Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-10-28
2001-08-14
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C523S114000, C523S115000, 62
Reexamination Certificate
active
06274159
ABSTRACT:
2. Field of the Invention
The present invention relates to drug depot or delivery systems.
3. Description of the Prior Art
The introduction of pharmaceutical agents and the like into a specific site within the body of a patient over a requisite time period by injection or infusion has been proven to be impractical. The predictable, controlled delivery of selected molecules into specific sites in the body is, therefore, preferably accomplished by injection or incorporation of the molecules into a “drug delivery system” or “drug depot” which is implanted into that site. Materials previously proposed to release therapeutic agents into bone tissue, for example, include a variety of resorbable and non-resorbable polymers including polylactic acid and polymethylmethacrylate, and synthetic calcium phosphates including the mineral hydroxyapatite and the compound tricalcium phosphate.
One of the more widely used materials for the construction of such depots are the silicone rubbers, e.g., Norplant® marketed by Wyeth-Ayerst. Drug depots constructed of silicone rubbers suffer, however, from the disadvantage that fibrous scar tissue capsules tend to form around the devices following implantation. This scar capsule is not well vascularized and hinders both the release and availability of the drug from the system. Drug levels have been shown to be reduced by as much as 75% after 21 days implantation [Munro et al,
Contraception
, Vol. 54, pages 43-53 (1996)].
The lack of biocompatibility of implantable materials has been described as being the main problem in the development of long-term drug delivery systems [Park et al,
Pharmaceutical Res
., Vol. 13, pages 1 770-1776 (1996)]. Current devices consist of silicone tubes filled with the desired drug or agent. When these are implanted, the drug slowly diffuses through the silicone and into the surrounding tissue. The above-noted decreased availability of drug due to incompatibility of the carrier system has a high degree of variation among individuals, thus requiring a large initial drug loading and making the calculation of required drug loading a difficult problem to overcome. Improved availability of the drug to the surrounding tissue would improve the reliability of these devices and could reduce the amount of the drug needed for sustained therapeutic delivery, thereby increasing the performance of the device, reducing the possible side effects of variable drug levels released from the implant, and reducing the cost and size associated with the device.
Despite these complications, many types of drugs have been delivered using silicone depots. The following table sets forth a representative number of examples of drugs having a variety of therapeutic effects that have been incorporated heretofore in silicone depots.
Name
Category
Drug
Duration
Norplant ® (Wyeth-Ayerst)
contraception
lovonorgestrel
5 years
Uniplant ® (South to South Corp.)
contraception
nomegstrol acetate
2 years
Experimental device [Vanin et al, Am. J. Obstet. Gynecol.,
hormone therapy
estradiol, norethindrone or
11 months
Vol. 173, pages 1491-1498 (1995)]
norgestimate
Experimental device [Milligan et al, Reprod. Fertil. Dev.,
hormone therapy
progesterone
Vol. 6, pages 235-239 (1994)]
Experimental device [Cohen et al, J. Reprod. Fertil.,
contraception
oestradiol
Vol. 99, pages 219-223 (1993)]
Experimental device [Becker, Brain Res., Vol. 508, pages 60-64
behavior asymmetry
dopamine
2 months
(1990)]
Experimental device [Wang, J. Biomed. Eng., Vol. 15, pages
hyperglycemia
insulin
106-112 (1993)]
Experimental device [Claus et al, Prostate, Vol. 22, pages
human benign prostatic
testosterone and beta-estradiol
4 weeks
199-215 (1993)]
hyperplasia
It is an object of the present invention to provide improved silicone rubber drug depot systems which are not subject to the above-noted disadvantages.
SUMMARY OF THE INVENTION
The above and other objects are realized by the present invention, one embodiment of which relates to an improved implantable pharmaceutical depot for the prolonged release of at least one biologically active substance, the depot comprising a carrier constructed of materials such as silicone and the biologically active substance, the improvement wherein the depot is coated with or surface modified by a biologically active material such as a biocompatible glass, glass-ceramic or ceramic material, the coating or modified surface being capable of forming a bond to soft tissue upon implantation.
Another embodiment of the invention relates to methods for forming the coating or surface modification comprising the biologically active and biocompatible glass, glass-ceramic or ceramic on the silicone based depot.
One method of forming the improved depot is to form a coating of the silicone or other suitable polymer and bioactive glass, glass-ceramic or ceramic on the biologically active substance containing depot. Another suitable method comprises incorporating the bioactive glass, glass-ceramic or ceramic in the silicone or other suitable polymer of construction during formation of the depot itself and then removing sufficient silicone (or other polymer) from the surface of the depot system to expose particles of the bioactive glass, glass-ceramic or ceramic thereon.
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Batich Christopher D.
Hardt Nancy S.
Marotta James S.
Azpuru Carlos A.
Clarks Dennis P.
Miles & Stockbridge
University of Florida
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