Compositions, methods and devices for the transdermal...

Details Compositions, methods and devices for the transdermal... Compositions, methods and devices for the transdermal...

1996-05-22

2001-04-10

Clardy, S. Mark (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S430000, C424S443000, C424S455000, C424S484000

Reexamination Certificate

active

06214374

ABSTRACT:

1. INTRODUCTION
The present invention relates to compositions for the transdermal delivery of hormones comprising a hydrogel-forming base mixture and a skin permeation enhancer. Methods for the treatment of disorders responsive to the administration of hormones are also provided. The present invention further relates to devices for the transdermal delivery of drugs.
2. BACKGROUND
A recent trend in the pharmaceutical industry has been the development of new drug delivery systems for both old and new drugs. Much of the current research in drug delivery technology is aimed at developing formulations and devices that improve the therapeutic effectiveness of drugs over conventional means of administration by controlling the rate, time and place of release of drugs in the body.
Conventional dosage types include sublingual (under the tongue), oral (capsules, tablets, liquids), injectable, nasal and parenteral (suppository and non-oral) forms. While oral dosage forms comprise a substantial majority of all present dosage forms and offer ease of administration and low cost-per-use, they can suffer from inconvenient dosing intervals, side effects and reduced efficacy. Conventional dosage forms have disadvantages in certain patients, including unpredictable blood levels, difficult or uncomfortable administration and poor compliance. In order to maintain optimum blood levels, some conventional forms of drug delivery require frequent doses which can be difficult to remember or understand, particularly for the elderly patient. Failure to comply with a recommended drug regimen can endanger a patient's health.
Controlled drug delivery systems have been introduced within the last decade to eliminate or reduce the limitations of conventional dosage forms. One type of controlled delivery is transdermal delivery, which involves delivery of a therapeutic agent through the skin for distribution within the body by the circulation of the blood. Transdermal delivery can be compared to continuous, controlled intravenous delivery of a drug using the skin as a port of entry instead of an intravenous needle. The therapeutic agent passes through the outer layers of the skin, diffuses into the capillaries, or tiny blood vessels in the skin, and then is transported into the main circulatory system.
Examples of drugs which have successfully been delivered transdermally include scopolamine for the treatment of motion sickness, nitroglycerin for the treatment of angina, estrogen and combined estrogen/progestogen for menopausal symptoms and osteoporosis, isosorbide dinitrate for angina, clonidine for hypertension, nicotine for smoking cessation, fentanyl for pain management and testosterone for male hypogonadism.
The hormone progesterone is used in the treatment of premenstrual syndrome, menopausal hormone replacement therapy (in combination with estrogen), infertility and a variety of gynecological conditions. The transdermal delivery of progesterone has been reported. However, due to the large size of the progesterone molecule, efforts to transdermally deliver progesterone in therapeutically effective amounts have often been unsuccessful. Progesterone is known to be metabolized within the skin by the 5-&agr;-reductase enzyme which converts it to inactive 5-&agr;-dihydroxyprogesterone (R. Sitruk-Ware, 1995, “Transdermal Application of Steroid Hormones for Contraception,” J. Steroid Biochem. Molec. Biol. 53 (1-6):247-251). Thus, relatively high, multiple doses are required to elicit the desired progestational effect. The desired goal of transdermal delivery of progesterone is to be able to maintain consistent serum levels of progesterone at relatively low dosage levels without requiring multiple dosing.
Low rates of transdermal delivery of progesterone have been reported by various researchers. For example, Guy et al. (1987, “Kinetics of Drug Absorption Across Human Skin In Vivo,” Pharmacol. Skin 1:70-76), disclose that about 1.2 &mgr;g/cm
2
penetrated in a 24-hour period, when the drug was applied as a thin film on the skin in vivo. Barry and Bennett, (1987, “Effect of Penetration Enhancers on the Permeation of Mannitol, Hydrocortisone, and Progesterone Through Human Skin,” J. Pharm. Pharmacol. 39:535-546), report a rate of 0.477 &mgr;g/cm
2
/hour in vitro through excised human skin. Both Guy et al. and Barry and Bennett measured penetration through the skin after progesterone was applied in an acetone solution, the solvent was allowed to evaporate, and the skin surface was hydrated, either by occlusion or by application of a small amount of water. Barry and Bennett reported higher rates of transdermal penetration of progesterone when penetration enhancers were applied to the skin following application of the acetone/progesterone solution and evaporation of the solvent. Rates of 11.4 (+/−4.6) and 12.4 (+/−4.4) &mgr;g/cm
2
/hour, respectively, were observed after application of 2-pyrrolidone and N-methylformamide permeation enhancers. However, neither the methods nor the solvent vehicles for application of progesterone to the skin disclosed by these references are appropriate or practical for use in a transdermal patch delivery system, for number of reasons. Application of acetone to the skin commonly results in skin irritation, an effect that may also be encountered with 2-pyrrolidone and N-methylformamide. Further, permeation enhancers such as 2-pyrrolidone and N-methylformamide may impose health risks. Also, the volatile solvent carriers disclosed by these references can be difficult and impractical to incorporate into a patch system.
The transdermal delivery of progesterone, progestins, estrogens and testosterone from gel-like matrices has been reported. R. Sitruk-Ware (1988, “Innovative Technology for Hormonal Replacement Therapy,” Maturitas, 10:79-81) discloses a progesterone cream for use as a topical therapy in benign breast diseases. R. Sitruk-Ware (1989, “Transdermal Delivery of Steroids,” Contraception 39, (1):1-20) discloses that only small amounts of progesterone can be obtained in plasma via skin penetration, but when applied on the breast, high amounts of progesterone can be obtained in the breast tissue. A five-fold increase in progesterone concentration was demonstrated in breast tissue of women treated topically with the steroid dissolved in an alcohol/water gel.
Compounds that act as permeation enhancers have been added to transdermal drug delivery systems for a number of drugs, including progesterone. Pfister and Hsieh (1990, in “Permeation Enhancers with Transdermal Drug Delivery Systems: Part II: System Design Considerations,” Pharmaceutical Technology, October 1990: 55-60), disclose a wide variety of permeation enhancers. For example, isopropyl palmitate and isopropyl myristate are disclosed as cosolvents to enhance the solubility of nitroglycerin in a polymer matrix-type transdermal system, which in turn optimizes the release of the drug from the system. Similarly, ethanol is disclosed as enhancing the solubility of 17-&bgr;-estradiol in the reservoir compartment of a transdermal drug delivery device. Other skin penetration enhancers are disclosed, including stearyl alcohol, glycerol, 2-pyrrolidone, urea, propylene glycol, oleic acid, and palmitic acid. D. R. Friend (1990, “Transdermal Delivery of Contraceptives”, Critical Reviews in Therapeutic Drug Carrier Systems 7 (2):149-186), discloses dimethyl sulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N,N-dimethyl-m-toluamide, urea, ethyl acetate, 1-dodecylazacycloheptan-2-one (azone), oleic acid and ethanol as permeation enhancers. Butylurea has also been disclosed as a permeation enhancer. For example, U.S. Pat. No. 5,128,376 discloses a method for percutaneous administration of a drug from a mixture of an adjuvant, a solvent and a diol/triol moderator, wherein the solvent, which enhances permeation, may be a substituted urea such as butylurea. U.S. Pat. No.

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