Oral and sublingual formulations of xanthine oxidase inhibitors and methods of treating disease

Abstract

The invention features formulations and compositions for oral and sublingual film administration of pharmaceutical products including xanthine oxidase inhibitors and methods of enhancing solubility, bioavailability, and pharmacokinetics for treating disease, therewith. The compositions can be used to treat a disease or medical condition that involves aberrant purine metabolism or elevated uric acid levels.

Description

[0001] Attorney Docket No. 12203-008PC0

[0002] Oral and Sublingual formulations of Xanthine Oxidase Inhibitors and methods of treating disease.

[0003] BACKGROUND

[0004] This invention relates to compositions including uric acid lowering agents, including uricosuric drugs, uricase based therapeutics, nucleotide or nucleoside therapeutics, or xanthine oxidase inhibitors and formulated for sublingual administration and the use of such compositions for the treatment of chronic kidney disease (CKD) or renal insufficiency and methods of dosing the same. The risk of developing kidney disease increases with age, and underlying genetic or non-genetic initiating factors.

[0005] Inhibitors of the enzyme xanthine oxidase, which converts hypoxanthine to xanthine, and xanthine to uric acid, have been indicated for the treatment of a variety of conditions. For example, the xanthine oxidase inhibitor, allopurinol, is used in the treatment of gout and hyperuricaemia (US Patent No. 5,484,605). Xanthine oxidase inhibitors have also been proposed for use in suppressing the harmful effects of oxygen radicals that mediate ischaemia-reperfusion injury in a variety of tissues including the heart, lung, kidney, gastrointestinal tract, and brain, and in inflammatory joint diseases such as rheumatoid arthritis. (See for example, US. Patent No.

[0006] 6,004,966). They have also been reported to be useful in treating excessive resorption of bone. (US Patent No. 5674887). Further, allopurinol, oxypurinol, and other xanthine oxidase inhibitors have been found to be effective in the treatment of congestive heart failure (US Patent No.

[0007] 6,569,862).

[0008] The xanthine oxidase inhibitors allopurinol and oxypurinol are poorly resorbed, and there have been a number of formulations developed for treatment of gout and chronic inflammatory intestinal diseases to address this problem. These formulations include oral dosing forms of oxypurinol alkali or alkaline earth salts, in an amorphous or crystalline, non-micronized state; and oxypurinol or its alkali or alkaline earth salts in the form of a solid dispersion with pharmacologically inert adjuvants in a ratio from 1 :0.2 to 1 :10. (U.S. Patent Nos. 5,661,154 and 5,368,864).Attorney Docket No. 12203-008PC0

[0009] The citation of any reference herein is not an admission that such reference is available as prior art to the instant invention.

[0010] Chronic kidney disease is a progressive degenerative disease of the cardiovascular system. The risk of developing chronic kidney disease increases with age, underlying disease, genetic factors and afflicted individuals first diagnosis seldom occurs early in disease progression. Chronic kidney disease occurs in all parts of the world and is estimated to affect more than 200 million individuals, with greater than 36 million individuals in the United States alone.

[0011] Chronic kidney disease symptoms vary from patient to patient, and based upon the originating cause of the disease. The most common symptoms may include structural, or functional changes to the kidney or cardiovascular symptoms including declining filtering capacity, inflammation, tubular injury, increased xanthine oxidase expression, increased uric acid concentration, in some diseases structural changes that include increased cyst genesis or cyst growth leading to increased total kidney volume, albuminuria, micro- or macro- proteinuria, or the accumulation of creatinine in the circulation. Additional symptoms include increased gout, kidney stones, leg and back pain, hyperfiltration, exhaustion and fatigue, peripheral edema, skin rash and itching, anemia, and neurological disorders such as confusion, dementia, memory loss, cognitive decline, Alzheimer’s. Common secondary symptoms include depression, sleep disturbance, dizziness, atherosclerosis, arthritis, and cardiovascular disease. The symptoms become progressively worse with time and ultimately result in death.

[0012] A limited variety of therapeutic treatments for chronic kidney disease are available.

[0013] Treatment usually consists of measures to control symptoms, reduce complications and slow progression of the disease and avoid end-stage kidney disease. Treatment of progressing chronic kidney disease with several classes of drugs is available: i)H igh blood pressure medications, ii) Edema medications, iii) anemic medications, iv) cholesterol lowering medications, and v) glucose management drugs in diabetic kidney disease. Blood pressure lowering drugs such as angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers may be used. Medications to reduce swelling - peripheral edema - such as diuretics are available. Treatments for anemia - erythropoietin may be prescribed. Decreased or declining kidney function can influence the amount of drug or drug metabolite that can be excreted, circulating concentrations of drug in the serum, concentration of metabolites in theAttorney Docket No. 12203-008PC0

[0014] serum such as uric acid concentrations, electrolyte and specifically when the drug, metabolite or electrolyte is excreted by the kidney. Many drugs have the potential to slow progression of kidney disease and improve symptoms, but because they are excreted by the kidney unstable concentrations of drug in the circulation can lead to serious side-effects, rash, cardiovascular, hepatic, renal injury and including nausea and vomiting.

[0015] Hyperuricemia is associated with worsening outcome in progressing kidney disease, and in some cases over expression of the enzyme that produces uric acid has been implicated in varied kidney diseases. Recently SGLT2 inhibitors such as have shown clinical evidence that in addition to being uricosuric agents, the combination of pharmacologic benefit of managing blood glucose may be beneficial.

[0016] Concurrent administration of one or more of the above agents, is often necessary to achieve a therapeutic benefit or significant improvement. Other therapies that decrease xanthine oxidase expression, or activity, with or without accompanied uric acid lowering may also be used to treat chronic kidney disease, and can be administered to CHD patients either alone or in combination with xanthine oxidase inhibitors or sirtuin modifying agents such as agonists, antagonists or receptor blockers. Modifiers of expression of xanthine oxidase or a sirtuin in a tissue is also contemplated as a means of modifying circulating and tissues expression, activity and pathology in kidney disease.

[0017] Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient’s altered physiology, and pharmacokinetic principles that influence the design of dosing regimens.

[0018] Either sub- or supratherapeutic dosing can occur when appropriate dose adjustments are not made in patients with kidney disease, and both have negative effects on patient outcomes, including morbidity, prolonged hospital admissions, and potentially, death.

[0019] Subtherapeutic dosing increases the risk of treatment failure, which may be life threatening (e.g., anti-infectives) or organ threatening (e.g., immunosuppressive drugs). The risk of supratherapeutic exposure from drugs (or their active or toxic metabolites) that rely on kidney elimination is amplified when the drug has a narrow therapeutic index, such as digoxin orAttorney Docket No. 12203-008PC0

[0020] lithium. In many cases, accumulation develops over weeks, and the onset of drug toxicity can be difficult to detect and monitor.

[0021] An individual’s response to a drug is determined by both the pharmacokinetics (PK) and pharmacodynamics (PD) of that drug. Pharmacodynamics is concerned with the effect of the drug on the body, including interactions between the drug, its target, and downstream biochemical effects. Pharmacokinetics describes the effect of the body on a drug and reflects the physiologic processes of absorption, distribution, metabolism, and excretion. Each of these processes may be altered in patients with kidney disease and affect therapeutic outcomes. Both effectiveness of the drug and side effect profile - safety are affected by PK and PD in the setting of CKD.

[0022] In the setting chronic kidney disease -renal insufficiency - subtherapeutic or supratherapeutic dosing represents suboptimal administration of a drug, yet with a safety profile that potentially places patient at risk. Physiologic challenges, such as physical exertion, dehydration, diet either nutritional, nutraceutical or pharmaceutical can also contribute to fluctuations of optimal serum or tissue drug concentrations secondarily causing intermittent sub-or supra therapeutic dosing and undesired effectiveness or safety of a therapeutic. Short-term or long-term fluctuations of therapeutic in an individual may be responsible for moderated to serious side-effects, rash, cardiovascular, hepatic, renal injury and including nausea.

[0023] Numerous formulations and routes of administration for renal therapeutics have been studied, more specifically, formulations of uric acid lowering therapies have been associated with sub-optimal pharmacologic of safety complications. For most therapeutics used to treat kidney disease it is unclear whether peak, trough or average serum concentrations of drug are optimal for effectiveness, safety and optimal therapeutic result. For example, oral administration of xanthine oxidase inhibitors is often associated with the induction of gout attacks during introductory administration of drug, similarly the appearance of rash is often associated with high initial doses to achieve the necessary therapeutic effect because allopurinol and febuxostat undergo rapid extensive metabolism in the liver or small intestine and / or upon absorption, in the liver; oral dosing of some drugs such as allopurinol or febuxostat is associated with Stomach upset, nausea, diarrhea, or drowsiness. In subjects with renal insufficiency (chronic kidney disease stage 4 and greater) it is recommended that starting doses are decreased, with escalating doses over time to minimize overdose, yet reach the optimal therapeutic serumAttorney Docket No. 12203-008PC0

[0024] concentration over time. Intravenous, administration of therapeutics including xanthine oxidase inhibitors to reach therapeutic serum concentration of drug is challenging for logistical reasons. Commonly, the dose of a medicine will be unique for each patient to reach optimal serum or tissue concentration. The number of doses taken each day, frequency or doses and the duration of time to take a drug depends on the medical problem for which the medicine is intended. Sublingual dosing will provide increased flexibility for dose, route and regimen for individuals with renal insufficiency, and so optimized therapeutic benefit.

[0025] There is a need for new formulations of drugs and prodrugs which are safe, effective, and easy for a patient with chronic kidney disease and renal insufficiency to use. Additionally, there is a need for new formulations of drugs and prodrugs which are safe, effective, and easy for a patient with acute kidney disease injury to use, most importantly in the case where an individual is unconscious or in a state of induced coma.

[0026] Sublingual and buccal medication administration are two different ways of giving medication by mouth. Sublingual administration involves placing a drug under your tongue to dissolve and absorb into your blood through the tissue there. Buccal administration involves placing a drug between your gums and cheek, where it also dissolves and is absorbed into your blood. Both sublingual and buccal drugs come in tablets, films, or sprays. The cheek and area under the tongue have many capillaries, or tiny blood vessels. There, drugs can be absorbed directly into the bloodstream without going through your digestive system. Intraluminal pH varies widely across the upper gastrointestinal tract from approximately a pH of 1 to 8.5. pH-dependent solubility and permeability profiles of individual drug predicts oral bioavailability, and is a modifiable factor in formulation of drug products.

[0027] The utility of drugs with limited aqueous solubility are often limited by drug bioavailable would benefit from inventions that provide increased sublingual absorption. Several advantages result from sublingual forms of drug, increased ease of administration, increased upper Gl tract absorption including in sublingual, buccal, gastric and ilium or small intestinal segments of the Gl tract may enhance earlier absorption of drug, and increased ease of administration permits more frequent dosing at decreased doses. Increased frequency of dosing will have the effect of decreasing fluctuations of circulating drug in an individual thereby permitting control of a desired concentration of drug, within the therapeutic range without accumulation of drug sufficient to encroach on circulating concentrations of drug that would be considered unsafe or capable ofAttorney Docket No. 12203-008PC0

[0028] inducing side effects, adverse events or serious adverse events. Preventing harmful accumulation of drug in individuals with renal insufficiency would be more manageable using a sublingual formulation of drug, may include management of dose strength or dose frequency.

[0029] DETAILED DESCRIPTION

[0030] The applicants were able to demonstrate formulations of xanthine oxidase inhibitor that resulted in earlier absorption of drug, increased peak serum concentrations of drug, exposure to drug, and methods of maintaining steady state serum concentrations of drug through novel dosing regimen. More specifically of oxypurinol using organic and or basic organic molecules, in aqueous solutions compared to oxypurinol free acid.

[0031] Disclosed herein are novel formulations, methods of oral deliver of xanthine oxidase inhibitors with inorganic and organic bases, especially oral formulations and formulations that enhance the equilibrium solubility, overall solubility and dissolution of xanthine oxidase inhibitors in the presence of solvents. These formulations can provide advantageous methods of treatment or protection (e.g. prevention of a condition or disease due to hyperuricemia) of subjects (patient or animal) by demonstrating improved chemical, biological, and / or physical properties compared to formulations comprising only a xanthine oxidase inhibitor. Thus, the formulations may address the need for more efficacious dosage forms for xanthine oxidase inhibitors, including formulation for enhancing sublingual, buccal or upper gastrointestinal dosing. Demonstrated here are properties of the invention that may enable increased solubility, faster dissolution, increased bioavailability and targeting of resorption than a comparable dose of unformulated xanthine oxidase inhibitors and oxypurinol free acid.

[0032] In an aspect, provided is a pharmaceutical composition comprising a xanthine oxidase inhibitor and a neutralizing agent that includes an inorganic or organic base that enhances or effects solubilisation of the xanthine oxidase inhibitor, and optionally a pharmaceutically acceptable carrier, excipient, vehicle or diluent.

[0033] In one aspect, the invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein the unit dosage form is a film including one or more disintegrants (e.g., materials that favor dis- integration or fast dissolution by virtue of their solubility in water, such as hydrolyzed starches, sugars, and glycerin, which may play a dual roleAttorney Docket No. 12203-008PC0

[0034] as a plasticizer and disintegrant) and a plasticizing agent, the film having a first portion including xanthine oxidase inhibitor, and a second portion including a pH neutralizing agent, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 80mg of xanthine oxidase inhibitor and the pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 7.5 and 10.0, preferably between 8 and 10, (e.g., a pH of between 7.5 and 9.5, 8.0 and 10.0, 7.5 and 10.5, 7.6 and 9.6, or 8.0 and 10.0) when the unit dosage form is placed in unbuffered water at pH 7 (e.g., the pH observed within 5 minutes of placing the unit dosage form in 1 , 5, or 10 mL of unbuffered water). The film can include from 1 to 50% (w / w) (e.g., 1±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w / w)) of the one or more disintegrants. In certain embodiments, the unit dosage form further includes a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl 30 cellulose. In other embodiments, the unit dosage form further includes a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and 35 methyl cellulose. The pH neutralizing agent can be an organic base (e.g., pyridoxine, meglumine, or any organic base described herein) or an inorganic base (e.g., magnesium hydroxide, sodium bicarbonate, or an inorganic base described herein). In particular embodiments, the unit dosage form includes 35±5% (w / w) disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 80mg, or from 50 to 200 mg of xanthine oxidase inhibitor present in an amount sufficient to produce a solution having a pH of between 8.0 and 10 when the unit dosage form is placed in unbuffered water at pH 7.

[0035] In a related aspect, the invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein the unit dosage form is a film including: (i) xanthine oxidase inhibitor; (ii) a low molecular weight polymer having a weight average molecular weight of 50 from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from 55 hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 80mg, or from 50 to 200 mg of xanthine oxidase inhibitor.Attorney Docket No. 12203-008PC0

[0036] The invention further features a pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein the unit dosage form is a bilayer, or multilayer film having a first layer and a second layer, the second layer including a pH neutralizing agent and the first layer including: (i) xanthine oxidase inhibitor; (ii) a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and (iii) a high molecular weight polymer having a weight average molecular weight of 5 greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, from 8 to 20 mg, , or from 50 to 200 mg of xanthine oxidase inhibitor and the a pH of between 7.5 and 10.0, preferably between 8 and 10, (e.g., a pH of between 7.5 and 9.5, 8.0 and 10.0, 7.5 and 10.5, 7.6 and 9.6, or 8.0 and 10.0) when the unit dosage form is placed in unbuffered water at pH 7 (e.g., the pH observed within 5 minutes of placing the unit dosage form in 1 , 5, or 10 mL of unbuffered water). The pH neutralizing agent can be an organic base (e.g., pyridoxine, meglu- mine, or any organic base described herein) or an inorganic base (e.g., magnesium hydroxide, sodium bicarbonate, sodium hydroxide, or an inorganic base described herein). In particular embodiments, the unit dosage form includes an antioxidant, 1 ±0.5% (w / w) glycerol monostereate, 35±5% (w / w) disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 80mg, or from 50 to 200 mg of xanthine oxidase inhibitor present in an amount sufficient to produce a solution having a pH of between 8.0 and 10 when the unit dosage form is placed in unbuffered water at pH 7 present in an amount sufficient to produce a solution having a pH of between 7.5 and 9.5 when the unit dosage form is placed in unbuffered water at pH 7.

[0037] In one embodiment of any of the above unit dosage forms, the unit dosage form can include from 0.2 to 5% (w / w) e.g., 0.5±0.25%, 0.75±0.25%, 1±0.5%, 1.5±0.5%, 2±0.5%, 2.5±0.5%, 3±0.5%, 3.5±0.5%, 4 ±0.5%, or 5±0.5% (w / w)) of a permeation enhancer (e.g., an ionic surfactant, nonionic surfactant, polysorbate, derivatives of tocopherol, poloxamer, monoglyceride, diglyceride, fatty acid, fatty alcohol, mixtures thereof, or any permeation enhancer described herein). In particular embodiments, the permeation enhancer is glycerol monostereate. In another embodiment of any of the above unit dosage forms, the unit dosage form can include an antioxidant (e.g., from 0.05 to 2.5% (w / w) (e.g., 0.05±0.025%, 0.1 ±0.075%, 0.3±0.1%, 0.5±0.25%, 0.75±0.25%, 1±0.5%, 1.5±0.5%, 2±0.5%, or 2.5±0.5% (w / w)) metabisulfite, or any antioxidant described herein. In certain embodiments of the above unit dosage forms, the unit dosage formAttorney Docket No. 12203-008PC0

[0038] can further include from 3 to 18% (w / w) (e.g., 3 to 12%, 3±1%, 5±2%,7.5±2.5%, 10±3%, 12±3%, 15±3%, or 18±3% (w / w)) plasticizing agent, such as a polyol (e.g., sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, or polyethylene glycol), oleic acid, or triacetin. In particular embodiments of the above unit dosage forms, the unit dosage form can include from 1 to 50% (w / w) (e.g., 1±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w / w)) hydrolyzed starch. The hydrolyzed starch can be a dextrin, a maltodextrin, or any hydrolyzed starch described herein. In still another embodiment of any of the unit dosage forms of the invention, the unit dosage form can have a sublingual bio- availability of greater than 40% (e.g., a sublingual bioavailability of from 40 to 70%, 45 to 85%, 55 to 95%, 65 to 100%, 70to 100%, 70to 99%, 75 to 100%, 75 to 99%, or 80to 99%).

[0039] In particular embodiments, any of the unit dosage forms described herein can have a Tmax of from 10 to 125 minutes (e.g.,9±3, 15±3,31±3, 42±3, 53±3, 64±3, 75±3,86±3, 97±3, 108±3, 120±3, 122±3, 124±3, or 125±3 minutes). In still another embodiment of any of the above unit dosage forms, the unit dosage form, following sublingual administration to a subject, produces an average circulating apomorphine concentration of at least 3 ng / mL within a period of from 5 to 15 minutes following the administration. For example, the unit dosage form can produce an average circulating concentration of from 3 to 6 ng / mL within 7 to 10 minutes, from 5 to 10 ng / mL within 5 to 10 minutes, from 7 to 12 ng / mL within 5 to 10 minutes, from 10 to 16 ng / mL within 5 to 10 minutes, from 3 to 6 ng / mL within 7 to 15 minutes, from 5 to 10 ng / mL within 7 to 15 minutes, from 7 to 12 ng / mL within 7 to 15 minutes, from 10 to 16 ng / mL within 7 to 15 minutes, from 3 to 6 ng / mL within 15 to 20 minutes, from 5 to 10 ng / mL within 15 to 20 minutes, from 7 to 12 ng / mL within 15 to 20 minutes, or from 10 to 16 ng / mL within 15 to 20 minutes following the administration. In one embodiment of any of the above unit dosage forms, the unit dosage form when administered sublingually to a subject is non-irritating (e.g., non-irritating using the test of Example 7). In one particular embodiment of any of the above unit dosage forms, the unit dosage form is an individual film packaged in a sealed plastic- lined aluminum foil, wherein the unit dosage form is stable for a period of at least 2 months, 4 months, or 6 months at 40° C. The invention features a pharmaceutical composition in unit dosage form formulated for sublingual administration, the unit dosage form having a first portion including basic addition salt of a xanthine oxidase inhibitor, or a xanthine oxidase inhibitor, and a second portion including a pH neutralizing agent. In particular embodiments, the unit dosage form is a lozenge, a pill, a tablet, a film, or a strip.Attorney Docket No. 12203-008PC0

[0040] In another aspect, provided is a pharmaceutical composition comprising a xanthine oxidase inhibitor and organic base that enhances or effects solubilisation of the xanthine oxidase inhibitor in an aqueous or organic solvent.

[0041] In a further aspect, disclosed is a liquid or solid composition comprising a xanthine oxidase inhibitor and a solvent system which enhances or effects solubilisation of the xanthine oxidase inhibitor. Also disclosed is a drug comprising a liquid composition of a xanthine oxidase inhibitor and at least one neutralizing agent “base” that is a solubilizing compound.

[0042] In a still further aspect, a composition is disclosed comprising a xanthine oxidase inhibitor and an neutralizing agent “base” that is adapted for oral administration of the xanthine oxidase inhibitor.

[0043] Disclosed herein are compositions that may upon metabolism result in increased nitric oxide availability or bioavailability, by providing a metabolic substrate for nitric oxide production apart or in combination with decreased production of oxygen free radicals.

[0044] In a specific composition embodiment, the xanthine oxidase inhibitor and neutralizing agent “base” may be in a ratio selected to augment the solubility of the xanthine oxidase inhibitor, augment the activity of the xanthine oxidase inhibitor, or provide a beneficial effect.

[0045] In a specific embodiment a basic amino acid is a subset of basic organic molecules.

[0046] In a specific embodiment a basic atom or molecule may be combined in liquid, solid or amorphous state to compose the formulation.

[0047] Another aspect of embodiment is a specific ratio of xanthine oxidase inhibitor and organic base that increases solubility of xanthine oxidase inhibitor in aqueous solutions and or further improve or decreases the side effects associate with the administration of xanthine oxidase inhibitors. In another embodiment a molar ratio of XOI to neutralizing agent “base” 1 :0.01 to 1 :100, more specifically 1 :0.1 to 1 :10.

[0048] An unique embodiment of the composition of xanthine oxidase inhibitor and base is improved or increased nitric oxide bioavailability in an animal or patient.Attorney Docket No. 12203-008PC0

[0049] A further aspect, disclosed is that a powder mixture of xanthine oxidase inhibitor and neutralizing agent “base” increases aqueous solubility and bioavailability for oral administration accompanying an aqueous solution.

[0050] In an aspect of the disclosed is a composition of xanthine oxidase inhibitor and neutralizing agent “base” that increases the solubility of purines, xanthine, nuclei acids, or uric acid in an animal. In particular the organic base may increase the solubility of purines or xanthine or nucleic acids or uric acid in situ in man.

[0051] One embodiment is a composition of xanthine oxidase inhibitor and basic inorganic or organic molecule that when administered and metabolized provides a source of nitric oxide. More specifically, an organic molecule such as citrulline or arginine or lysine or an organic molecule derived from citrulline or arginine, or pharmaceutically acceptable salt thereof.

[0052] In another embodiment, provided is a composition of a xanthine oxidase inhibitor and neutralizing agent “base”, in particular a composition, that induces a decrease in hypertension, in new onset hypertension, pre-hypertension or hypertension, and / or improves systemic vascular resistance, reduces insulin resistance, decreases metabolic syndrome, delays, prevents or treats diabetes, delays, prevents or treats diabetic nephropathy, delays, prevents or treats diabetic retinopathy.

[0053] In a further embodiment, a composition, especially a sublingual solid, liquid or amorphous composition, is provided comprising a xanthine oxidase inhibitor and a basic amino acid, meglumine, tris (hydroxymethyl)-aminomethane, or choline.

[0054] In a further embodiment, a composition, especially a sublingual solid, liquid or amorphous composition, is provided comprising a xanthine oxidase inhibitor and a basic neutralizing agent.

[0055] Yet, another embodiment the composition of a xanthine oxidase inhibitor and organic molecule, where the organic molecule has a solubility in water of greater than 5 mg / ml.

[0056] Yet, another embodiment the composition of a xanthine oxidase inhibitor and basic neutralizing agent molecule, where the basic molecule has a solubility in water of greater than 5Attorney Docket No. 12203-008PC0

[0057] mg / ml.

[0058] In a specific embodiment the composition contains a xanthine oxidase inhibitor, a basic neutralizing agent molecule and or other excipients. Where the basic neutralizing agent molecule produces a basic solution upon exposure to aqueous solvent. A description of an organic base can be described as defined in the “Handbook of Pharmaceutical Salts, Properties, Selection and Use” P. Heinrich Stahl and Camille G Wermuth (Eds), Published by VHCA (Switzerland) and Wiley- VCH (FRG), 2011.

[0059] In a particular embodiment, a composition, especially a oral or sublingual composition, is provided comprising a xanthine oxidase inhibitor and a basic amino acid, in particular arginine or lysine or modified amino acid with basic properties in aqueous solution.

[0060] In certain embodiments, the xanthine oxidase inhibitor in a composition of the invention is allopurinol, oxypurinol, febuxostat, tisopurine, topiroxostat, and inositols ( phytic acid or myoinositol) or pharmaceutically acceptable salts therof. In particular, provided is a stable and substantially purified liquid composition comprising allopurinol or oxypurinol, more particularly oxypurinol, and an basic neutralizing agent base, and optionally a pharmaceutically acceptable carrier, excipient, vehicle or diluent.

[0061] Also provided is a process for preparing xanthine oxidase inhibitor containing compositions. In a specific related aspect, the process for preparing a composition comprises one that includes allopurinol or oxypurinol or other xanthine oxidase inhibitors and an organic base or bases, and, or other basic, neutral or acidic, excipients.

[0062] In an embodiment, the invention describes a method of preparing a pharmaceutical composition comprising mixing a xanthine oxidase inhibitor (e.g. allopurinol or oxypurinol) and an basic neutralizing agent base that enhances solubilization of the xanthine oxidase inhibitor, and optionally a pharmaceutically acceptable carrier, excipient, vehicle, or diluent.

[0063] A method of increasing aqueous solubility of a xanthine oxidase inhibitor is contemplated, comprising a xanthine oxidase inhibitor and an neutralizing agent base that enhances or effects solubilization of the xanthine oxidase inhibitor. In an embodiment the organic base is a hydrotropic agent.Attorney Docket No. 12203-008PC0

[0064] Compositions provided herein can be administered to a subject to treat or prevent a condition or disease which requires modulation of xanthine oxidase expression, activity or which utilizes xanthine oxidase inhibitors to treat or prevent the condition or disease. (See for example, US patent publication 20080096904; 20100120796 or 20090130078. Therefore, the invention relates to a method for preventing or treating a condition or disease which requires modulation of xanthine oxidase or which utilizes xanthine oxidase inhibitors to treat or prevent the condition or disease comprising administering a therapeutically effective amount of a composition of the invention. Prophylactic and therapeutic methods are also provided comprising administering to a subject in need a therapeutically effective amount of a composition of the invention.

[0065] Pharmaceutical compositions provided herein may be adapted for administration to a subject in a number of ways. They may be administered in a convenient manner such as by oral and parenteral (e.g. intravenous, intraperitoneal, intramuscular, intraarticular, intrasternal, injection, infusion, and subcutaneous) routes.

[0066] As used herein, the terms “about” and “approximately” as used herein refer to values that are ± 10% of the stated value.

[0067] The invention contemplates a method of administering a poorly soluble xanthine oxidase inhibitor to a subject in need thereof comprising administering a composition containing the xanthine oxidase inhibitor and a neutralizing agent base that enhances or effects solubilization of the xanthine oxidase inhibitor.

[0068] The invention also contemplates the use of any of the compositions of the invention for preventing, and / or ameliorating disease severity, disease symptoms, and / or periodicity of recurrence of a condition or disease described herein.

[0069] The invention also contemplates the use of any of the compositions of the invention for preventing, and / or ameliorating disease severity, disease symptoms, and / or periodicity of recurrence of a condition or disease described herein, in the presence of renal insufficiency or kidney dysfunction.Attorney Docket No. 12203-008PC0

[0070] The invention relates to the use of a xanthine oxidase inhibitor and a neutralizing agent base in the preparation of a medicament for treating a condition or disease described herein.

[0071] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Claims

Attorney Docket No. 12203-008PC0CLAIMSWhat is claimed:

1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, said unit dosage form having a first portion comprising a base or a base salt of a xanthine oxidase inhibitor, or a xanthine oxidase inhibitor prodrug, and a second portion comprising a pH neutralizing agent.

2. The pharmaceutical composition of claim 1 , wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or a strip.

3. The pharmaceutical composition of claim 1 or claim 2, wherein said pH neutralizing agent is selected from polyamines, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

4. The pharmaceutical composition of any of claims 1-3, wherein said pH neutralizing agent is selected from polyamines, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

5. The pharmaceutical composition of claim 1 , wherein said unit dosage form is a film or a strip and wherein said unit dosage form comprises a mucoadhesive polymer.

6. The pharmaceutical composition of any of claims 1-5, wherein said base addition salt of oxypurinol, or an oxypurinol prodrug, is oxypurinol sodium.

7. The pharmaceutical composition of any of claims 1-6, wherein said base addition salt of oxypurinol, or an oxypurinol prodrug, is protonated oxypurinol complexed to an anionic polyelectrolyte.

8. The pharmaceutical composition of claim 6, wherein said anionic polyelectrolyte is selected from alginates, carrageenan, xanthan gum, polyacrylate, and carboxymethylcellulose.Attorney Docket No. 12203-008PC09. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is a film or a strip, wherein said first portion is a first layer and said second portion is a second layer, said first layer being basic and comprising said base addition salt of xanthine oxidase inhibitor, or an oxypurinol pro drug, and said second layer comprising said pH neutralizing agent.

10. The pharmaceutical composition of claim 1 or claim 9, further comprising an antioxidant.

11. The pharmaceutical composition of claim 1 , wherein said first portion is a film comprising a solid solution of a base addition salt of xanthine oxidase inhibitor, or a xanthine oxidase inhibitor prodrug, and said second portion is a particulate base on or within said unit dosage form.

12. The pharmaceutical composition of claim 10, wherein said particulate base comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, or a mixture thereof.

13. The pharmaceutical composition of claim 1 , wherein said first portion is separated from said second portion by a barrier.

14. The pharmaceutical composition of claim 12, wherein said barrier is a film or a coating.

15. A pharmaceutical composition formulated for sublingual administration comprising xanthine oxidase inhibitor, or more specifically particles having an effective particle size of from 20 nm to 10 pm, wherein said particles comprise xanthine oxidase inhibitor, a xanthine oxidase inhibitor prodrug, or a salt thereof.

16. The pharmaceutical composition of claim 14, wherein said pharmaceutical composition is in a unit dosage form selected from a lozenge, a pill, a tablet, a film, or a strip.

17. The pharmaceutical composition of claim 14, wherein said pharmaceutical composition is a sublingual gel.

18. The pharmaceutical composition of claim 16, wherein said xanthine oxidase inhibitor particles having an effective particle size of from 1 pm to 10 pm.

19. The pharmaceutical composition of claim 17, wherein said xanthine oxidase inhibitor particles having an effective particle size of from 2 pm to 7 pm.

20. The pharmaceutical composition of claim 16, wherein said xanthine oxidase inhibitor particles having an effective particle size of from 20 nm to 1 pm.

21. The pharmaceutical composition of claim 19, wherein said xanthine oxidase inhibitor particles having an effective particle size of from 50 nm to 700 nm.Attorney Docket No. 12203-008PC022. The pharmaceutical composition of claim 14, further comprising a mucoadhesive polymer.

23. The pharmaceutical composition of claim 14, wherein said xanthine oxidase inhibitor particles comprise an base addition salt of xanthine oxidase inhibitor, or a xanthine oxidase inhibitor prodrug.

24. The pharmaceutical composition of claim 22, wherein said xanthine oxidase inhibitor particles comprise oxypurinol sodium or oxypurinol arginine.

25. The pharmaceutical composition of claim 14, wherein said unit dosage form is a film or a strip and wherein said unit dosage form comprises a mucoadhesive polymer.

26. The pharmaceutical composition of claim 24, wherein said pharmaceutical composition comprises a first layer and a second layer, said first layer being basic and comprising said xanthine oxidase inhibitor or oxypurinol particles and said second layer comprising a pH neutralizing agent.

27. The pharmaceutical composition of claim 25, wherein said pH neutralizing agent is selected from polyamines, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

28. The pharmaceutical composition of claim 14, further comprising an antioxidant.

29. A pharmaceutical composition formulated for sublingual administration comprising protonated xanthine oxidase inhibitor, or a xanthine oxidase inhibitor prodrug, complexed to an anionic polyelectrolyte.

30. The pharmaceutical composition of claim 28, wherein said anionic polyelectrolyte is selected from alginates, carrageenan, xanthan gum, polyacrylate, and carboxymethylcellulose.

31. The pharmaceutical composition of claim 28, further comprising an antioxidant.

32. The pharmaceutical composition of claim 28, wherein said pharmaceutical composition is in a unit dosage form selected from a lozenge, a pill, a tablet, a film, or a strip.

33. The pharmaceutical composition of claim 28, wherein said pharmaceutical composition is a sublingual gel.Attorney Docket No. 12203-008PC034. A pharmaceutical composition in unit dosage form formulated for sublingual administration, said unit dosage form comprising from 2 to 100 mg of a xanthine oxidase inhibitor prodrug.

35. The pharmaceutical composition of claim 33, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or strip comprising from 2 to 100 mg of a xanthine oxidase inhibitor prodrug in its free acid form.

36. The pharmaceutical composition of claim 33, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or strip comprising a solid solution of a xanthine oxidase inhibitor prodrug in its free acid form.

37. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein said pharmaceutical composition is in a unit dosage form comprising from 2 to 60 mg of oxypurinol, an oxypurinol prodrug, or a base addition salt thereof.

38. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein said unit dosage form when placed in 1 mL of unbuffered water at pH 7 results in a solution having a pH of between 3.0 and 9.3.

39. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein following sublingual administration to a subject said unit dosage form produces an average circulating concentration of at least 3 ng / mL within a period of from 5 to 15 minutes.

40. A method of treating disease in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.

41. A method for treating kidney disease in a mammal afflicted with genetic or lifestyle disease, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to slow or alleviate said progressive kidney disease.

42. A method for slowing or alleviating kidney disease in a mammal afflicted with Diabetes disease, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to alleviate said kidney disease progression.

43. A method of treating sexual dysfunction in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.Attorney Docket No. 12203-008PC044. A method of treating a cognitive disorder in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.

45. The method of any of claims 39, further comprising the administration of an effective amount of an anti-emetic agent.

46. The method of claim 44, wherein said anti-emetic agent is selected from nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride, and diphenidol hydrochloride.

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