Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-09-22
2002-05-21
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S499000, C424S422000, C424S423000, C424S425000, C424S426000, C424S451000, C424S457000, C424S464000, C424S484000, C424S488000, C424S489000
Reexamination Certificate
active
06391336
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the production and use of inorganic-polymer complexes for the controlled release of compounds including medicinals.
BACKGROUND OF THE INVENTION
Systemic antibiotic treatment is often unsatisfactory in cases of osteomyelitis as well as infections in devitalized tissue, avascular scar tissue, and other areas with insufficient blood supply. Increasing blood levels of antibiotics can result in toxicity. For example, aminoglycosides can produce ototoxicity and nephrotoxicity. Another problem with long-term systemic treatment with antibiotics is the selection of drug-resistant mutants. In poorly vascularized areas, the infectious organism may encounter concentrations below the minimum lethal concentration which provides the opportunity for selection of a resistant form. Also, in large-animal veterinary practice, the cost of the antibiotic for systemic use can be an issue.
Antibiotic formulations of polymethylmethacrylate have been employed as antiseptic bone cement and as beads either free or attached to a wire which is used for percutaneous removal [H. W. Bucholz, et al,
Chiburg
, 43, 446 (1970)]. PMMA is not bioerodible.
An alternative is plaster of Paris (POP) which has been used without matrix biopolymers or medicinal complexing agents as CaSO
4
.1/2H
2
O [D. Mackey, et al,
Clin. Orthop
., 167, 263 (1982); and G. W. Bowyer, et al,
J. Trauma
, 36, 331 (1994)]. Polymethylmethacrylate and POP have been compared with regard to release profiles. Release rates from POP tend to be very fast.
Both polymethylmethacrylate and POP can be used to produce dimensionally stable beads and other structures. The acrylate cements or beads are formed by mixing pre-formed polymethylmethacrylate polymer, methylmethacrylate monomer, and a free-radical initiator. An exothermic reaction ensues which results in matrix temperatures as high as 100° C. Many antibiotics such as polymyxin and tetracycline are inactivated by these conditions [G. J. Popham, et al,
Orth. Rev
., 20, 331 (1991)]. As mentioned above, polymethylmethacrylate is biocompatible but not resorbable. Therefore, beads used to treat local infection must be retrieved by surgery which is accompanied by the risk of reinfection.
POP beads or pellets are resorbable but show inferior drug release profiles [G. W. Bowyer, et al,
J. Trauma
, 36, 331 (1994)].
Compositions containing hyaluronic acid have been used for topical administration of pharmacological substances [F. Della Valle, et al, U.S. Pat. No. 5,166,331 and U.S. Pat. No. 4,736,024].
OBJECTS OF THE INVENTION
It is an object of the invention to provide a safe resorbable delivery system which enables controlled release of medicinals.
It is an object of the invention to provide a delivery system with controllable setting time.
It is a further object of the invention to provide a delivery system which is an injectable liquid which solidifies in a timely way once in place.
SUMMARY OF THE INVENTION
The subject invention relates to a delivery system comprising:
a) an inorganic compound capable of undergoing hydration and/or crystalization, and
b) a matrix polymer, and/or
c) a complexing agent.
In another embodiment, the system comprises a complexing agent and a medicinal. Included within the invention are methods of producing sustained release of a medicinal in a mammal by administering the system with a medicinal to a mammal. A still further embodiment of the invention is a method of diagnosing disease in a mammal by administering a radiopaque matrix to the mammal.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention relates to a resorbable matrix with favorable release kinetics. Inorganic compounds such as CaSO
4
.1/2 H
2
O can be combined with biopolymers in the presence of a bioactive agent including medicinals to produce a matrix.
In addition to the inorganic compound there are:
(i) a matrix polymer, and/or (ii) a complexing agent. As used herein, the term “matrix polymer” refers to a polymer (often a biopolymer) which serves to control the erosion rate, setting time, and influences the release profile by raising the viscosity of the medium in the pores and channels of the delivery system. As used herein, the term “complexing agent,” refers to an agent (often a biopolymer), which is used to form a salt or conjugate with the active agent which in effect raises the molecular weight of the active agent and lowers its rate of efflux. The complexing agent is typically a small molecule capable of aggregation which has affinity for the active agent. Pharmacologically acceptable hydrophobic medicinal complexing agents include proteins such as albumin, lipids or cyclodextrins which can be used to complex neutral medicinal molecules or charged molecules which contain an apolar moiety. Liposomes containing a medicinal can be entrapped within the calcium sulfate matrix.
The reaction scheme for forming a matrix including a medicinal is shown below:
The consistency and viscosity of the slurry is dependent on the amount and nature of the matrix biopolymer. The slurry can be injected with subsequent formation of a solid in vivo.
A medicinal can exist in the inorganic-biopolymer complex either free or complexed to the medicinal complexing agent. The free compound is released relatively fast. The complexed medicinal is released relatively slowly often contingent on the bioerosion of the inorganic-biopolymer complex. Antibiotics and local anesthetics are used to illustrate this principle:
The resorbable inorganic-biopolymer complex can contain free antibiotic (e.g., as the sodium salt) or in the form of a biopolymer complex with a polycation such as polylysine or polymyxin B. Lidocaine is conveniently employed as the hydrochloride, the free base, or complexed as the salt of chondroitin sulfate or polyglutamate.
I. General Considerations
The delivery system of the subject invention for use with medicinals must meet the following requirements:
1. Safety—non-toxic, non-immunogenic, non-pyrogenic, non-allergenic.
2. Resorbablility—all components should be either assimilable or readily excreted.
3. Stability—the matrix should be sterilizable and precursors should have an acceptable shelf-life. Cast forms should be dimensionally stable.
4. Compatibility—the materials and the preparative conditions should not alter the chemistry or activity of the medicinal.
5. Programmability—the residence time and release profile should be adjustable.
There are typically two or three components in the inorganic-polymer complex matrix
1. An inorganic compound, for example, CaSO
4
.1/2H
2
O
2. Matrix polymer, for example, hyaluronic acid or dextran
3. Complexing agent, for example, chondroitin sulfate, polylysine, or cyclodextrin.
Inorganic Compounds
Calcium sulfate.1/2H
2
O (hemihydrate) is the preferred inorganic component. The hemihydrate takes up water and crystallizes as the higher hydrate. Unadulterated calcium sulfate matrix exhibits poor drug release profiles. With matrix polymers and complexing agent-active agent complexes the release profiles are improved. Other inorganics may be employee such as calcium silicates, aluminates, hydroxides and/or phosphates (see pages 72, 95, 327 in Reference Book of Inorganic Chemistry (1951) Latimer, W. H., and Hildebrand, J. M., Macmillan, New York, hereby incorporated by reference in its entirety).
The inorganic compound goes from slurry to solid in a reasonable time period, i.e., 10 minutes-two hours. The matrix biopolymer influences the setting time and the release profile.
Polymers
In order to slow the efflux of active agent, e.g., medicinal, from the dosage form, polymers, often biopolymers, are included in the matrix to raise the viscosity. Hyaluronic acid (e.g., 1-5%), proteins, e.g., collagen (gelatin), fibrinogen, which form viscous solutions (e.g.,1-30%), and dextran (e.g., 1-50%) are examples. Viscosity can be changed as a function of time. Hydrolytic enzymes such as a protease, can be included to lower the viscosity as a function of time to speed the efflu
Geist Gary
Nixon & Vanderhye P.C.
Royer Biomedical, Inc.
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