Pharmaceutical Compositions for Topical Application

• US 20070287688A1
• Filed: 07/09/2004
• Published: 12/13/2007
• Est. Priority Date: 07/11/2003
• Status: Abandoned Application

• Current Assignee: MacroChem Corp. (Abeona Therapeutics Inc.)
• Original Assignee: Macro Chem Corporation
• Inventors: Chan, Thomas, Krauser, Scott
• Application Number:
  US10/564,199
• Publication Number:
  US 20070287688A1
• Time in Patent Office: Days
• US Class Current: 514/169
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/40 : Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

Compounds of Formula I are useful as skin penetration enhancing agents: (I) wherein: R represents a linear, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and X represents a —(CO)O—, —O(CO)—, C═O, CONH, O, NHCONH, S, or S═O radical. Compositions and methods using these compounds are also described.

Claims

1. A pharmaceutical composition comprising:

a) at least one active agent; and

b) a skin penetration enhancer represented by the following Formula I;

wherein;

R represents a linear, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X represents a —

(CO)O—

, —

O(CO)—

, C═

O, CONH, O, NHCONH, S, or S═

O radical.

2. A pharmaceutical composition comprising:

a) at least one active agent; and

b) a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

3. The pharmaceutical composition according to claim 2, wherein the skin penetration enhancer comprises a compound of Formula IA.

4. The pharmaceutical composition according to claim 2, wherein the skin penetration enhancer comprises a compound of Formula IB.

5. The pharmaceutical composition according to claim 2, wherein R₁ represents a linear C6-C20 alkyl radical.

6. The pharmaceutical composition according to claim 2, wherein R₁ represents a linear C6-C16 alkyl radical.

7. The pharmaceutical composition according to claim 2, wherein R₁ represents a linear C6-C14 alkyl radical.

8. The pharmaceutical composition according to claim 2, wherein R₁ represents a linear C8-C14 alkyl radical.

9. The pharmaceutical composition according to claim 2, wherein R₁ represents an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or tetradecyl radical.

10. The pharmaceutical composition according to claim 2, wherein R₁ represents an octyl, decyl, dodecyl or tetradecyl radical.

11. The pharmaceutical composition according to claim 2, wherein X₁ represents an oxygen atom.

12. The pharmaceutical composition according to claim 2, wherein X₁ represents an N—

H radical.

13. The pharmaceutical composition according to claim 2, wherein the skin penetration enhancer of formula IA or IB is decyl pivalate, dodecyl pivalate, tetradecyl pivalate, N-decyl pivalamide, N-dodecyl pivalamide, tert-butyl decanoate, tert-butyl laurate, or tert-butyl myristate.

14. The pharmaceutical composition according to claim 2, further comprising a pharmaceutically acceptable vehicle.

15. The pharmaceutical composition of claim 14, which is in the form of a liquid.

16. The pharmaceutical composition of claim 14, which is in the form of a cream.

17. The pharmaceutical composition of claim 14, which is in the form of a lotion.

18. The pharmaceutical composition of claim 14, which is in the form of an ointment.

19. The pharmaceutical composition of claim 14, which is in the form of a gel.

20. The pharmaceutical composition of claim 14, which is in the form of a spray.

21. The pharmaceutical composition of claim 14, which is in the form of an aerosol.

22. The pharmaceutical composition of claim 2, wherein said active agent comprises at least one compound selected from amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, or pyrithione.

23. The pharmaceutical composition of claim 2, wherein said active agent comprises at least one compound selected from papaverine, dioxyline, ethaverine, minoxidil, or nitroglycerin.

24. The pharmaceutical composition of claim 2, wherein said active agent comprises at least one compound selected from alprostadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2-alpha), or misoprostol.

25. The pharmaceutical composition of claim 2, wherein said active agent comprises at least one compound selected from tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, fhilenamic acid, piroxicam, tenoxicam, phenylbutazone, oxyphenthatrazone, nabumetone.

26. A pharmaceutical composition according to claim 2, comprising:

a) from about 1 wt. % to about 15 wt. % buspirone hydrochloride; and

b) a penetration enhancing amount of a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

27. A pharmaceutical composition according to claim 2, comprising:

a) from about 1 wt. % to about 10 wt. % ibuprofen; and

b) a penetration enhancing amount of a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

28. A pharmaceutical composition according to claim 2, comprising:

a) from about 0.5 wt. % to about 5 wt. % testosterone; and

b) a penetration enhancing amount of a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

29. A pharmaceutical composition according to claim 2, comprising:

a) from about 0.5 wt. % to about 5 wt. % PGE-1; and

b) a penetration enhancing amount of a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

30. A pharmaceutical composition according to claim 2, comprising:

a) from about 1.5 wt. % to about 3.5 wt. % hydroquinone; and

b) a penetration enhancing amount of a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

31. A method for forming a pharmaceutical or cosmetic composition comprising, mixing:

a) from about 1 wt. % to about 10 wt. % of an active agent; and

b) a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

32. A method of administering an active agent to an animal in need thereof comprising topically applying to said animal a pharmaceutical composition comprising:

a) an active agent; and

b) a skin penetration enhancer represented by the Formulas IA or IB

wherein;

R₁ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted hydrocarbyl radical; and

X₁ is either an oxygen atom or an NH radical.

33. The method of claim 32, wherein said animal or plant is a human.

34. The method according to claim 32, wherein said active agent is a pharmacologically active agent.

35. The method according to claim 32, wherein said active agent is a cosmetic agent.

36. The method according to claim 32, wherein said active agent is a bronchodilator, diuretic agent, antibacterial agent, antifungal agent, antiacne agent, sedative, tranquilizer, psychostimulant, anxiolytic agent, oestrogen, hormone, ovulation inducer, antipyretic agent, narcotic analgesic, hypoglycaemiant, antispasmodic agent, antimalaria agent, beta-blocker, antiarthritic agent, non-steroidal antiinflammatory drug, anti-osteoporotic agent, skin bleaching agent, vasodilator, prostaglandin, corticosteroid, steroidal agent, anti-hypertensive agent, antiparkinsonian agent, antimigraine agent, antiulcer agent, anticancer agent or nutritional agent.

37. The method according to claim 32, wherein the active agent is at least one compound selected from the group consisting of:

sodium cromoglycate, salbutamol, theophylline, furosemide, hydrochlorothiazide, penicillin, tetracycline, oxytetracycline, chlortetracycline, chloramphenicol, amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione, erythromycin, pentobarbital, secobarbital, codeine, 3-(2-aminopropyl)indole acetate, 3-(2-aminobutyl)indole acetate, diazepam, chlordiazepoxide, reserpine, chlorpromazine, buspirone hydrochloride thiopropazate, oestradiol, oestriol, oestrone, ethinyloestradiol, mestranol, stilboestrol, dienoestrol, epioestriol, estropipate, zeranol, androstenediol, androisoxazole, testosterone, dihydrotestosterone, dehydroepiandrostenone, 17 beta-estradiol, estradiol-3,17-diacetate, estradiol-3-acetate, estradiol-17-acetate, estradiol-3,17-valerate, estradiol-3-valerate, estradiol-17-valerate, ethinyl estradiol, estrone, progesterone, norethindrone, norgestrieone, norgestadienone, norgestrel, norgestimate, progestogenic acid, dihydroprogesterol, nomagesterol, clomiphene, acetylsalicylic acid, salicylamide, sodium salicylate, methyl salicylate, morphine, glypizide, glyburic, chlorpropamide, insulin, atropine, methscopolamine bromide, 4-aminoquinoline, 9-aminoquinoline, metoprolol, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, tenoxicam, phenylbutazone, oxyphenthatrazone, nabumetone, etidronate, tiludronate, ascorbic acid, hydroquinone, dipyridamole, trinitrine, isosorbide dinitrate, misoprostol, papaverine, dioxyline, ethaverine, minoxidil, nitroglycerin, betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone, fluoracetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, chloroprednisone, clorcortelone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, cortisone acetate, hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrysone, amcinafal, amcinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, triamcinolone hexacetonide, cortivazol, formocortal, nivazol, propanolol, prazosin, diltiazem, clonidine, methyldopa, selegiline, dihydroergotamine, cimetidine, tamoxifen or cis-platin.

38. The method according to claim 32, wherein the active agent is at least one compound selected from hydromorphone, hydroquinone, tentanyl, nalozone, nalbuphine, buprenorphine, methylphenidate, selegiline, pimozide, buspirone, oxybutynin, tacrolimus, mupirocin, bromocryptine, naproxen, diclofenac, ibuprofen, prostaglandin E1, testosterone, terbinafine or econazole.