone salts were prepared using a two-fold molar excess of anisic acid, sebacic acid, sorbic acid or p-aminobenzoic acid. Formulations of the naltrexone salts were placed into drug delivery devices and the release of naltrexone was measured in vitro and, for the naltrexone anisate formulation, in vivo. Results are shown in FIGS. 10A-10B. FIG. 10A shows the cumulative in vitro release of naltrexone, in mg, as a function of time, in days, from devices filled with naltrexone anisate (triangles), naltrexone sebacate (inverted triangles), naltrexone sorbate (circles), naltrexone-PABA (diamonds), or naltrexone base (squares, control). The compositions of naltrexone and a molar excess of the organic acid compounds provided release of naltrexone for at least about one month or for at least about two months at a rate higher than that provided from a device comprising naltrexone base. The in vivo data in FIG. 10B for the device comprising naltrexone anisate shows an extended, controlled release of naltrexone is achieved for greater than a 60 day period.

Other studies were conducted using the methods detailed herein with buprenorphine. Salts of buprenorphine were prepared using a molar excess of certain organic acid compounds. The formulations of the buprenorphine salts were placed in devices and release of buprenorphine was determined. FIG. 11 shows the cumulative amount of buprenorphine released from devices tested in vitro that contained buprenorphine base (triangles), buprenorphine mandelate with two-fold (open triangles) or three-fold (inverted triangles) molar excess of mandelic acid, buprenorphine nicotinate prepared with three-fold (solid circles) or four-fold (diamonds) molar excess of nicotinic acid, buprenorphine suberate prepared with three-fold molar excess of suberic acid (squares), or buprenorphine benzoate prepared with four-fold molar excess of benzoic acid (open circles). Buprenorphine when formulated to the salt forms was released from the devices for a period of more than 60 days and at a release rate exceeding that of buprenorphine release from a device containing buprenorphine base (triangles).

In another study, formulations and delivery devices comprising buspirone as the therapeutic agent were prepared. Buspirone is a therapeutic agent for treatment of anxiety disorders and for treating depression. It has a room temperature water solubility of about 21 mg/L, or less than 1.0 g/L. Following the methods detailed herein with other therapeutic agents, salts of buspirone were prepared using a molar excess of certain organic acid compounds. The formulations of the buspirone salts were placed in devices and release of buspirone was determined. FIG. 12A shows the cumulative amount of buspirone released in vitro, in mg, from devices containing formulations of buspirone vanillate (1:2 drug:acid mole ratio, squares), buspirone anisate (1:2 drug:acid mole ratio, triangles), buspirone suberate (1:2 drug:acid mole ratio, circles). A device with buspirone base was include as a control (diamonds). The devices with a formulation comprising the therapeutic agent compounded with a molar excess of a partially soluble organic acid compound released buspirone at a rate at least about 10%, 15%, 20%, 25%, or 30% faster relative to a device with a formulation comprising the base form of the drug and released the therapeutic agent in an amount sufficient to provide a therapeutic effect for a delivery period of at least about 30 days or for at least about 60 days.

FIG. 12B shows results from an in vivo study conducted with implantable devices filled with buspirone vanillate (1:2 drug:acid mole ratio). The devices were implanted subcutaneously in rats (n=3) and plasma drug concentration was measured for about 21 days. In vivo, the buspirone vanillate formulation provided a steady, prolonged release of the therapeutic agent.

Rotigotine is a small molecule therapeutic agent used for treatment of Parkinson's disease and for restless leg syndrome. It is practically insoluble in water. Following the methods detailed herein with other therapeutic agents, salts of rotigotine were prepared using a molar excess of certain organic acid compounds. The formulations of the rotigotine salts were placed in devices and release of rotigotine was determined. FIG. 13A shows the cumulative amount of rotigotine released in vitro, in mg, from devices containing formulations of rotigotine homophthalate (1:3 drug:acid mole ratio, diamonds), rotigotine sorbate (1:4 drug:acid mole ratio, squares), rotigotine sebacate (1:3 drug:acid mole ratio, triangles), rotigotine vanillate (1:4 drug:acid mole ratio, inverted triangles) or rotigotine nicotinate (1:4 drug:acid mole ratio, circles). The release of rotigotine from the devices comprising formulations of rotigotine homophthalate, rotigotine sorbate, rotigotine sebacate and rotigotine vanillate released rotogotine for a period of greater than 60 days and with controlled release kinetics of near zero-order. (The data points corresponding to release from the rotigotine homophthalate formulation fall almost identically along the data points over the first 10 days of release from the rotigotine sebacate formulation and thus are not visible in FIG. 13A). An in vivo study was conducted in rats with devices filled with rotigotine vanillate (1:4 drug:acid mole ratio). FIG. 13B shows the plasma concentration of rotigotine, in ng/mL, as a function of time, in days, from subcutaneously implanted drug delivery devices comprising in the device reservoir an aqueous formulation of rotigotine vanillate (1:4 drug:acid mole ratio). Devices with rotigotine vanillate provided a prolonged, steady, controlled release of the drug for more than 60 days.

Escitalopram is a small molecule therapeutic agent used for treatment of anxiety disorders and depression. It is practically insoluble in water. Following the methods detailed herein with other therapeutic agents, escitalopram-p-aminobenzoate was prepared using a two-fold molar excess of PABA. The escitalopram-p-aminobenzoate was placed in devices and release of escitalopram was determined. FIGS. 14A-14B are graphs showing cumulative release of escitalopram (mg) in vitro (FIG. 14A) and in vivo (FIG. 14B) as a function of time, in days, for drug delivery devices comprising in the device reservoir an aqueous formulation of escitalopram-p-aminobenzoate (1:2 drug:acid mole ratio).

Studies were also conducted with ondansetron, vardenafil, and rivastigmine as additional exemplary therapeutic agents that have limited water solubility. Following the methods detailed herein with other therapeutic agents, the p-aminobenzoate salts of these therapeutic agents were prepared using a molar excess of PABA. The p-aminobenzoate salt forms of the drugs were placed in the reservoir of drug delivery devices and release of drug was determined. Results for ondansetron are shown in FIG. 15. Ondansetron, an anti-nausea drug, was released in vitro from drug delivery devices comprising an aqueous formulation of ondansetron-p-aminobenzoate (1:2 drug:acid mole ratio) at a rate of approximately 1.4 mg/day over a period of at least about 30 days. Results for vardenafil are shown in FIG. 16. Vardenafil, a medication for erectile dysfunction, was released in vitro from drug delivery devices (n=3) filled with an aqueous formulation of vardenafil-p-aminobenzoate (1:3 drug:acid mole ratio) over a period of about three weeks. It will be appreciated that devices initially filled with more formulation of vardenafil-p-aminobenzoate would provide release of drug for a longer period. Results for rivastigmine are shown in FIG. 17. Rivastigmine, a medication for treating Alzheimer's disease and dementia, is poorly water soluble. Devices filled with an aqueous formulation of rivastigmine-p-aminobenzoate (1:2 drug:acid mole ratio) released the drug in vitro at a constant, near zero-order rate of release, as seen in FIG. 17.

Accordingly, in one embodiment, a formulation and a device for delivery of a therapeutic agent are provided. The therapeutic agent (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base. The therapeutic agent is present in the formulation or the device in an amount sufficient to provide a therapeutic effect for a delivery period of at least about 30 days or for at least about 60 days. The formulation also comprises an organic acid compound that (i) has a water solubility at room temperature between 0.1 and 10 g/L, (ii) has a molar mass of less than 500 grams per mole, (iii) is present in a stoichiometric (molar) excess relative to the therapeutic agent, and/or (iv) maintains a pH of the formulation when hydrated in its environment of use of between 3.0-6.5 for the delivery period.

In one embodiment, a formulation comprising a small molecule therapeutic agent (also referred to herein as “drug” or “therapeutic agent”) and an organic acid, with the organic acid present in a stoichiometric amount or in stoichiometric excess, provides an increase in the release rate of the small molecule therapeutic agent of at least 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50% compared to a formulation of the small molecule therapeutic agent with no organic acid or with less than a stoichiometric amount of organic acid. In one embodiment, the increased rate of release is for a period of at least 14 days, at least 2 weeks, at least 30 days or at least 45 days or at least 60 days or at least 90 days or at least 180 days. In another embodiment, the increased rate of release approaches zero-order kinetic release for the period.

Drug delivery devices other than the one specifically described herein, which is merely exemplary, are known in the art. The compositions described herein are useful for a variety of devices, including those comprise a drug reservoir for retaining the small molecule therapeutic agent and organic acid formulation and those that have a substrate or matrix that can hold or contain the formulation. Controlled drug release devices suitable for use in the present invention generally can provide for delivery of the drug from the device at a selected or otherwise patterned amount and/or rate to a selected site in the subject. The drug delivery device must be capable of containing an amount of the formulation to provide a therapeutically effective amount of the small molecule for the period of therapy. The period of delivery will vary according to the therapeutic agent, the condition being treated, and the individual patient. In one embodiment, the period of delivery, also referred to herein as a sustained period of time, intends a period of at least about two weeks to about six months. In another embodiment, a sustained period of time intends a period of at least about two weeks, or at least about three weeks, or at least about four weeks to about six months, or to about four months, or to about three months. In another embodiment, a sustained period of time intends 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, the period of time is from about 2 hours to about 72 hours, from about 4 hours to about 36 hours, from about 12 hours to about 24 hours, from about 2 days to about 30 days, from about 5 days to about 20 days, from about 7 days or more, from about 10 days or more, from about 100 days or more; from about 1 week to about 4 weeks, from about 1 month to about 24 months, from about 2 months to about 12 months, from about 3 months to about 9 months, from about 1 month or more, from about 2 months or more, or from about 6 months or more.

Accordingly, in another aspect, an implantable device is contemplated. The device comprises a reservoir comprising a formulation of a small molecule therapeutic agent, the formulation comprising (i) an amount of the therapeutic agent to provide substantially zero-order release of the therapeutic agent for a delivery period of at least about 30 days and at a rate that provides a therapeutic effect and (ii) an organic acid that (a) maintains a pH of the formulation when hydrated in its environment of use of between 3.0-6.0 for the delivery period, (b) is present in a stoichiometric (molar) excess relative to the therapeutic agent, and (c) is present at the end of the delivery period in an amount approximately equal to or above its saturation concentration in the formulation when hydrated.

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

In one embodiment, the formulation comprising a small molecule therapeutic agent and a stoichiometric excess of an organic acid is in a dry form. For example, the dry formulation may be present in the reservoir of a device as a powder, a tablet or a film. The device when in use, in vitro or in vivo, imbibes fluid from the surrounding environment to hydrate the dry formulation, thus forming in situ an aqueous suspension containing particles of both the salt form of the therapeutic agent and undissolved excess acid.

The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to, a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are preferred because of convenience in implantation and removal of the drug delivery device. Exemplary subcutaneous delivery sites include under the skin of the arm, shoulder, neck, back, or leg. Sites within a body cavity are also suitable implantation sites. Methods for implanting or otherwise positioning drug delivery devices for subcutaneous delivery of a drug are well known in the art. In general, placement of the drug delivery device will be accomplished using methods and tools that are well known in the art, and performed under aseptic conditions with at least some local or general anesthesia administered to the subject.

In other aspects, methods of treatment using the compositions and devices described herein are contemplated. In one embodiment, a method for sustained, controlled delivery of a therapeutic agent is contemplated, where a composition or a delivery device comprising a formulation of the therapeutic agent and stoichiometric amount or a molar excess of an organic acid compound as described herein is provided. In one embodiment, the therapeutic agent is an opioid agonist or antagonist, useful for pain relief. Exemplary agents are 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 anticonvulsant, such as peramanel, an anti-Parkinsonian agent, such as pramipexole, ropinirole, cabergoline, or bromocriptine, a cholinesterase inhibitor, such as rivastigmine or donepezil, a skeletal muscle relaxant such as tizanidine, a nicotine agonist or partial agonist, such as varenicline, an alpha-blocker such as prazosin, a cardiac inotropic agent such as dobutamine, an antimalarial such as primaquine, an immunomodulator such is fingolimod, an aromatase inhibitor such as anastrazole or letrozole, or an antiestrogen compound such as tamoxifen or raloxifene. In one embodiment, the therapeutic agent is not an anti-psychotic therapeutic agent. In another embodiment, the therapeutic agent is not risperidone, olanzapine, asenapine, aripiprazole, or brexpiprazole.

In another embodiment, a method for maintaining therapeutic plasma levels of a therapeutic agent described herein is contemplated, thus delaying relapse for stable, previously medicated patients for at least 4 weeks is contemplated.

Based on the foregoing, the compositions described herein comprised of a small molecule therapeutic agent and an organic acid provide release of the therapeutic agent for an extended period of time—for at least about 14 days or for at least about 30 days—at a constant rate that approaches zero-order release kinetics for the period. The composition comprises the therapeutic agent in an amount sufficient for a therapeutic dose of the agent for period, and an amount of the organic acid to maintain either (i) a concentration of the protonated therapeutic agent at or near its saturation concentration in the hydrated composition for the period and/or (ii) a concentration of the organic acid equal to or above its saturation concentration in the hydrated composition at the end of the delivery period. The near-saturated concentration of drug is with respect to the aqueous phase of the composition. The composition is, in some embodiments, retained in a drug delivery system (or device) and when placed in an environment of use (such as a subcutaneous implantation site, e.g., plasma or interstitial fluid with a constant pH˜7.4) produces a constant concentration gradient between the device interior and its environment of use that facilitates a constant release rate (substantially zero-order kinetics) of the therapeutic agent over a period of at least about 30 days or at least about 60 days.

The following examples are illustrative in nature and are in no way intended to be limiting.

Risperidone was compounded with p-aminobenzoic acid (PABA) at acid:drug ratios of 1:1, 1.5:1, or 2:1 (molar basis), tableted with lactose binder (13%), and loaded into delivery devices equipped with 0.1 micron polyvinylidene fluoride (DURAPORE®) membranes. In some devices, approximately 50% of the available membrane surface area was blocked to measure the influence of surface area upon output rate. All devices were vacuum back-filled with phosphate buffer and transferred to jars containing a volume (˜100 mL) of the same buffer. The sealed jars were then incubated at 37° C., and small aliquots (˜500 μL) of receiving buffer were withdrawn at selected time points to quantify the released drug by high pressure liquid chromatography (HPLC). Release of risperidone is shown in FIG. 2.

Olanzapine was compounded with p-aminobenzoic acid (PABA) or with p-toluic acid at acid:drug ratios of 1.5:1 (molar basis), tableted with lactose binder (13%), and loaded into delivery devices equipped with 0.1 micron polyvinylidene fluoride (DURAPORE®) membranes. Devices were vacuum back-filled with phosphate buffer and transferred to jars containing a volume (˜100 mL) of the same buffer. The sealed jars were then incubated at 37° C., and small aliquots (˜500 μL) of receiving buffer were withdrawn at selected time points to quantify the released drug by high pressure liquid chromatography (HPLC). Release of olanzapine is shown in FIG. 3A.

Risperidone base (75.00 g, 0.1827 mol) was weighed and transferred to a 1.0 L media bottle containing a stir bar. PABA (50.00 g, 0.3646 mol) was weighed and added to the bottle containing risperidone. Approximately 750 mL of methanol was then added. The bottle containing the formulation was sealed and mixed via magnetic mixer. The mixture was inspected visually for full dissolution of the drug and acid, and the stir bar was removed. The solution was then filtered (0.45μ DURAPORE®) directly into a rotary evaporator and allowed to undergo a primary drying step under vacuum until the bulk of the solvent was evaporated, with the start and end times recorded. After completion of rotary (primary) drying, the vacuum was released, and the resulting foamy material was briefly reduced by hand before being subjected to a secondary drying under high vacuum.

Following secondary drying, all mixtures were transferred to a glove box for pulverization. Formulations were transferred into a grinding chamber equipped with a blade for grinding dry materials and ground using a 20,000 rpm blender base. To prevent overheating of the formulation a custom-made polypropylene sleeve was used to surround the chamber with dry ice. The mixture was ground for 5 cycles. The resulting powder was mixed with 12% by weight polyvinylpyrrolidone (PVP˜40K, Sigma Aldrich) as a binding agent and with 1% by weight stearic acid (1% of the final powder mass, Sigma Aldrich) as a lubricant. Tablets were produced using a tablet press and custom die sets obtained from Vanguard Pharmaceutical Machinery (Spring, Tex.). Dies used for tableting had diameters matched to the internal diameters of the device reservoirs (4.30 mm).

Drug delivery devices were manufactured from titanium, measuring 40.0 mm in length, and having an internal reservoir. Cap subassemblies (see FIGS. 1C-1K) included a DURAPORE® porous membrane (0.1 micron, Millipore Corp). An assembled cap was affixed to a device reservoir and weighed with another assembled cap to obtain the weight of an empty device. Each reservoir subassembly (reservoir+cap at one end) was manually loaded with tablets using forceps before being capped with a second cap subassembly and weighed again to obtain a tablet fill weight. The average fill weight of each device was 460 mg (which corresponds to 230 mg of risperidone as a free base).

After weighing, the assembled devices were individually placed into 20 mL lyophilization vials. The vials were loosely capped with igloo-style rubber septa and placed into a lyophilizer equipped with a stoppering tray system. The air space within each device and vial was evacuated to a vacuum pressure of <1 torr for no less than 30 minutes before sealing.

During the manufacturing process, efforts were made to maintain a low bioburden during the compounding, device assembly, and trocar assembly process. A final, terminal sterilization of both the filled devices and their implanter tools was performed using electron beam sterilization with a split dose of 25 kGy.

Immediately before implantation in vivo, each device was back-filled with sterile phosphate-buffered saline (PBS) using a 20 mL syringe equipped with a blunt fill needle. Upon insertion of the needle through the rubber septa, the vacuum within the vial rapidly drew the hydration solution into the vial and device without any application of manual force to the plunger. After hydration, the needle was withdrawn from the septum, and the device was left for approximately 10 minutes. Each device was then retrieved from its vial, wiped with a tissue to absorb any external fluid, and weighed. Animals were implanted subcutaneously in the dorsum to one side of the midline using a custom implanter tool and the incision closed with a suture or surgical glue. Whole blood samples were obtained for pharmacokinetic (PK) analysis and local safety was assessed for six months. The implant was well tolerated by all animals. PK results are shown in FIG. 4 for the first 6 months. Plasma levels of risperidone active moiety (risperidone plus its active metabolite 9-OH risperidone) peaked in the first few days and then reached a steady state plasma level of about 50 ng/mL for the entire 6-month implantation period. Mass balance analysis revealed that devices removed after 6 months released drug at an average rate of 0.70 mg/day and contained an average of 108 mg of unreleased risperidone. These findings indicate that the devices would have operated for another 154 days in vivo for a total operating period of 337 days. To extend the time period of operation the device reservoir can be sized and filled with drug and organic acid sufficient for the period of delivery at a desired rate. For example, to create a 12-month system the reservoir length is increased by 10% from 40.0 mm to 44.0 mm. Accordingly, the dose rate is scaled by increasing the diameter of the device, or by implanting more than one device per subject.

Risperidone base (75.00 g, 0.1827 mol) was weighed and transferred to a 1.0 L media bottle containing a stir bar. Sebacic acid (74.91 g, 0.3704 mol) was weighed and added to the bottle containing risperidone. Approximately 75 mL of methanol was then added. The bottle containing the formulation was sealed and mixed via magnetic mixer. The mixture was inspected visually for full dissolution of the drug and acid, and the stir bar was removed. The mixture was dried, granulated, tableted, loaded into device reservoirs and terminally sterilized as described in Example 3. The device reservoir size was 41.4 mm in length with an inner diameter of 3.6 mm and an outer diameter of 5.21 mm. Five devices were filled with an average of 400 mg of tablets (corresponding to 167 mg equivalents of risperidone base).

Each device was then retrieved from its vial, wiped with a tissue to absorb any external fluid, and weighed. Animals were implanted subcutaneously in the dorsum to one side of the midline using a custom implanter tool and the incision closed with a suture or surgical glue. Whole blood samples were obtained for pharmacokinetic (PK) analysis and local safety was assessed for six months. The implant was well tolerated by all animals. PK results are shown in FIG. 4.

Various salts of risperidone were prepared by dissolving the drug and a two-fold molar excess of the selected acid in methanol. The solvent was removed under reduced pressure. The dried cake was further dried, pulverized, tableted (in some cases), filled into reservoirs, capped and vacuum vialed as described in Example 3. The loaded devices were hydrated and placed in 100 mL of PBS at 37° C. on a planetary rotator (50 rpm). Aliquots of the receiving buffer were analyzed for risperidone concentration (spectrophotometer or HPLC). FIG. 5 presents the cumulative in vitro release (expressed as the percent of total loaded drug released into a receiving medium) for the various risperidone salts.

A formulation was prepared consisting of tizanidine (2.537 g.; 10.00 mmol) and 4-aminobenzoic acid (PABA; 2.743 g.; 20 mmol). Solids were blended together in 200 mL of methanol, stirred for approximately 30 min to encourage salt formation, and dried by rotary evaporation to yield a powder. Two device groups (n=3 per group) were filled with either ˜100 mg of tizanidine free base per device to function as a control, or ˜208 mg of the PABA formulation per device (equivalent to 100 mg of the base). Devices were capped, vialed under vacuum, hydrated with PBS, and transferred to jars containing PBS receiving buffer for incubation at 37° C., as described in previous examples. Aliquots were drawn from the jars every 1-2 days, and HPLC analysis was performed to quantify the amount of tizanidine released by each device. Cumulative release of drug (in mg) is plotted against time (days) in FIG. 8.

Various salts of tizanidine were prepared by dissolving in methanol the drug and a 2-fold (PABA, vanillate, suberate, mandelate, p-coumarate, benzoate), 2.5-fold (sorbate) or 3-fold (nicotinate, suberate, homophthalate) molar excess of the selected acid. The solvent was removed under reduced pressure. The dried cake was further dried, pulverized, tableted (in some cases), filled into reservoirs, capped and vacuum vialed as described in Example 3. The loaded devices were hydrated and placed in 100 mL of phosphate buffered saline (PBS) at 37° C. on a planetary rotator (50 rpm). Aliquots of the receiving buffer were analyzed for tizanidine concentration (spectrophotometer or HPLC). FIG. 9A presents the cumulative in vitro release (expressed as the percent of total loaded drug released into a receiving medium) as a function of time, in days, for the various tizanidine salts.

Devices loaded with formulations of tizanidine compounded with a 2-fold molar excess of suberic acid were tested in vivo, as described in Example 3. Blood samples were taken from the rats (n=3) over the study period. FIG. 9B shows a plot of weight-normalized average plasma concentrations of tizanidine (ng/mL, ±SD) as a function of time (elapsed days) for rats (n=3) implanted with devices loaded with formulations of tizanidine compounded with a 2-fold molar excess of suberic acid (˜42 days) or suberic acid (˜90 days).

Various salts of naltrexone were prepared by dissolving in methanol the drug and a 2-fold molar excess of the acid to form naltrexone anisate, naltrexone sebacate, naltrexone sorbate and naltrexone-PABA. The solvent was removed under reduced pressure. The dried cake was further dried, pulverized, tableted (in some cases), filled into reservoirs, capped and vacuum vialed as described in Example 3. The loaded devices were hydrated and placed in 100 mL of phosphate buffered saline (PBS) at 37° C. on a planetary rotator (50 rpm). Aliquots of the receiving buffer were analyzed for naltrexone concentration (spectrophotometer or HPLC). FIG. 10A presents the cumulative in vitro release (expressed as the percent of total loaded drug released into a receiving medium) as a function of time, in days, for the various naltrexone salts and for a control device with naltrexone base.

Devices loaded with formulations of naltrexone compounded with a 2-fold molar excess of p-anisic acid were tested in vivo, as described in Example 3. Blood samples were taken from the rats (n=3) over the study period. FIG. 10B shows a plot of weight-normalized average plasma concentrations of naltrexone (ng/mL, ±SD) as a function of time (elapsed days) for rats (n=3) implanted with the devices.