Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-04-04
2002-07-02
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S785000, C514S946000, C514S947000, C514S782000
Reexamination Certificate
active
06414028
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions for transdermal administration of prostaglandin drugs to a patient.
BACKGROUND OF THE INVENTION
Prostaglandin E
1
is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula:
and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation “Alprostadil USP” and from The Upjohn Company (Kalamazoo, Mich.) under the designation “Prostin VR.”
Prostaglandin E
1
is a vasodilator useful to maintain open blood vessels and therefore, to treat peripheral vascular disease among other ailments. While the potential benefits from transdermal delivery of prostaglandin E
1
have long been recognized, prior efforts at developing a topical composition for prostaglandin delivery have not been fully successful.
In particular, there is presently no commercial source for a topical semi-solid formulation that is useful without a supporting device such as a patch, adhesive strip, and the like. For example, U.S. Pat. No. 5,380,760 to Wendel et al. is directed to a topical prostaglandin formulation that includes a pressure-sensitive, adhesive sheet of polyisobutylene.
Working alone most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not affect available dosage forms (e.g. cream or gel), or cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example,
Percutaneous Penetration Enhancers
, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Büyüktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in
Transdermal and Topical Drug Delivery Systems
, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).
A fully successful formulation for prostaglandin E
1
has not yet been identified. Unfortunately, prostaglandin E
1
is readily transformed by rearrangement and other reactions. This relative instability tends to complicate efforts at formulating composition for transdermal delivery.
The present invention addresses these problems by providing a semi-solid, separation resistant composition for relatively rapid, sustained delivery of prostaglandin E
1
.
SUMMARY OF THE INVENTION
A pharmaceutical composition suitable for topical application comprises prostaglandin E
1
, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. The penetration enhancer can be an alkyl-2-(substituted amino)-alkanoate ester, a (substituted amino)-alkanol alkanoate, a mixture of these, or an acid addition salt thereof. The acid can be organic or inorganic. The lipophilic compound may be an aliphatic C
1
to C
8
alcohol, an aliphatic C
8
to C
30
ester, or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4. If desired, stabilizers and emulsifiers may be included.
Compositions of the present invention can take the form of a semi-solid suitable for topical application. In use as a topical agent, these compositions exhibit relatively high prostaglandin penetration and bioavailability without requiring a wasteful overloading prostaglandin concentration. The compositions further exhibit reduced skin irritation, sensitivity and damage.
Other and further aims, purposes, features, advantages, embodiments and the like will be apparent to those skilled in the art from the present specification and the appended claims.
REFERENCES:
patent: 4661524 (1987-04-01), Thomson et al.
patent: 4731241 (1988-03-01), Yamada et al.
patent: 4732892 (1988-03-01), Sarpotdar et al.
patent: 4771004 (1988-09-01), Higuchi
patent: 4808414 (1989-02-01), Peck et al.
patent: 4865848 (1989-09-01), Cheng et al.
patent: 4973468 (1990-11-01), Chiang et al.
patent: 4980378 (1990-12-01), Wong et al.
patent: 5082866 (1992-01-01), Wong et al.
patent: 5413794 (1995-05-01), Suzuki et al.
patent: 5534260 (1996-07-01), Petersen et al.
patent: 5534554 (1996-07-01), Katz et al.
patent: 5942545 (1999-08-01), Samour et al.
patent: 6046244 (2000-04-01), Buyuktimkin et al.
patent: 2001/0019721 (2001-09-01), Brandt et al.
Uekama et al.Improved Trandermal Delivery of Prostaglandin E1Through Hairless Mouse Skin: Combined Use of Carboxymethyl-ethyl-beta-cyclodextrin and Penetration Enhancers, Journal of Pharmaceutical Pharmacology, Freb. 1992. vol. 44, No. 2, pp. 119-121.
Adachi et al. Inhibitory Effect of Prostaglandin E1on Laurate-Induced Peripheral Vascular Occlusive Sequelae in Rabbits: Optimized Topical Formulation with Beta-Cyclodextrin Derivative and Penetration Enhancer HPE-101, Journal of Pharmaceutical Pharmacology Dec. 1992. vol. 44, No. 12, pp. 1033-1035.
Article, “Alkyl N,N-Disubstituted-Amino Acetates”, Büyüktimkin, N., et al., pp. 91-102, appearing in “Percutaneous Penetration Enhancers,” 1995 by CRC Press, Inc.
Abstract No. 2686, 1997 AAPS Annual Meeting Contributed Papers Abstracts, American Association of Pharmaceutical Scientists.
Büyüktimkin Nadir
Büyüktimkin Servet
Yeager James L.
Jones Dameron L.
NexMed (Holdings) , Inc.
Olson & Hierl Ltd.
Wells Lauren Q.
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