Injectable implant

Details Injectable implant Injectable implant

1999-08-16

2001-10-16

Azpuru, Carlos (Department: 2165)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C514S772300

Reexamination Certificate

active

06303137

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
REFERENCE TO A “MICROFICHE APPENDIX”
Not applicable.
1. Field of Invention
This invention relates to an in-situ implant that can be produced by placing a sterile, injectable, and water-insoluble complex from a biodegradable polymer and a biocompatable polyether with functional end-groups in the organism, and coagulating them under the influence of the body fluid.
2. Description of the Related Art
Known implants for applying bioactive substances consist of microparticles or are produced by pressing under aseptic conditions. The commercial preparation Zoladex® is an example of a pressed implant. This implant causes considerable pain at the place of application. Similar disadvantages can be found with th epreparatoins injected in the form of microparticles such as Parlodel®, Profact® Depot, Enantone®-Gyn one-month depot, and Decapeptyle Gyn.
The most common manufacturing process for microparticles or microspheres is the solvent evaporation technique that uses organic solvents that are toxic for the living organism.
The solvent evaporation technique uses an emulsion of a biodegradable polymer from which the solvent is gradually removed. Suitable solvents such as methylene chloride [Hora, M. S. et al., Bio/Technology 8(1990), pp. 755-758; Bodmeier, R. et al., Pharm. Res. 12 (8/1995), pp. 1211-1217; Lu, W. Q. et al., Biotechn. Prog. 11 (2/1995), pp. 224-227; Cohen, S. et al., Pharm. Res. 6 (8/1991), pp. 713-720], mixtures of methylene chloride and methanol [Mehta, R. C. et al., J. Contr. Rel. 29 (1994), pp. 375-384], dichloromethane [Kissel, T. et al., J. Contr. Rel. 39 (1996), pp. 315-326], or chloroform [Hayashi, Y. et al., Pharm. Res. 11 (2/1994), pp. 337-340] are at least physiologically risky. The biodegradable polymer is also dissolved in solvents such as methylene chloride when the spray drying method is used [Bodmeier, R. et al., Pharm. Res. 12 (8/1995), pp. 1211-1217] and subsequently converted into the solid form with the bioactive substance in a spray process. A joint disadvantage of both manufacturing processes for microparticles is their content of residual solvent. In addition, the spray drying method requires a large amount of chemical engineering equipment.
U.S. Pat. No. 4,938,763 describes the manufacturing of implants formed in situ. The process described therein starts with dissolving biodegradable polymers such as polylactides and polylactide co-glycolides in a solvent. This solution is injected. When it comes into contact with body fluid, a solid implant is formed that consists of the precipitated biodegradable polymer and the bioactive substance while the solvent completely leaves the implant and is dissipated in the organism. Solvents named are ethanol, propylene glycol, ketones, and others. A disadvantage of this method, however, is that the solvents listed are physiologically active and can therefore be applied parenterally to a limited extent only. Furthermore, a method for producing implants formed in situ is described according to which a solution of monomers or oligomers (prepolymers) is injected with an admixture of starter substances and/or catalysts. After the injection the ingredients become a biodegradable polymer. With this method, highly reactive substances have to be used to start polymerization, and these are toxic.
According to Eliaz et al. [Proc. 3rd Jerusalem Conference to Pharmaceutical Sciences and Clinical Pharmacology, Sep. 1-6, 1996] the same method can be used to produce an implant formed in situ if glycofurol is used as low-molecular solvent for homo- and copolymers of polylactic acid. The implants produced in this way are particularly suited for proteins. The protein-containing solutions are low-viscous and can be injected easily. Glycofurol can be mixed with water and is physiologically relatively harmless.
During the process of in-situ forming, the glycofurol is immediately drained off with the watery environment. This can have an adverse effect on the release of the active ingredient from the implant. Studies have confirmed this result.
U.S. Pat. No. 3,887,699 describes a method for producing implants for subcutaneous application which consists in forming formed balls on the basis of polylactic acid homopolymers or copolymers with glycolic acid of a sufficiently high molecular weight and an active ingredient. The integrity of the balls produced is retained for a long period after implanting, and release of the active ingredient is delayed. Suitable active ingredients mentioned are steroids that act as contraceptives.
A major disadvantage of these particles containing active ingredients is their production using the solvent evaporation method and organic solvents (chloroform). The risks that residual solvents hold were mentioned above.
U.S. Pat. No. 3,773,919 describes a similar method. It says that pharmaceutic depot formulations that release adequate quantities of active ingredient parenterally and in a controlled way can be produced easily if the depot of active ingredient is greater than an individual dose and if there is a homogeneous mixture of polylactic acid and active ingredient at a ratio of 1 to 99 each. The active ingredient in this case should be an substance acting on the endocrine system or a fertility-controlling substance.
It is a disadvantage of this method that the solid particles have to be suspended in a saline solution or in a pharmaceutically suitable oil before they can be injected. Homogeneity problems of these suspensions have to be expected.
WO-9517901 describes a cytostatic composition that can be injected into lesions. It contains the cytostatic in a matrix consisting of a fatty acid that cannot be mixed with water.
This composition has the benefit that it is flowable to an extent that it can be injected. But the extended action of the cytostatic is caused by the viscosity of the matrix. The viscosity of the matrix, however, is an unreliable parameter as it may vary depending on the quantity of body fluid available. It is further known that fatty acids are biocompatible to a limited extent only and may damage the tissue.
WO-9103491 describes a matrix based on protein that is to effectively inhibit cell proliferation. It either contains a collagen or a fibrinogen.
This matrix requires smaller quantities of protein as compared to conventional systems. The disadvantages of this invention are that the release of the active ingredient cannot be controlled by the composition of the matrix, and that a vasoconstrictor is required for retardation.
EP-0341007 refers to a method for producing an adhesive formed in situ that coagulates with the wound plasma by contacting the collagen-containing agent.
The advantage of this method is that it acts immediately after administration by forming the coagulate that results in wound closure. This technique, however, can only be applied to dermal preparations during and after surgery and does not include the incorporation of active ingredients.
EP-0328389 describes a method of injecting a macromolecular matrix using vinca alkaloids for the treatment of intracranial tumors.
The macromolecular matrix on a protein base enhances the drift of the alkaloid away from the injury, thereby ensuring high levels of local efficacy. It is disadvantageous, however, that a vasodilator has to be added for this effect, so that control of local efficacy remains to be a problem.
A similar situation is found in WO-8902734. This invention deals with a pharmaceutical vehicle that administers vasoconstrictors and cytotoxically acting substances for the treatment of neoplastic injuries.
This vehicle, however, requires modifiers that modify the cell structure to change cell permeability.
According to U.S. Pat. No. 4,619,913 a collagen- or fibrinogen-containing matrix can be produced that forms an amorphous flowable mass in an aqueous medium which enables the treatment of neoplastic injuries or the surrounding tissue.
This technique is to prevent the active ingre

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