Preparation of Implants

Materials :
Although many polymers can by used to prepare rate-limiting membranes for controlled release relatively few are employed for implantation purpose because in addition to being a good rate-limiting barrier the polymer should also be biocompatible and sterilizable. Implantable polymers can be classified into biodegradable and nonbiodegradable polymers. Several nonpolymeric materials such as fatty substances (e.g. cholesterol) and metals (e.g. titanium, stainless steel 316) may be used in implantation devices.

Silicone polymers
Silicone polymers are among the most widely used polymers in controlled drug delivery. They provide several advantages such biocompatibility ease of fabrication resistance to heat sterilization and high permeability for many lipophillic drugs. They are available in polymer form or as multicomponent system to be polymerized in situ. Depending on the components  different degrees of elasticity can be conferred upon the polymer matrix.

Therapeutic products prepared with silicone elastomers include Norplant a subdermal implant to deliver levonorgestrel for contraception a dual-release vaginal ring and certain Transdermal patches.

Polyethylene-vinyl acetate
Ethylene vinyl acetate (EVAc) copolymers gave been used for many investigational and commercial devices. The vinyl acetate of the copolymer can vary from very small amounts to 40%. Increasing the vinyl acetate content increase elasticity permeability and glass transition temperature and reduces crystalline. The polymer is being used in the Alza ocular insert (Ocusert) and in IUD reservoir-type systems (Progestasert).

Cellulose acetate
Cellulose is naturally occurring and one of the most abundant organic polymers. Although various cellulose derivatives are used in controlled drug delivery devices application to implants is usually restricted to cellulose acetate. Cellulose acetate is formed by the acetylation of the hydroxyl groups in he glucose backbone. This acetylation increases water sorption by the polymer and at about 13% acetylation the polymer is water-soluble. A further increase in acetylation increase hydrophobicity. The polymer becomes insoluble at around 19%acetylation: water sorption decreases with further acetylation. Commercial cellulose acetate is available with 36 to 43 % acetylation. Because of their high water permeability and low salt permeability cellulose acetate membranes have been used extensively in the Alzet osmotic pumps.

Processes:
Processes used in manufacturing these devices depend on the type. In any case implants need to be sterile and therefore they are prepared aseptically or under reduced bioburden and then sterilized most commonly using gamma radiation.

Traditional steroid implants are prepared by compressing large crystals of drug under high pressure or by the solidification of molten drug in cylindrical molds. Diffusion-controlled polymeric devices can be prepared by a variety; of techniques. Membrane type polymeric devices may be prepared by coextrusion of the drug core and the polymeric membrane as in the case of silicone capsules. Spherical membrane-coated devices are prepared with conventional pharmaceutical coating equipment such as a pan coater or a Wurster coating apparatus, Many specialized techniques gave been developed for coating microcapsules. Matrix-type devices are simpler to prepare: techniques include compression under high pressure with or without heat solvent casting of drug dispersion in polymer solution meltextrusion and in situ polymerization.

Testing:
Besides sterility drug content and content uniformity implants need to be evaluated for the rate of the drug release. Several in vitro release-testing procedures are used for this purpose. The shaking-flask technique or its minor modifications are commonly used. The implant is placed inside a screw-capped flask-containing buffer at physiological pH and ionic strength. The flask is placed in water bath at 37 degree centigrade oscillating at a low speed to provide mild agitation. Periodically samples are removed from the flask and the buffer is replenished. The samples are analyzed for the cumulative amount of drug released.

A major disadvantage of this technique is that for poorly soluble drugs frequent replenishing of the entire medium is necessary in order to maintain sink conditions. Another disadvantage is that with chemically unstable drugs significant drug activity can be lost before sampling. Modifications of this technique include the incorporation of ethanol in the dissolution medium to increase to solubility of poorly soluble drugs and shortening the in vitro duration of drug release.

A flow-through cell system provides an alternative to the shaking-flask technique while minimizing the above-mentioned disadvantages. In this system the implant is placed in a flow cell maintained at 37 degree centigrade. The dissolution medium is gently perused through the flow cell and the perfused is collected by a fraction collector for subsequent analysis or passed through on line detectors for immediate analysis of drug content. Hollenbeck successfully utilized the above concept for determining the release rate from polyanhydrides implants containing 1.3-bis (2-chloroethyl-1-nitrosourea (BCNU), a water-unstable drug. Both the rate of drug and monomer release was monitored using the above technique. An added advantage is the extensive characterization of release profiles and possibilities for complete automation of the release studies. For a methotrexate microsphere formulation in biodegradable polyanhydrides good correlation was observed between in vitro release profiles obtained using the flow-through cell system and in vivo drug levels.

Regulatory assessment
All novel drug delivery systems are considered new drugs requiring complete new drug applications as a basis of approval. Besides the safety and efficacy demonstration plasma-blood level variation and drug pharmacodynamics need to be established. Establishment of the reproducibility of release, both in vivo and in vitro demonstration of the absence of dose dumping and a well-defined pharmacokinetic profile to support drug labeling is needed.