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Last Updated: November 25, 2020

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Claims for Patent: 4,557,934

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Summary for Patent: 4,557,934
Title: Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
Abstract:Improved topical pharmaceutical compositions containing a pharmaceutically-active agent and the penetration enhancing agent 1-dodecylazacycloheptan-2-one are disclosed. This agent is used at selected levels in combination with certain C.sub.3 -C.sub.4 diols or a 1-substituted azacycloalkyl-2-one. This composition provides marked transepidermal and percutaneous delivery of the selected pharmaceutically-active agent. A method of treating certain pathologies and conditions responsive to the selected active, systemically or locally, is also disclosed.
Inventor(s): Cooper; Eugene R. (Cincinnati, OH)
Assignee: The Procter & Gamble Company (Cincinnati, OH)
Application Number:06/506,275
Patent Claims:1. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of a non-steroidal anti-inflammatory agent selected from the group consisting of salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, indomethacin, piroxicam, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentan-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

2. A composition according to claim 1 wherein the ratio by weight of component (d) to 1-dodecylazacycloheptan-2-one is from about 1:5 to about 100:1.

3. A composition according to claim 2 wherein the ratio by weight of component (d) to 1-dodecylazacycloheptan-2-one is from about 3:1 to about 100:1.

4. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of a corticosteroid selected from the group consisting of triamcinolone acetonide, hydrocortisone acetate, betamethasone valerate, fluocinolone acetonide, flupamesone, or mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentan-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

5. A composition according to claim 1 wherein the non-steroidal anti-inflammatory agent is present at a level of about 0.05% to about 10% by weight.

6. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of an antiviral agent selected from the group consisting of idoxuridine, iododeoxy uridine, amantadine, methisazone, cytarabine, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 15% to about 99% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentan-2-one and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

7. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of an antiviral agent having the formula ##STR8## wherein P' is sulfur or oxygen, R.sup.31 is hydrogen, a halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino; R.sup.32 is hydrogen, a halogen alkylthio, acylamino, amino or azide; R.sup.33 is hydrogen, a straight, branched or cyclic alkyl, hydroxyalkyl benzyloxyalkyl or phenyl; R.sup.34 is hydrogen, hydroxy or alkyl; R.sup.35 is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxymethyl, sulfamoyloxy, phosphate carboxypropionyloxy, straight chain or cyclic acyloxyl having from 1 to 8 carbon atoms, or substituted carbamoyl group having the formula NHCO--Q; wherein Q is alkyl, aryl, or aralkyl optionally substituted by one or more substituents selected from sulfonyl, amino, carbamoyl or hydrogen; R.sup.36 is hydrogen or an alkyl, provided that when P' is oxygen and R.sup.32, R.sup.33, R.sup.34 and R.sup.36 are H, R.sup.31 is not amino or methylamino when R.sup.35 is hydrogen or hydroxy, pharmaceutically-acceptable salts of these compounds, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 15% to about 99% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)azacyclopentan-2-one, and mixtures there; and

(e) about 1.0% to about 35% by weight 1-dodecylazacyloheptan-2-one.

8. A composition according to claim 7 wherein P' is sulfur or oxygen, R.sup.31 is hydroxy, R.sup.32 is amino, R.sup.33 is hydrogen, a straight or branched chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl, R.sup.34 is hydrogen, hydroxy or lower alkyl, R.sup.35 is hydrogen, hydroxy amino, alkyl, hydroxyalkyl, benzoyloxy, benzoyloxy alkyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, or acetoxy, R.sup.36 is hydrogen, alkyl or hydroxyalkyl, or a pharmaceutically-acceptable salt of the above.

9. A composition according to claim 8 wherein the antiviral compound is 9-(2-hydroxyethoxymethyl)guanine, 2-amino-9-(2-hydroxyethoxymethyl)adenine, and mixtures thereof.

10. A composition according to claim 9 wherein the antiviral is 9-(2-hydroxyethoxymethyl)guanine.

11. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of a pharmaceutically-active antitussive agent selected from the group consisting of ephedrine, phenylpropanolamine, theophylline, codeine, pholcodine, hydrocodone, noscapine, dextromethorphan, levopropoxyphene, carbetapentane, pipazethate, isoaminile, chlorphendianol, benzonatate, dimemorphan and zipeprol, or mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 15% to about 99% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)azacyclopentan-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacyloheptan-2-one.

12. A penetration-enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10%, by weight, of a pharmaceutically-active bone-active organophosphate;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 15% to about 99% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)azacyclopentan-2-one, and mixtures thereof;

(e) about 1.0% to about 35% by weight 1-dodecylazacyloheptan-2-one.

13. A composition according to claim 12 wherein the bone-active organophosphonate is selected from dichloromethanediphosphonic acid, ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid, the pharmaceutically-acceptable salts of these acids, and mixtures thereof.

14. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 15% by weight of a sedative hypnotic or barbituate selected from the group consisting of amobarbital, aprobarbital, barbital, hexobarbital, mephobarbital, methohexital, pentobarbital, phenobarbital, probarbital, secobarbital, talbutal, thiamylal, thiopental, chlorodesmethyldiazepam, estazolam, flunitrazepam, flurazepam, fosazepam, lorazempam, nimetazepam, nitrazepam, nordiazepam, quazepam, triazolam, pyrithyldione, iminophenimide, ethinazone, mecloqualone, methaqualone, clomethizole, fenadiazole, ethinamate, hexapropymate, meprobamate, oxanamide, valnoctamide, butesamide, diethylallylacetamide, trimethobenzglycine, ibrotamide, capuride, ectylurea, apronalide, bromvalurea, acetylcarbromal, carbromal, amylene hydrate, chloretone, methylpentynol, brommethylpentynol, ethchlorvynol, methylphenylbutyndiol, paraldehyde, chloral hydrate and its derivatives, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

15. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of an antianxiety agent selected from the group consisting of meprobamate, tybamate, phenprobamate, emylcamate, chlormezanone, nordiazepam, nitrazepam, diazepam, oxazepam, hemisuccinate, temazepam, camazepam, lorazepam, clonazepam, bromazepam, prazepam, flurazepam, chlordiazepoxide, demoxepam, clorazepate dipotassium, medazepam, triazolam, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

16. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of an antihypertensive agent selected from the group consisting of clonidine, flutonidine, tolonidine, naphazoline, tetrahydrozoline, triamenidine, xylazine, guanabenz, alpha-methyldopa, metaraminol, methyloctopamine, dopamine-beta-hydroxylase, guanethidine sulfate, bethanidine, guanoxan, guanadrel, guanachlor, aminoethylguanines, debrisoquin, bretylium, phentolamine, tolazoline, phenoxybenzamine, prazosin, indoramine, nicergoline, methyl-apogalanthamine, propanolol, pindolol, alprenolol, oxprenolol, bunitrolol, tolamolol, practolol, atenolol, metoprolol, acebutolol, nadolol, timolol, satalol, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

17. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of a cardiac drug selected from the group consisting of verapamil, guinidine, digitoxin, beta-methyldigoxin, digoxin, lanatoside C, lanthanum, lidocaine, propranolol, phenytoin, disopyramide, guinidine, procaine, procainamide, practolol, bretylium tosylate, aprindine, mexiletine, diphenidol, propafenone, tocainide, sodium nitrate, amyl nitrite, nitroglycerin, erythritol tetranitrate, pentaerythriol tetranitrate, mannitol hexanitrate, isosorbide dinitrate, trolnitrate phosphate, phentolamine, tolazoline, sodium nitroprusside, prazosin, hydralazine, varapamil HCl, diltiazem HCl, nifedipine, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

18. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of a dieuretic or uricosuric selected from the group consisting of hydrochlorothiazides, bendroflumethiazide, benzthiazide, buthiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, alipamide, chlorthalidone, clopamide, clorexolone, diapamide, mefruside, metolazone, quinethazone, chlorthalidones, 1-oxoisoindolines, ethacrynic acid, bumetanide, furosemide, indapamide, xipamide, piretanide, triflocin, muzolimine, 2-aminomethyl-3,4,6-trichlorophenol, etozolin, spironolactone, potassium canrenoate, potassium prorenoate, potassium mexrenoate, metyrapone, xanthines, aminouracils, 1-allyl-3-ethyl-6-aminouracil, amiloride, aminometradine, amisometradine, chlorazanil, clazolimine, aminophylline, triamterene, triazines, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

19. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of a drug useful in treating neoplastic diseases selected from the group consisting of glutamine, folic acid, pyrimidine, purine antagonists, ribonucleoside diphosphonate and reductase inhibitors, nitrogen mustards, aziridines, methanesulfonic esters, 1,2-epoxides, nitrosoureas, triazenolimidazoles, procarbazine, mitotic inhibitors, hormones, L-asparaginase, mexthotrexate-5-fluoro-uracil, hexamethylmelamine, cis-dichlorodiamineplatinum (II), actinomycins, mithramycins, bleomycins, anthracyclines, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

20. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of a local anesthetic selected from the group consisting of benzocaine, lidocaine, ketocaine, chloroprocaine, procain, ambucaine, propoxycaine, etidocaine, mepivacaine, prilocaine, quatracaine, tetracaine, tolcaine, aptocaine, bupivacaine, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

21. A penetration enhancing pharmaceutical composition for topical application comprising:

(a) about 0.01% to about 10% by weight of an anorexigenic agent selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, benzphetamine, fenfluramine, chlorphentermine, chlortermine, phentermine, diethylpropion, phenylpropanolamine, 1-methyl-2-phenylmorpholine, phendimetrazine, phenmetrazine, mazindol, oxazolines, thioimidazolines, phenoxyalkyleneamines, biguanides, L-histidine, and mixtures thereof;

(b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol;

(c) 0% to about 80% by weight water;

(d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)-azacyclopentane-2-one, and mixtures thereof; and

(e) about 1.0% to about 35% by weight 1-dodecylazacycloheptan-2-one.

22. A composition according to claim 1 wherein said composition is substantially free of any single member of the saturated straight chain C.sub.16 -C.sub.20 normal fatty alcohols or saturated straight chain C.sub.4 -C.sub.20 mono- or dicarboxylic acids.

23. A composition according to claim 22 wherein said composition contains less than 3.5%, by weight, of any single member of the saturated, straight chain C.sub.16 -C.sub.20 normal fatty alcohols or saturated straight chain C.sub.4 -C.sub.20 mono- and dicarboxylic acids.

Details for Patent 4,557,934

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10   Start Trial The Procter & Gamble Company (Cincinnati, OH) 2039-03-29 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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