Formulations for transdermal or transmucosal application

• US 7,470,433 B2
• Filed: 03/30/2007
• Issued: 12/30/2008
• Est. Priority Date: 08/03/2000
• Status: Expired due to Term

• Current Assignee: Antares Pharma Incorporated
• Original Assignee: Antares Pharma Incorporated
• Inventors: Besse, Celine, Lehman, Leah M., Simes, Stephen M., Carrara, Dario Norberto R., Grenier, Arnaud
• Primary Examiner(s): Richter; Johann R
• Assistant Examiner(s): George; Konata M
• Application Number:
  US11/693,988
• Publication Number:
  US 20070166361A1
• Time in Patent Office: 641 Days
• Field of Search: 424/448, 424/449, 514/169
• US Class Current: 424/448
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

The present invention relates generally to formulations for transdermal or transmucosal administration of an active agent such as estradiol. The invention is a substantially malodorous-free and irritation free transdermal formulation which is substantially free of long chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.

Claims

1. A gel formulation for transdermal or transmucosal administration of an active agent, the formulation comprising:

at least one active agent comprising estrogen;

a gelling agent and a delivery vehicle comprising a C₂ to C₄ alkanol, a polyalcohol, and a permeation enhancer of monoalkyl ether of diethylene glycol present in an amount sufficient to provide permeation enhancement of the active agent through dermal or mucosal surfaces;

wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters in order to avoid undesirable odor and irritation effects caused by such compounds during use of the formulation;

provided that a progestin is not present in the formulation.

2. The formulation of claim 1, wherein the amount of estrogen is between about 0.01% to 10% by weight of the formulation and the daily administration of the formulation in an amount of from about 0.625 g to about 2.5 g.

3. The formulation of claim 2, wherein the amount of estrogen is about 0.06% by weight of the formulation and the daily administration of the formulation is made in an amount of about 1.25 g to about 2.5 g.

4. The formulation of claim 1, wherein the estrogen is selected from the group consisting of 17 beta-estradiol, estradiol, estradiol benzoate, estradiol 17 beta-cypionate, estriol, estrone, ethynil estradiol, mestranol, moxestrol, mytatrienediol, polyestradiol phosphate, quinestradiol, quinestrol, and any combination thereof.

5. The formulation of claim 1, wherein the polyalcohol is present in an amount between about 1% and 30% by weight of the vehicle;

the alkanol is present in an amount of 5 to 75% by weight of the vehicle, and the permeation enhancer is present in an amount of between about 0.2% and 25% by weight of the vehicle.

6. The formulation of claim 5, wherein the alkanol is present in an amount between about 20 to 65% by weight of the formulation;

the polyalcohol is present in an amount between about 1% to 15% by weight of the formulation; and

the permeation enhancer is present in an amount between about 1% to 15% by weight of the formulation.

7. The formulation of claim 6, wherein the alkanol is selected from the group consisting of ethanol, isopropanol and n-propanol, and wherein the polyalcohol is polypropylene glycol.

8. The formulation of claim 7, wherein the polyalcohol and permeation enhancer are present in a weight ratio of 1.25:

1 to 1.2;

1 and the formulation further comprises a gelling agent present in an amount of between 0.05% to about 4% by weight of the formulation, a neutralizing agent present in an amount between about 0.05% and 1% by weight of the formulation, and water present in an amount between about 20% to 65% by weight of the formulation so that the formulation is provided as a gel.

9. The formulation of claim 1, wherein the formulation further comprises at least one of a neutralizing agent, sequestering agent, buffering agent, moisturizing agent, humectant, surfactant, antioxidant, emollient, buffer or a combination thereof.

10. The formulation of claim 9, wherein the gelling agent is selected from the group consisting of carbomer, carboxyethylene, polyacrylic acid, ethylcellulose, hydroxypropylmethylcellulose, ethylhydrooxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, natural gums, arabic, xanthan, guar gums, alginates, polyvinylpyrrolidone polymers, polyoxyethylene polyoxypropylene copolymers, chitosan, polyvinyl alcohol, pectin, and veegum;

the buffering agent is selected from the group consisting of carbonate buffers, citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid, lactic acid, tartaric acid, diethylamine, triethylamine, diisopropylamine, tetrahydroxypropylethylendiamine, and aminomethylamine;

or the sequestering agent is edetic acid.

11. The formulation of claim 1 wherein the active agent is estradiol.

12. The formulation of claim 1 comprising the following composition:

0.01 to 1% by weight of estradiol, 1.2% by weight of carbomer 940, 0.4% by weight of triethanolamine (adjust to pH 5.9), 46.28% by weight of alcohol, 6% by weight of propylene glycol, 5% by weight of diethylene glycol monoethyl ether, 0.06% by weight of disodium EDTA and 100% by weight of ion exchange purified water q. ad.

13. A gel formulation for transdermal or transmucosal administration of an active agent, the formulation comprising:

estrogen;

a gelling agent; and

a delivery vehicle comprising a C₂ to C₄ alkanol, a polyalcohol, and a permeation enhancer of monoalkyl ether of diethylene glycol to provide permeation enhancement of the active agent through dermal or mucosal surfaces, wherein the polyalcohol is propylene glycol and is present in an amount between about 1% and 30% of the vehicle, the permeation enhancer is diethylene glycol monoethyl ether and is present in an amount of between about 0.2% and 25% of the vehicle, the alkanol is ethanol and is present in an amount of 5 to 75% by weight of the vehicle wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty in order to avoid undesirable odor and irritation effects caused by such compounds during use of the formulation;

provided that a progestin is not present in the formulation.

14. The formulation of claim 13, wherein the amount of estrogen is between about 0.01% to 10% by weight of the formulation and the daily administration of the formulation in an amount of from about 0.625 g to about 2.5 g.

15. The formulation of claim 13, wherein the amount of estrogen is about 0.06% by weight of the formulation and the daily administration of the formulation is made in an amount of about 1.25 g to about 2.5 g.

16. The formulation of claim 13, wherein the alkanol is present in an amount between about 20 to 65% of the formulation;

the polyalcohol is propylene glycol present in an amount between about 1% to 15% of the formulation;

the permeation enhancer is diethylene glycol monoethyl ether present in an amount between about 1% to 15% of the formulation, and further wherein the formulation comprises a gelling agent present in an amount of between 0.05% to about 4% of the formulation, a neutralizing agent present in an amount between about 0.05% and 1% of the formulation, and water present in an amount between about 20% to 65% of the formulation so that the formulation is in the form of a gel.

17. The formulation of claim 13 wherein the active agent is estradiol.

18. The formulation of claim 13 comprising the following composition:

0.01 to 2% by weight of estradiol, 0.05-4% by weight of carbomer, 0.05-1% by weight of triethanolamine (adjust to pH 5.9), 20-65% by weight of alcohol, 1-15% by weight of propylene glycol, 1-15% by weight of diethylene glycol monoethyl ether, 20-65% by weight of ion exchange purified water q. ad.