Topical pharmaceutical formulations and methods of treatment

• US 7,754,240 B2
• Filed: 06/26/2001
• Issued: 07/13/2010
• Est. Priority Date: 06/26/2000
• Status: Expired due to Fees

• Current Assignee: PharmaKodex Ltd. (Orexo AB)
• Original Assignee: PharmaKodex Ltd. (Orexo AB)
• Inventors: Tobyn, Michael John, Staniforth, John Nicholas
• Primary Examiner(s): Silverman; Eric E.
• Application Number:
  US10/312,475
• Publication Number:
  US 20030138503A1
• Time in Patent Office: 3,304 Days
• Field of Search: None
• US Class Current: 424/484
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications

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.

Claims

1. A pharmaceutical formulation for dermal administration to a mammal, the formulation being a solid, unit dosage form and comprising a unit dose of a therapeutically effective amount of at least 1% by weight of one or more therapeutic agents and a pharmaceutically acceptable carrier medium,

said formulation being solid at ambient temperature and having 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 a mammalian patient to be treated, 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,

wherein said formulation is in the form of a tablet and has at least one surface which is flat, and

wherein the carrier medium comprises cocoa butter or one or more glycerides, where the glycerides are selected from the group consisting of mono-glycerides, di-glycerides and tri-glycerides and

the formulation is not provided as a medicinal transdermal patch or plaster.

2. A pharmaceutical formulation as claimed in claim 1, comprising 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.

3. The formulation of claim 2, wherein the compacted granulate is cooled to a temperature of not more than 15°

C. prior to compaction.

4. The formulation of claim 2, wherein the compacted granulate is cooled to a temperature of not more than 10°

C. prior to compaction.

5. The formulation of claim 2, wherein the compacted granulate is cooled to a temperature of not more than 0°

C. prior to compaction.

6. The formulation as claimed in claim 1, which has an aspect ratio (wall:

face) of less than 1;

1.

7. The formulation of 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.

8. The formulation of claim 1, which comprises at least one concave surface.

9. The formulation of claim 1, which comprises at least one convex surface.

10. The formulation of claim 1, which comprises two flat surfaces.

11. The formulation of claim 1, which has a total weight from about 50 mg to less than 1 g.

12. The formulation of claim 11, which has a total weight from 100 mg to 900 mg.

13. A pharmaceutical formulation 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 and pharmaceutically acceptable salts, and any therapeutically effective combination thereof.

14. A pharmaceutical formulation according to claim 13, comprising an analgesic agent and an anti-inflammatory agent.

15. A pharmaceutical formulation according to claim 14, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent, and the analgesic agent is an opiate or an opiate-based agent.

16. A pharmaceutical formulation according to claim 1, wherein the therapeutic agent is a non-steroidal anti-inflammatory agent.

17. A pharmaceutical formulation according to claim 16, wherein the therapeutic agent is selected from the group consisting of diclofenac, ketolorac, ibuprofen, ketoprofen, naproxen, aspirin and paracetamol, pharmaceutically acceptable salts thereof;

and any therapeutically effective combination thereof.

18. The formulation according to claim 1, further comprising a penetration enhancer.

19. The formulation according to claim 18, wherein the penetration enhancer is menthol.

20. The formulation of claim 1, wherein said patient is human.

21. The pharmaceutical formulation of claim 1, 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;

and any therapeutically effective combinations thereof.

22. A pharmaceutical formulation according to claim 1, 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 thereof, framycetin, chlortetracycline hydrochloride, fusidic acid, clotrimazole, econazole, amorolfine and terbenafine, and any therapeutically effective combination thereof.

23. The pharmaceutical formulation according to claim 1, 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 mixtures thereof.

24. The pharmaceutical formulation according to claim 1, wherein the therapeutic agent is hydrocortisone.

25. The pharmaceutical formulation of claim 1, wherein the therapeutic agent is a non-steroidal anti-inflammatory agent.

26. A pharmaceutical formulation according to claim 1, wherein the therapeutic agent is diclofenac, ketolorac, ibuprofen, ketoprofen, naproxen, aspirin or paracetamol, pharmaceutically acceptable salts or conjugates thereof or any therapeutically effective combination thereof.

27. The pharmaceutical formulation of claim 1, 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 thereof or any therapeutically effective combinations thereof.

28. The pharmaceutical formulation of claim 1, further comprising one or more therapeutic agents having a systemic effect.

29. The pharmaceutical formulation of claim 28, 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 thereof;

and any therapeutically effective combinations thereof.

30. The pharmaceutical formulation according to claim 29, 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 thereof;

and any therapeutically effective combinations thereof.

31. A pharmaceutical formulation according to claim 29, 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 thereof;

and any therapeutically effective combinations thereof.

32. A pharmaceutical formulation according to claim 31, 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 thereof;

and any therapeutically effective combinations thereof.

33. A pharmaceutical formulation according to claim 29, wherein the therapeutic agent is selected from the group of benzodiazapines.

34. A pharmaceutical formulation according to claim 33, wherein the therapeutic agent is selected from the group consisting of diazepam, lorazepam, clonazepam, clobazam, medazolam, pharmaceutically acceptable salts thereof;

and any therapeutically effective combinations thereof.

35. A pharmaceutical formulation according to claim 29, wherein the therapeutic agent is omeprazole or lansoprazole.

36. The pharmaceutical formulation of claim 1, wherein said formulation is a compressed tablet.

37. The pharmaceutical formulation of claim 1, wherein said formulation is free of preservatives.

38. The formulation of claim 11, which has a total weight from about 250 mg to about 750 mg.

39. A pharmaceutical formulation 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 thereof;

and any therapeutically effective combinations thereof.

40. A pharmaceutical formulation according to claim 39, 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 thereof and any therapeutically effective combinations thereof.

41. A pharmaceutical formulation as claimed in claim 28, wherein the one or more therapeutic agents having a systemic effect are absorbed through the skin in sufficient quantity to provide a therapeutic systemic effect.

42. The pharmaceutical formulation of claim 1, wherein the glycerides are glycerol esters of C₈-C₁₈ fatty acids or polyglycolysed glycerides.

43. The pharmaceutical formulation of claim 1, wherein said formulation is not bullet shaped and not conical shaped.

44. The pharmaceutical formulation of claim 1, wherein said formulation is spreadable at room temperature.

45. The pharmaceutical formulation of claim 1, wherein the therapeutic agent is selected from the group consisting of an androgen, an estrogen or a pharmaceutically acceptable salt thereof.

46. The pharmaceutical formulation of claim 1, wherein the therapeutic agent is testosterone or a pharmaceutically acceptable salt thereof.