Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-09-21
2001-03-06
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S423000
Reexamination Certificate
active
06197342
ABSTRACT:
The present invention relates to a particulate, biologically active ceramic-glass material in conjunction with one or more therapeutically beneficial microencapsulated drugs and its use as a means for the controlled delivery of the drugs into the body of a mammal in need thereof.
BACKGROUND OF THE INVENTION
A drug may be administered to a patient systemically or locally. When a drug is administered systemically, it enters the circulatory system, i.e., the blood stream, travels throughout the body, and hopefully, an effective amount of the drug will reach the part of the patient's body in need of treatment before the drug is degraded by metabolism and excreted. Typically, a drug is taken orally in the form of a syrup, tablet, capsule and the like, passes through the stomach then into the intestines where it passes through the intestine walls into the blood stream. Alternatively, the drug may be injected directly into the blood stream or into soft tissue where it diffuses into the blood stream.
In recent years, drugs have also been administered systemically by transdermal delivery. That is, the drug is placed on the skin (typically the drug is incorporated into a patch) and allowed to diffuse through the skin to enter the blood stream. In a variation of this form of administration, a drug formulation in a metabolizable matrix or a container is implanted under the skin where the drug is slowly released and finds its way into the patient's blood stream. This form of drug delivery is particularly advantageous when a continuous, constant, low level of drug is desirable. For example, this method is currently being used to administer small amounts of nicotine to help patients stop smoking, and to deliver a birth control drug over several weeks.
Topical administration is the most common form of local drug delivery. Typically a drug containing formulation is placed directly on the area of the body needing the drug. For example, an antibiotic in the form of a cream or ointment may be spread onto an injured area of the skin, or a drug in the form of an aerosol may be sprayed onto an inflamed mucus membrane. Drugs may also be locally administered by injection. For example, a dentist may inject an anesthetic into a patient's gums to deaden the pain of a tooth extraction.
Often systemic delivery of a drug is inefficient because only a small amount of the administered dose reaches its site of therapeutic action. In many cases, especially where the toxicity of the drug is low, this inefficiency may be off set by giving the patient a large enough dose of the drug to compensate for its loss while it travels through the patient's body. In some cases, local drug delivery is very difficult, if not impossible, leaving systemic administration as the only viable alternative. For example, if the patient is in need of an antipsychotic drug, injection directly into the brain would not be considered. Perhaps the biggest problem with systemic delivery is that a drug can enter parts of the body where it can actually do harm or produce a noxious side effect.
Since the early days of modern medicine, physicians have sought to replace damaged bone tissue with an artificial material. In many cases the goal has been not merely to replace the bone with a prosthesis, but to provide a matrix upon which new bone tissue could grow. Of course, such a replacement material must be essentially nontoxic and nonallergenic, relatively stable in physiologic environments, and mechanically strong, but it should also bind to living tissue. Many polymeric and noble metal materials have been used as bone replacement materials with limited success rates. Generally, living tissue does not bind well, if at all, with these relatively inert materials, which has limited their successful use.
In recent years, more biologically active, “bioactive,” materials have been developed to which living bone tissue binds well. In particular, certain inorganic, that is, ceramic, glass and ceramic-glass, materials with relatively high bioactivity are now available. These inorganic materials can be made with a porous structure which supports new bone tissue. Ideally, the living tissue grows on and into the replacement material to ultimately incorporate the material into a new bone structure. See U.S. Pat. Nos. 4,159,358; 4,234,972; 4,103,002; 4,189,325; 4,171,544; 4,775,646; 4,857,046; and 5,074,916 (all incorporated herein by reference) for information on ceramic-glass bioactive materials.
These bioactive materials have been shown to develop a strong bond with hard tissue because of a series of ion exchange reactions between the implant surface and body fluids that result in the formation of a biologically active calcium phosphate film at the implant tissue interface. See Hench et al,
J. Biomed. Mater. Res.,
Vol. 5, pp. 117-141 (1971), and Hench et al,
J. Biomed. Mater. Res.,
Vol. 7, pp. 25-42 (1973). Bio-active glasses have also been shown to form firm bonds with soft tissue. See Wilson, et al,
J. Biomed. Mater. Res.,
Vol. 15, pp. 805-817 (1981); Wilson and Merwin,
J. Biomed. Mater. Res.: Applied Biomaterials,
Vol. 22, No. A2, pp. 159-177 (1988); and Wilson, Low et al,
Biomaterials and Clinical Applications,
Ed. By Pizzoferrato et al, Elsevier Science Publishers B.V., Amsterdam (1987). Many of these inorganic materials are biodegraded at a slow rate, so that in time, the replacement material disappears leaving natural bone structure in its place.
In conjunction with implantation of biologically active materials, parenteral or oral administration of beneficial drugs, e.g., antibiotics, hormones, and hormone-like material, have been demonstrated to enhance formation of new bone and to prevent infection, with varying degrees of success. However, the systemic delivery of such drugs results in distribution of the drugs to sites where their effects are not required and where they may do harm. Further, local administration has been difficult and not practical.
The physical mixing of antibiotic drugs either in free drug form (Otsuka, et al.
Bioceramics,
5, 241 (1992)) or in the form of pulverized binder containing antibiotic tablets with the bone substitute, results in uneven biological activity and nonuniform release (Otsuka, et al.
Chem. Pharm. Bull.,
40, 3346 (1992)). In particular, in cases where a drug has been uniformly mixed with ceramic-glass and implanted to form a matrix onto which new bone can grow (for example see, U.S. Pat. No. 5,591,453), the concentration of the drug rapidly rises to a therapeutic range. Unfortunately, the concentration of the drug continues to rise, exceeding the therapeutic range and entering the potentially toxic range. As metabolism and diffusion take effect, the concentration of the drug drops back into the therapeutic range but continues to drop. The concentration of the drug rapidly becomes sub-optimal and its therapeutic benefit is lost. Although there are no reports of a hormone being mixed directly with ceramic glass in lieu of an antibiotic drug, it is logical that the changes in hormone level would follow a similar pattern.
The object of the present invention is to provide a particulate, biologically active ceramic-glass impregnated with one or more therapeutically beneficial drugs in a microencapsulated form and capable of releasing the drugs at a controlled, predetermined rate. The ceramic-glass may act as a bone substitute or a depot for the therapeutically beneficial drugs to be released for systemic or local treatment.
SUMMARY OF THE INVENTION
An aspect of the present invention is a particulate, biologically active, ceramic-glass material in conjunction with one or more microencapsulated therapeutically beneficial drugs, capable of releasing the drugs at a predetermined rate when placed in a physiological environment, either in bone or soft tissue. This impregnated biologically active, ceramic-glass material is referred to as “ceramodrug matrix”.
A second aspect of the present invention is a method for preparing the ceramodrug matrix of the first aspect comprising the follow
Greenspan David C.
Litkowski Leonard J.
Thut Paul D.
Burns Doane Swecker & Mathis L.L.P.
Thut Paul D.
Webman Edward J.
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