Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1999-12-23
2002-11-05
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S843000, C424S422000, C424S423000, C424S424000, C424S486000
Reexamination Certificate
active
06476079
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to devices for the controlled release of drugs having antiprogestinic properties, particularly to implantable devices, intrauterine or intravaginal devices, or transdermal devices for the administration of said drug at a desirable rate over a prolonged period of time.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
The use of drug delivery devices, which provide for the slow release of a drug to the body at a controlled rate over a prolonged period of time to achieve a desired physiological or pharmacological effect, his proved beneficial in many therapeutic areas. A principal advantage of employing sustained-release compositions is that many therapeutic agents would otherwise be rapidly metabolised or cleared from the patient's system thus necessitating frequent administration of the drag to maintain a therapeutically effective concentration.
A variety of methods have been described in the literature, including the physiological modification of absorption or excretion, modification of the solvent, chemical modification of the drug, absorption of drug on an insoluble carrier, use of suspensions and implantation pellets. Other methods include mixing the drug with a carrier such as waxes, oils, fats, and soluble polymers, which are gradually disintegrated by the environment resulting in release of the drug. Much attention has been directed to the reservoir type of device, i.e., a device in which a drug is encased within a polymeric container, with or without a solvent or carrier, which allows passage of drug from the reservoir.
Still another type of drug delivery device is the type in which a drug is dispersed in a polymer and from which the drug is released either by degradation of the polymer or by passage of the drug through the polymer membrane.
In principle any polymer can be used as a carrier as long as it is biocompatible. However, the release kinetics of a drug from a polymeric delivery system depend on the molecular weight, solubility, diffusivity, and charge of the active substance as well as the characteristics of the polymer, the percentage of drug loading, the distance the drug must diffuse through the device body to reach its surface and the characteristics of any matrix or membrane coating. The importance of these factors coupled with the specific pharmacology, toxicology, and therapeutic goals necessitate that the design of a polymeric device for a specific agent must be carefully constructed.
Examples of commonly used polymeric materials include elastomers such as polysiloxanes, ethylene/vinyl acetate copolymers (EVA), and copolymers of dimethylsiloxanes and methylvinylsiloxanes. The structural integrity of the material may be enhanced by the addition of a particulate material such as silica or diatomaceous earth.
Devices manufactured from EVA suffer from certain drawbacks. The materials are rather stiff and non-flexible and are therefore rather inconvenient to wear as implants beneath the skin.
Polysiloxanes, in particular poly(dimethyl siloxane) (PDMS), are highly suitable for use as a membrane or matrix regulating the permeation rate of drugs in various drug forms, in particularly in implants, intrauterine devices and vaginal rings.
Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required strength properties.
It is known from the literature that adding of poly(ethylene oxide) groups, i.e. PEO groups to a PDMS polymer may increase the permeation rate of the drugs. Publication Ullman et al. Journal of Controlled Release 10 (1989) 251-260 describes membranes from a block copolymer which contains PEO and PDMS and the penetration of various steroids through these membranes. It is noted that an increasing PEO amount in the block polymer tends to increase the penetration of hydrophilic steroids, while the penetration of lipophilic steroids decreases. However, the block copolymer described in the publication is very complicated in its structure and preparation and would therefore not be facile in more extensive technical production.
Contraceptive subcutaneous implants are known in the art and they are described e.g. in U.S. Pat. Nos. 4,957,119, 5,088,505, 5,035,891, 5,565,443 and 5,633,000. Implants of the matrix type produced from polydimethyl siloxanes are described in the literature (Nash, Robertson and coworkers, Contraception 18, 1978, 367).
The commercially available Norplant® system is an implant having a core containing the synthetic progestin, levonorgestrel as the active substance, and where the core is surrounded by a membrane of a silicone elastomer of poly(dimethylsiloxane). A special preparation of this kind is Jadelle® in which the core is a poly(dimethylsiloxane) based matrix with levonorgestrel dispersed therein. The membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane also retards the permeation of the active agent through the membrane.
U.S. Pat No. 3,279,996 (Long et al.) describes an implant which contains an active substance encased by a polysiloxane membrane.
Dutch Patent No. 167,850 (Zaffaroni) describes an implant, in which the active substance is contained in a polymer and this polymer loaded with active substance is encased by a polymer membrane, which completely controls the release rate. However, the dimensions, the degree of rigidity and the release duration of the contraceptive substance for these implants are not practical.
U.S. Pat. No. 3,854,480 describes a drug delivery device, e.g. an implant, for releasing a drug at a controlled rate for a prolonged period of time. The device has a core matrix in which the drug is dispersed. The core is surrounded by a membrane, that is insoluble in body fluids. The core matrix as well as membrane are permeable to the drug by diffusion. The materials of the core and membrane are chosen so that the drug diffuses through the membrane at a lesser rate than through the core matrix. Thus the membrane controls the release rate of the drug. As a suitable polymer for the core matrix is mentioned poly(dimethyl siloxane) and as suitable polymers for the membrane are mentioned polyethylene and a copolymer of ethylene and vinyl acetate (EVA).
U.S. Pat. No. 5,660,848 discloses a subdermally implantable drug-delivery device, which contains a central core extending in an anal direction and having an outer surface and opposing ends. The core includes a matrix with a therapeutically effective amount of a subdermally administrable drug substantially uniformly dispersed in a polymeric base material; an intermediate polymeric layer overlying the outer surface of the central core; and an outer polymeric layer overlying the intermediate layer, wherein the intermediate layer controls the rate of diffusion of the drug from the central core to the outer layer. In preferred embodiments, the drug is a contraceptive agent; the polymeric base material and the outer polymeric layer each contain a polydimethylsiloxane and the intermediate layer contains a porous material such as cellulose.
Numerous types of vaginal rings have been described in the patent and non-patent literature like, e.g., U.S. Pat. Nos. 4,012,496 and 4,155,991 (both to Schopflin et al.), U.S. Pat. No. 4,292,965 (Nash), U.S. Pat. No. 3,545,439 (Duncan), U.S. Pat. No. 3,920,805 (Roseman), U.S. Pat. Nos. 3,991,760 and 3,995,634 both to Drobish et al.), U.S. Pat. No. 3,995,633 (Gougen), U.S. Pat. Nos. 4,250,611 and 4,286,587 (both to Wong), U.S. Pat. No. 4,596,576 (de Nijs); WO95/00199 (Lehtinen et al.), Contraception 19:507-516 (1979), (Jackanicz).
Implants or intravaginal devices for administration of antiprogestins have generally been disclosed e.g. in U.S. Pat. Nos. 5,516,769, 5,521,166, 5,439,913, 5,622,943 and 5,681,817.
OBJECT AND SUMMARY OF THE INVENTION
The o
Ala-sorvari Juha
Jukarainen Harri
Lehtinen Matti
Markkula Tommi
Ruohonen Jarkko
Fubara Blessing
Leiras Oy
Lydon James C.
Page Thurman K.
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