Topical pharmaceutical formulations and methods of treatment

Abstract

In certain embodiments, the present invention is directed to a pharmaceutical formulation for topical administration on a mammal, comprising a unit dose of a therapeutically effective amount of a therapeutic agent and a pharmaceutically acceptable carrier medium therefor, said formulation being solid at ambient temperature and having a softening point of not higher than 35° C., such that when the formulation is placed in continuous contact with the skin of a mammalian patient, it is softened to a consistency to effect substantial application of the unit dose of said therapeutic agent onto a desired skin area of the mammalian patient within a time period of less than 10 minutes.

1 . A method of treating a mammalian patient comprising applying to the skin of said patient a pharmaceutical formulation;
 wherein the formulation is a solid substantially unitary dosage form comprising a unit dose of a therapeutically effective amount of one or more therapeutic agents and a pharmaceutically acceptable carrier medium, wherein the carrier medium comprises cocoa butter or one or more glycerides, where the glycerides can be mono-glycerides, di-glycerides or tri-glycerides;   and thereafter rubbing said dosage form against the skin of said patient at an application pressure which does not cause substantial irritation to said area;   wherein the formulation is solid at ambient temperature and has a softening point from 30° C. to not higher than 35° C., such that upon being placed in continuous contact with an area of the skin of the patient and rubbed against the skin, it is softened or melted to effect administration of the unit dose of said therapeutic agent to the mammalian patient within a time period of less than 5 minutes.   
     
     
         2 . A method as claimed in  claim 1 , wherein the glycerides comprise glycerol esters of C 12 -C 18  fatty acids or polyglycolysed glycerides. 
     
     
         3 . A method as claimed in  claim 1 , wherein said dosage form comprises a compacted granulate of the dose of a therapeutic agent and a pharmaceutically acceptable carrier medium, said compacted granulate having a softening point of not higher than 35° C. 
     
     
         4 . A method as claimed in  claim 3 , wherein the compacted granulate is cooled to a temperature of not more than 15° C. prior to compaction. 
     
     
         5 . A method as claimed in  claim 3 , wherein the compacted granulate is cooled to a temperature of not more than 10° C. prior to compaction. 
     
     
         6 . A method as claimed in  claim 3 , wherein the compacted granulate is cooled to a temperature of not more than 0° C. prior to compaction. 
     
     
         7 . A method as claimed in  claim 1 , wherein the dosage form has an aspect ratio (wall:face) of less than 1:1. 
     
     
         8 . A method as claimed in  claims 1 , wherein the dosage form is in the form of a tablet. 
     
     
         9 . A method as claimed in  claim 1 , wherein said therapeutic agent is a locally active agent and said unit dose is effective to treat an area of the skin of said mammal. 
     
     
         10 . A method as claimed in  claim 1 , wherein the dosage form has at least one surface which is flat. 
     
     
         11 . A method as claimed in  claim 1 , wherein the dosage form has at least one concave surface. 
     
     
         12 . A method as claimed in  claim 1 , wherein the dosage form has at least one convex surface. 
     
     
         13 . A method as claimed in  claim 1 , wherein the dosage form has at least two flat surfaces. 
     
     
         14 . A method as claimed in  claim 1 , wherein the dosage form has a total weight from 100 mg to 900 mg. 
     
     
         15 . A method as claimed in  claim 14 , wherein the dosage form has a total weight from 50 mg to less than 1 g. 
     
     
         16 . A method according to  claim 1 , wherein the therapeutic agent is selected from the group consisting of ACE inhibitors, adenohypophoseal hormones, adrenergic neuron blocking agents, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical steroids, alpha-adrenergic agonists, alpha-adrenergic antagonists, selective alpha-two-adrenergic agonists, analgesics, antipyretics and anti-inflammatory agents, androgens, local and general anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic agents, antiasthmatic agents, anticholinergic agents, anticholinesterase agents, anticoagulants, antidiabetic agents, antidiarrheal agents, antidiuretic, antiemetic and prokinetic agents, antiepileptic agents, antiestrogens, antifungal agents, antihypertensive agents, antimicrobial agents, antimigraine agents, antimuscarinic agents, antineoplastic agents, antiparasitic agents, antiparkinson's agents, antiplatelet agents, antiprogestins, antithyroid agents, antitussives, antiviral agents, atypical antidepressants, azaspirodecanediones, barbituates, benzodiazepines, benzothiadiazides, beta-adrenergic agonists, betaadrenergic antagonists, selective beta-one-adrenergic antagonists, selective beta-two-adrenergic agonists, bile salts, agents affecting volume and composition of body fluids, butyrophenones, agents affecting calcification, calcium channel blockers, cardiovascular drugs, catecholamines and sympathomimetic drugs, cholinergic agonists, cholinesterase reactivators, dermatological agents, diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, ganglionic blocking agents, ganglionic stimulating agents, hydantoins, agents for control of gastric acidity and treatment of peptic ulcers, hematopoietic agents, histamines, histamine antagonists, 5-hydroxytryptamine antagonists, drugs for the treatment of hyperlipoproteinemia, hypnotics and sedatives, immunosupressive agents, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blocking agents, organic nitrates, pancreatic enzymes, phenothiazines, progestins, prostaglandins, agents for the treatment of psychiatric disorders, retinoids, sodium channel blockers, agents for spasticity and acute muscle spasms, succinimides, thioxanthines, thrombolytic agents, thyroid agents, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, drugs affecting uterine motility, vasodilators, vitamins, pharmaceutically acceptable salts, prodrugs, and metabolites thereof, or a therapeutically effective combination thereof. 
     
     
         17 . A method according to  claim 16 , wherein the dosage form comprises an analgesic agent and an anti-inflammatory agent. 
     
     
         18 . A method according to  claim 17 , wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent, and the analgesic agent is an opiate or an opiate-based agent. 
     
     
         19 . A method according to  claim 1 , wherein the therapeutic agent is a non-steroidal anti-inflammatory agent. 
     
     
         20 . A method according to  claim 19 , wherein the therapeutic agent is selected from the group consisting of diclofenac, ketolorac, ibuprofen, ketoprofen, naproxen, aspirin and paracetamol, pharmaceutically acceptable salts, prodrugs and metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         21 . The method according to  claim 1 , wherein the dosage form further comprises a penetration enhancer. 
     
     
         22 . The method according to  claim 21 , wherein the penetration enhancer is menthol. 
     
     
         23 . The method of  claim 1 , wherein said patient is human. 
     
     
         24 . The method of  claim 1 , wherein said therapeutic agent is a locally active agent effective to treat a skin condition, disease or disorder. 
     
     
         25 . The method of  claim 24 , wherein said therapeutic agent is selected from the group consisting of antiviral agents, antifungal agents, corticosteroids, antibacterial agents, antibiotic agents, antiseptics, antiparasitics, analgesics, anti-inflammatory agents, local anesthetics, and anti-itch and irritation-reducing compounds, pharmaceutically acceptable salts, pro-drugs and metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         26 . A method according to  claim 24 , wherein the therapeutic agent is selected from the group consisting of tetracaine, benzocaine, lignocaine, hydrocortisone, beclomethasone diproprionate, clobetasol proprionate, fluticasone proprionate, ichthammol, lithium succinate, coal tar, dithranol, benzoyl peroxide, tretinoin, sulphur, vitamin D and prodrugs, and metabolites thereof, framycetin, chlortetracycline hydrochloride, fusidic acid, clotrimazole, econazole, amorolfine and terbenafine, and a therapeutically effective combination thereof. 
     
     
         27 . The method according to  claim 24 , wherein said locally active agent is selected from the group consisting of bupivacaine, levobupivacaine, ropivacaine, benzocaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, lignocaine, etidocaine, tetracaine, lidocaine, and xylocaine and anesthetically active prodrugs, metabolites, isomers and mixtures thereof. 
     
     
         28 . The method according to  claim 24 , wherein the therapeutic agent is hydrocortisone. 
     
     
         29 . The method of  claim 24 , wherein the therapeutic agent is a non-steroidal anti-inflammatory agent. 
     
     
         30 . A method according to  claim 29 , wherein the therapeutic agent is diclofenac, ketolorac, ibuprofen, ketoprofen, naproxen, aspirin or paracetamol, pharmaceutically acceptable salts or conjugates thereof or a therapeutically effective combination thereof. 
     
     
         31 . The method of  claim 24 , wherein said therapeutic agent is a steroidal compound selected from the group consisting of dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, alclometasone, amcinonide, diflorasone, pharmaceutically acceptable salts or conjugates thereof or a therapeutically effective combination thereof. 
     
     
         32 . The method of  claim 1 , wherein said therapeutic agent is systemically active and is absorbed through the skin in sufficient quantity to provide a therapeutic systemic effect. 
     
     
         33 . The method of  claim 32 , wherein said therapeutic agent is selected from the group consisting of anti-inflammatories, an antihypertensive agent, a cardiovascular agent, a hormonal agent and an analgesic, vasodilators, active substances for the treatment of motion sickness, gastric acidity and peptic ulcers, contraceptive agents, anti-asthmatic agents, anti-epileptic agents, or smoking cessation aids, pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         34 . The method according to  claim 33 , wherein the therapeutic agent is selected from the group consisting of nitroglycerin, scopolamine, estradiol, norethisterone, fentanyl, morphine, pethidine, oxycodone, oxymorphone, codeine, hydrocodone, hydromorphone, buprenorphine, nicotine, diclofenac, ketolorac, ibuprofen, ketoprofen, naproxen, aspirin and paracetamol, pharmaceutically acceptable salts, prodrugs and metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         35 . A method according to  claim 33 , wherein the therapeutic agent is selected from the group consisting of beta-adrenergic agonists, anti-muscarinic agents, steroids, leukotriene antagonists and cromones, pharmaceutically acceptable salts, prodrugs or metabolites thereof; and a therapeutically effective combinations thereof. 
     
     
         36 . A method according to  claim 33 , wherein the therapeutic agent is selected from the group consisting of salbutamol, salmeterol, formoterol, clenbuterol, ipratropium, glycotropium, tiotropium, oxytropium, beclomethasone, betamethasone, fluticasone, budesonide, montelukast, cromolyn sodium, nedocromil and pharmaceutically acceptable salts, prodrugs or metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         37 . A method according to  claim 33 , wherein the therapeutic agent is a benzodiazapine. 
     
     
         38 . A method according to  claim 37 , wherein the therapeutic agent is selected from the group consisting of diazepam, lorazepam, clonazepam, clobazam, medazolam, pharmaceutically acceptable salts, prodrugs and metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         39 . A method according to  claim 33 , wherein the therapeutic agent is omeprazole or lansoprazole. 
     
     
         40 . The method of  claim 1 , wherein said formulation is substantially free of preservatives. 
     
     
         41 . The method of  claim 14 , wherein the dosage form has a total weight from about 250 mg to about 750 mg. 
     
     
         42 . A method according to  claim 1 , wherein the therapeutic agent is selected from the group consisting of beta-adrenergic agonists, anti-muscarinic agents, steroids, leukotriene antagonists and cromones, pharmaceutically acceptable salts prodrugs or metabolites thereof; and a therapeutically effective combination thereof. 
     
     
         43 . A method according to  claim 43 , wherein the therapeutic agent is selected from the group consisting of salbutamol, salmeterol, formoterol, clenbuterol, ipratropium, glycotropium, tiotropium, oxytropium, beclomethasone, betamethasone, fluticasone, budesonide, montelukast, cromolyn sodium, nedocromil and pharmaceutically acceptable salts prodrugs and metabolites thereof and a therapeutically effective combination thereof. 
     
     
         44 . A method of treating a skin condition in a patient in need thereof comprising applying to the affected skin area of said patient, a pharmaceutical formulation consisting of a matrix comprising at least one topically active agent and a pharmaceutically acceptable carrier, wherein the carrier comprises cocoa butter or one or more glycerides;
 and thereafter rubbing said formulation against the skin of the patient at an application pressure which does not cause substantial irritation to said area;   wherein the formulation is a substantially unitary dosage form which is solid at ambient temperature and has a softening point from 30° C. to not higher than 35° C., such that upon being placed in continuous contact with an area of the skin of the patient and rubbed against the skin, it is softened or melted to effect administration of the unit dose of said therapeutic agent to the mammalian patient within a time period of less than 5 minutes.   
     
     
         45 . The method of  claim 44  where the glycerides is selected from the group consisting of mono-glycerides, di-glycerides and tri-glycerides. 
     
     
         46 . The method of  claim 44  where the glycerides comprise glycerol esters of C 8 -C 18  fatty acids or polyglycolysed glycerides.