Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-12-14
2003-05-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S443000, C424S445000, C424S447000, C424S448000, C514S946000, C514S947000, C514S944000
Reexamination Certificate
active
06562368
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to transdermal administration of pharmacologically active agents, and more particularly relates to methods and compositions for transdermally administering oxybutynin.
BACKGROUND
The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences—e.g., gastrointestinal irritation and the like—are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low.
In order to increase the rate at which a drug penetrates through the skin, then, various approaches have been followed, each of which involves the use of either a chemical penetration enhancer or a physical penetration enhancer. Physical enhancement of skin permeation include, for example, electrophoretic techniques such as iontophoresis. The use of ultrasound (or “phonophoresis”) as a physical penetration enhancer has also been researched. Chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or “permeation enhancers,” as the compounds are referred to herein) are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum.
Nevertheless, the number of drugs that can be safely and effectively administered through the skin, without concomitant problems such as irritation and sensitization, remains limited.
The present invention is directed to the transdermal administration of 4-diethylamino-2-butynyl phenylcyclohexlglycolate, or “oxybutynin.” Preparation of the drug in racemic form is described in U.K. Patent No. 940,540. Oxybutynin is classified as an anticholinergic antispasmodic drug and is commonly used in treating individuals suffering from an overactive bladder, e.g., neurogenic bladder. See, for example, U.S. Pat. No. 5,674,895 to Guittard et al.
Oxybutynin has the molecular structure (I)
and, as may be seen, contains a chiral center. Thus, oxybutynin exists as two different isomers, as follows:
Isomer (Ia) represents the enantiomer of oxybutynin having the S absolute stereochemistry and exhibits dextrorotatory properties. Isomer (Ib) represents the enantiomer of oxybutynin having the R absolute stereochemistry and exhibits levorotatory properties. Commercially available preparations contain racemic oxybutynin in the form of the hydrochloride salt. The amount of oxybutynin in these preparations ranges from 5 mg to 30 mg per unit dose.
Current formulations of oxybutynin are administered orally, in tablet or syrup form. Conventional tablets are available that are generally taken two to three times daily. In addition, extended release tablets are also commercially available for once daily dosing. The present invention, however, is directed to the transdermal administration of oxybutynin. There are a number of advantages to administering oxybutynin transdermally: continuous delivery provides for sustained blood levels of the drug, there is no first-pass effect; side effects typically associated with oral administration may be avoided; continuous delivery provides for sustained blood levels; the transdermal patch is easily removable if any side effects do occur; and the likelihood of both patient acceptance and patient compliance is significantly improved.
Transdermal administration of oxybutynin has been proposed. U.S. Pat. No. 5,614,211 to Gale et al. describes a device for transdermally administering oxybutynin, the device comprising a special layer that eliminates blooming and delamination between the contact adhesive and drug reservoir due to migration of surfactant into other layers of the device. U.S. Pat. No. 5,500,222 to Lee et al. also describes transdermal administration of oxybutynin. In the aforementioned patent, however, a dual permeation enhancer mixture comprising lauryl acetate and a monoglyceride is required for sufficient flux of oxybutynin through the skin. U.S. Pat. No. 5,532,278 to Aberg et al. describes methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin. Although transdermal administration of (S)-oxybutynin is discussed, the patent describes transdermal systems that include only conventional permeation enhancers. Furthermore, U.S. Pat. No. 6,123,961 Aberg describes transdermal administration of (R)-oxybutynin. Permeations enhancers, however, are not mentioned. As will also be appreciated, conversion of the salt forms of oxybutynin, e.g., oxybutynin hydrochloride, is typically necessary before incorporation into a transdermal drug delivery system, since the acid addition salt exhibits even lower skin flux than the free base. See, for example, the '211 patent.
Accordingly, there is a need in the art for a way to transdermally administer oxybutynin without being limited by the drug's low skin flux.
As indicated above, various compounds for enhancing the permeability of skin are known in the art and described in the pertinent texts and literature. Compounds that have been used to enhance skin permeability include: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C
10
MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Nelson Research & Development Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid; and certain peptides, e.g., peptides having Pro-Leu at the N-terminus and followed by a protective group (see U.S. Pat. No. 5,534,496).
Percutaneous Penetra
No affiliations
No associations
LandOfFree
Transdermal administration of oxybutynin using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transdermal administration of oxybutynin using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transdermal administration of oxybutynin using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3036738