Compositions and methods for topical administration of pharmaceutically active agents

• US 5,719,197 A
• Filed: 06/07/1995
• Issued: 02/17/1998
• Est. Priority Date: 03/04/1988
• Status: Expired due to Term

• Current Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Original Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Inventors: Mantelle, Juan A., Kanios, David P., Gentile, Joseph A., Sablotsky, Steven
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US08/477,361
• Time in Patent Office: 986 Days
• Field of Search: 424/449, 424/435, 424/443, 424/447, 424/450, 514/772.6, 514/781-782, 514/818, 514/947
• US Class Current: 514/772.6
• CPC Class Codes: A61F 13/0276 Apparatus or processes for manufacturing adhesive dressings or bandages
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• 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: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61L 15/18 containing inorganic materials
• CPC Class Codes: A61L 15/58 Adhesives
• CPC Class Codes: A61L 15/585 Mixtures of macromolecular compounds
• CPC Class Codes: B26F 1/384 using rotating drums
• CPC Class Codes: C08L 31/04 Homopolymers or copolymers of vinyl acetate

Abstract

Compositions for topical application comprising a therapeutically effective amount of a pharmaceutical agent(s), a pharmaceutically acceptable bioadhesive carrier, a solvent for the pharmaceutical agent(s) in the carrier and a clay, and methods of administering the pharmaceutical agents to a mammal are disclosed.

Claims

1. A flexible, finite, bioadhesive composition for topical application comprising:

(a) a therapeutically effective amount of at least one pharmaceutically active agent;

(b) a pharmaceutically acceptable solvent for the pharmaceutically active agent and a plasticizer;

(c) in admixture with the pharmaceutically active agent in the solvent, a pharmaceutically acceptable bioadhesive carrier in an amount from about 5 to 50 percent based on the weight of the whole composition; and

(d) a cohesive increasing amount of a clay;

wherein the composition is substantially free of water, substantially water insoluble and is a bioadhesive; and

wherein the pharmaceutically active agent is present in non-crystallized form in the composition.

2. The composition of claim 1, wherein the pharmaceutically acceptable solvent is in an amount from about 20 to about 50 weight percent based on the weight of the whole composition, of which the plasticizer represents about 10 to about 30 weight percent based on the weight of the whole composition, the bioadhesive carrier is in an amount from about 20 to about 50 weight percent and the clay represents about 0.5 to 20% based on the weight of the whole composition.

3. The composition of claim 1, wherein the pharmaceutically active agent is at least one local anesthetic in an amount of about 10 to 40 weight percent based on the weight of the total composition.

4. The composition of claim 1, wherein the pharmaceutically active agent is from a class of drugs selected from the group consisting of analgesic anti-inflammatory drugs, central nervous system drugs, antihistaminic or antiallergic drugs, acitonide anti-inflammatory drugs, androgenic and estrogenic steroids, respiratory drugs, sympathomimetic drugs, antimicrobial drugs, antihypertensive drugs, cardiotonic drugs, coronary vasodilators, vasoconstrictors, beta blocking and antiarrhythemic drugs, calcium antagonistic and other circulatory anticonvulsants, anti-vertigo-tranquilizing drugs, antipsychotic drugs, muscle-reactants drugs, anti-Parkinson drugs, non-steroidal hormones, anti-hormones, vitamins, anti-tumor, enzymes, herb medicines or crude extracts, miotics, cholinergic agonists, antimuscarinic or muscarinic cholinergic blocking drugs, mydriatics, psychic energizers, humoral agents, antispasmodic drugs, antidepressants, antidiabetics, anorexic drugs, anti-allergic drugs, decongestants, antipyretics, anti-migraine drugs, antimalarial, antiulcer drugs, peptides, and anti-estrogens.

5. The composition of claim 4, in which the pharmaceutically active agent is one or more steroids selected from the group consisting of androgenic steroids, including testosterone;

methyltestosterone;

fluoxymesterone;

estrogenic steroids, including conjugated estrogens, esterified estrogens, estropipate, 17β

-estradiol, 17β

-estradiol esters such as 17β

-estradiol valerate, equilin, mestranol, estrone, estriol;

17β

-estradiol derivatives such as 17β

-ethinyl estradiol;

diethylstilbestrol, progestational agents, including progesterone and progesterone analogs such as 19-norprogesterone, hydroxyprogesterone caproate, 17β

-hydroxyprogesterone, dydrogesterone, medroxyprogesterone acetate; and

norethindrone, norethindrone acetate, melengestrol, chlormadinone;

ethynodiol diacetate, norethynodrel, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone, megestrol acetate, anti-estrogen and anti-androgenic steroids.

6. The composition of claim 3, wherein the anesthetic agent is selected from the group consisting of procaine, lidocaine, prilocaine, mepivacaine, dyclonine, dibucaine, benzocaine, chloroprocaine, tetracaine, bupivacaine, and etidocaine and is in the form of the base or an acid-addition salt or both forms.

7. The composition of claim 6, wherein the acid-addition salt is hydrochloride.

8. The composition of claim 1, wherein the bioadhesive is selected from the group consisting of gums and celluloses.

9. The composition of claim 8, wherein the gum is selected from the group consisting of karaya gum, tragacanth gum, pectin gum, xanthan gum, guar gum, cellulose, and cellulose derivatives.

10. The composition of claim 3, wherein the solvent for the anesthetic agent is at least one polyhydric alcohol.

11. The composition of claim 10, wherein the polyhydric alcohol is a polyalkylene glycol.

12. The composition of claim 11, wherein the glycol is selected from the group consisting of dipropylene glycol, propylene glycol, ethylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polypropylene glycol, and sorbitol.

13. The composition of claim 1 further comprising a backing material conforming to the size and shape of a single dosage of the composition.

14. The composition of claim 1 comprising about 20 to 35 weight percent of karaya gum, about 20 to 40 weight percent of at least one glycol, about 10 to 25 weight percent of lidocaine base, and 1 to 7 percent smectite clay, and further comprising a binder in an amount sufficient to bind the other ingredients.

15. The composition of claim 1 comprising about 10 weight percent of karaya gum, about 13 weight percent of at least one glycol, and about 8 weight percent of lidocaine base, and further comprising a binder in an amount sufficient to bind the other ingredients.

16. The composition of claim 1 comprising about 7 weight percent of karaya gum, about 13 weight percent of at least one glycol, and about 8 weight percent of lidocaine base, and further comprising a binder in an amount sufficient to bind the other ingredients.

17. The composition of claim 1 comprising about 5 weight percent of karaya gum, about 13 weight percent of at least one glycol, and about 8 weight percent of lidocaine base, 2 percent Bentonite, and further comprising a binder in an amount sufficient to bind the other ingredients.

18. The composition of claim 1 comprising about 5 weight percent of karaya gum, about 13 weight percent of at least one glycol, and about 8 weight percent of lidocaine base, 2 percent Bentonite, and further comprising a binder in an amount sufficient to bind the other ingredients.

19. The composition of claim 1, wherein the pharmaceutically active agent is an anti-microbial agent.

20. The composition of claim 19, wherein the anti-microbial agent in an antifungal agent.

21. The composition of claim 20, wherein the anti-microbial agent is clotrimazole.

22. The composition of claim 20, wherein the antimicrobial agent is miconazole.

23. A method of administering one or more pharmaceutically active agents to a subject comprising the steps of:

providing the composition set forth in claim 1; and

contacting an area of skin or mucous membrane with the composition to administer the pharmaceutically active agent.

24. The method of claim 21, wherein the pharmaceutically active agent is an anesthetic agent selected from the group consisting of procaine, dyclonine, lidocaine, prilocaine, mepivacaine, benzocaine, propoxycaine, chloroprocaine, tetracaine, bupivacaine, etidocaine, and dibucaine.

25. The method of claim 22, wherein the anesthetic agent is administered in the form of a free base.

26. The method of claim 22, wherein the anesthetic agent is administered in the form of an acid-addition salt.

27. The method of claim 22, wherein the solvent is at least one polyhydric alcohol.