Pharma Tips

Pharmaceutical Implants

By: Pharma Tips | Views: 6938 | Date: 14-Jun-2010

In 1861 Lafarge first introduced the concept of implantable systems for sustained drug administration. The concept was later used to produce solid implants containing steroid hormonoes.initiating the use of implantable system for long- term delivery.these traditional pharmaceutical pellets consisted of pure drug with no added excipient and were defined as small. Rod shaped or ovoid shaped.

1. INTRODUCTION
In 1861 Lafarge first introduced the concept of implantable systems for sustained drug administration. The concept was later used to produce solid implants containing  steroid hormonoes.initiating the use of implantable system for long- term delivery.these traditional pharmaceutical pellets consisted of pure drug with no added excipient and were defined as small. Rod shaped or ovoid shaped. sterile tablets consisting of the highly purified drug. usually compressed without excipient. Intended for subcutaneous implantation in body tissue. The devices thus prepared had a high degree of hardness and virtually zero porosity. since water did not penetrate the matrix, drug release occurred principally by surface dissolution. Due to the inherently poor solubility of steroid drugs. this method provided a good form of depot medication. There are still a few of the traditional implants in commercial use. including desoxycorticosterone acetate (percorten pellet. Ciba) . and estradiol and testosterone (Progynon and Oerton pellets. respectively . Schering).
 
Pharmaceutical Implants
 

Pharmaceutical Implants


For incorporation of a variety of therapeutic agents with different physicochemical properties and for better control of drug release a limited number of excipient is now used. Thus more recent implants usually contain the drug in a rate controlling systems. These systems are available in a variety of sizes and shapes. Some of the recently approved implantation products include leuprolide acetate and nafarelin acetate in biodegradable dl-lactic and glycolic acidc copolymer for one-month release (Lupron depot micro spheres. TAP and Zoladex pellot ICI, respectively). Also new on the market is a silicone polymer capsule system containing levonorgestrone for five year contraception (Norplant. Wyeth-Ayerst). In addition, several implantable pumps for prolonged  drug delivery are in commercial use. With rapid advances in  implantation therapy and excipients to control the release pattern, the USP XXII identifies a much broader definition of implants, recognizing the presence of excipients and implantation in the body at sites other than subcutaneous.


1.1 ADVANTAGES AND DISADVANTAGES OF IMPLANTATION  THERAPY
Implants possess several advantages, but also disadvantages, as drug delivery systems depending on the nature of the drug being delivered. A brief overview of both the advantage and disadvantages of implantable drug delivery is given below.

Advantages:
The advantages of implantation therapy include.
Convenience:- 
Effecting drug concentrations in the bloodstream can be maintained for long periods by methods such as continuous intravenous infusion or frequent injections. However, under these regimens patients are often required to stay in hospital during administration for continuous medical monitoring. A short-acting drug exacerbates the situation, as the number of injections or the infusion rate must be increased, in order to maintain a therapeutically effective level of the drug. In contrast, implantation therapy permits patients to receive medication outside the hospital setting with minimal medical surveillance. Implantation therapy is also characterized by a lower incidence of infection related complications in comparison to indwelling catheter-based infusion system

Compliance: 
By allowing a reduction, or complete elimination, of patient-involved dosing compliance is increased immensely. A person can forget to take a tablet, but drug delivery from an implant is largely independent of patient input. Some implantable systems involve periodical refilling but despite this factor the patient has less involvement in delivering the required medication.

Potential for controlled release:-
Implants are available which deliver drugs by zero-order controlled release kinetics. Zero order controlled release offers the advantages of

(a) Avoiding the peaks (risk of toxicity) and troughs (risk of ineffectiveness) of conventional therapy;
(b) Reducing  the dosing frequency;
(c) Increasing patient compliance.

Potential for intermittent release:
Externally programmable pumps can facilitate intermittent release. Intermittent release can facilitate drug release in response to such factors as :

(a) Circadian rhythms;
(b) Fluctuating metabolic needs;
(c) The pulsatile release of many peptides and proteins.

Potential for bio-responsive release:
Bio-responsive release from implants is an area of ongoing research.

Improved drug delivery: 
Using an implant system the drug is delivered locally or to be systemic circulation with minimal interference buy biological or metabolic barriers. For example, the drug moiety by passed the gastrointestinal tract and the liver. The bypassing effect is particularly of benefit to drugs, which are either absorbed poorly or easily inactivated in the gastrointestinal tract and/or the liver before systemic distribution.

Flexibility: 
Considerable flexibility is possible with these systems, in the choice of materials, methods of manufacture, degree of drug loading, drug release rate  etc.

Commercial an implantable dosage form diversifies the product portfolio of a given drug. From a regulatory perspective, it is regarded as a new drug product and can extend the market protection of the drug for an additional 5 years (for a new drug entry) or 3 years (for existing drugs)

Disadvantages: 

The disadvantages of implantation therapy include such factors as:

Invasive: 
Either a minor or a major surgical procedure is required to initiate therapy. The requires the appropriate surgical personnel, and may be traumatic, time-consuming. Cause some scar formation at the site of implantation and in a very small portion of patient may result in surgery-related complications. The patient may also feel uncomfortable wearing the device.

Termination: 
Non-biodegradable polymeric implants and osmotic pumps also be surgically retrieved at the end of treatment. Although a biodegradable polymeric implant does not require surgical retrieval. its continuing biodegradation makes it difficult to terminate drug delivery. or to maintain the correct does at the end of its lifetime.

Danger of device failure: 
There is no concomitant danger with this therapy that the device may for some reason fail to operate. which again requires surgical intervention to correct.

Limited to potent drugs : 
The size of an implant is usually small. in order to minimize patients discomfort. Therefore most systems have a limited loading capacity so that often only quite potent drugs such as hormones. May be suitable for delivery by implantable devices.

Possibility of adverse reactions: 
The site of implantation receives a high concentration of the drug delivered by an implant. This local high drug concentration may trigger adverse reactions.

Biocompatibility issues: 
Concerns over body responses to a foreign material often raise the issues of biocompatibility and safety of an implant.

Commercial disadvantages: 
Developing an implantable drug delivery system requires an enormous amount of R&D investment in terms of cost, effort and time. If a new biomaterial is proposed to fabricate an implant its safety and incompatibility must be thoroughly evaluated to secure the approval of regulatory authorities. These issues can attribute to significant delay in the development marketing and cost of a new implant.


1.2 MECHANISM OF DRUG RELEASE FROM IMPLANTABLE DEVICES
Drug release from most implantable devices is controlled by any one of six different mechanisms discussed below. Although an attempt is made here to cover the most importable types it is not possible to cover all the mechanisms under investigation.

Diffusion controlled
These devices are based on Flick’s law of diffusion which states the rate of transfer of a diffusing substance through unit area of a section. In this case the rate of release is controlled by diffusion of drug through a polymeric membrane. In general nonerodible diffusion-controlled drug delivery system work best for drugs with molecular weight of 1000 Daltons or less. Domb et al have shown that the essential parameters affecting permeability of peptides through a hydrogel are the volume of solute and the water content of the membrane which are correlated to its pore size. Diffusion-controlled devices can be further classified into membrane-permeation controlled matrix-controlled and micro reservoir-dissolution controlled.

Membrane-permeation controlled
In membrane-permeation controlled devices the drug reservoir is surrounded by a membrane (coating) and because of the presence of he two distinct drug-reservoir and membrane phases these are known as heterogeneous devices when the device containing a highly hydrophilic drug is placed in the aqueous dissolution medium water penetrates the coating and dissolves the drug and the concentrated drug solution diffuses out through the polymeric membrane. The release rate of the drug is controlled by the diffusion rate of drug solution through the polymeric membrane. The rate of drug release dM/dt through a spherical membrane-permeation controlled system with saturated reservoir is given by equation.

DM/dt = 4DK(C1 – C2) ab / b-a………….(1)

Where, D is the diffusivity of drug unit thickness of polymer k is the partition coefficient (ratio of solubility of drug in the polymer divided by the solubility of drug in the surrounding medium) of drug across the polymer membrane c2 is the concentration of drug inside the sphere c2 is the concentration of drug in the surroundings a is the inner radius of the coat and b is the outer radius of the coat.
Mathematical models describing the effect of device geometry on the release pattern have been developed. An important advantage of the reservoir system as shown by eq. (1), is that at steady state zero-order drug release is possible. It the drug elimination rate is constant during therapy, a constant drug-plasma level may be achieved. On the other hand any disruption or crack in the membrane could lead to the release of a large amount of drug (dose dumping) with possible toxic effects in the patient. Furthermore reservoir systems are generally more expensive to manufacture.
Diffusion-controlled reservoir systems can also be based on a biodegradable polymer. In this case, the drug is encapsulated in a biodegradable polymer and the release rate is determined by the principles governing membrane-permeation controlled systems. Only after the entire drug is exhausted from the device does the polymer undergo significant erosion and eventually dissolves.
Currently marketed and approved membrane reservoir systems for implantation therapy include the Ocusert an ocular insert for controlled pilocarpine release for the treatment of glaucoma; Progestasert. a T-shaped contraceptive intrauterine device the controlled progesterone release and Norplant which is comprised of six small injectable cylinders for controlled release of levonorgestrone for contraception.

Matrix controlled
In matrix-controlled devices the drug is uniformly distributed (dissolved of dispersed) throughout the polymer and hence these are known as homogeneous devices. In the presence of dissolution medium drug at the surface dissolves first and is released in the dissolution medium. In many cases the dissolved drug creates a depletion boundary separating the empty or drug-depleted polymer from the drug-loaded polymer matrix. Water penetrates the channels and a pore created by drug depletion and dissolves the drug
at the depletion boundary. The drug release rate is controlled by the diffusivity barrier provided by the empty matrix which increases in thickness with time. This increased thickness results in a decrease in drug release rate with time. For a matrix system that is exposed to the dissolution medium on all the sides the surface area of the inward-moving depletion boundary decrease resulting in a decrease I in drug release rate which depends on the device-geometry.

Mathematical equation describing release have been reported which predict that in general the drug release rate is expected to decrease with time. In case of damage to the device though the drug release rate may increase slightly significant dose dumping is not expected. Therefore these devices have a safety design superior to that of the membrane-controlled system. Furthermore matrix systems are less expensive to manufacture. It has been shown that manipulation of the shape or drug distribution may allow a constant delivery rate.

Microreservoir dissolution-controlled
In these devices the drug reservoir is made of a suspension of solid drug particles in an aqueous solution of a water miscible polymer forming millions of microscopic drug reservoirs in a polymer matrix. the device is coated with a rate-controlling membrane to further modify the drug release rate. Among the other factors the release rate is dependent on the solubility of drug in the liquid compartment and on the polymer matrix. Mathematical relationships for the control of drug release have been described.

The Syncro-Mate-M implant provides an example of this type of device. It is a cylindrical implant fabricated by dispersing the drug reservoir (a suspension of norgestomer in an aqueous solution of PEG 400) in silicone elastomers. This emulsion is placed into medical-grade silicone tubing and polymerized in situ. The tubing is then cut to obtain a cylinder-shaped device with open ends. This device is implanted subcutaneously in he earflap of livestock for about 20 days delivery of norgestomet for control and synchronization of estrus and ovulation. Other examples include the Nitrodics system and a dual-release vaginal contraceptive ring system.

Chemically controlled
Chemically controlled drug delivery systems regulate the drug release rate by a chemical reaction with the polymer. Their principal advantage is that in contrast to a nonbioerodible system the polymer is dissolved and absorbed by the body and there is no need for surgical removal of the device at the completion of drug delivery. However the fate of these polymeric products in the body must be carefully observed and rigorous testing is required to confirm the safety of the polymer. The two predominant mechanisms for chemically controlling drug release are bioerosion and pendent chain.

Bioerosion
The bioerosion or biodegradation systems (both terms are used interchangeably in this article) involve breakdown of the polymer into small water-soluble molecules. Bioerosion-controlled devices are matrix controlled with uniform drug distribution inside the polymer. As the polymer is broken down water comes in contact with the drug leading to its dissolution and release. Depending on the hydrophilicity of the polymer and device properties such as porosity and the presence of water-soluble components water may penetrate throughout the device or come in contact only with the surface. In the former case polymer erosion starts throughout the matrix; these devices are known as bulk eroding. Although the drug release initially occurs predominantly from the erosion of the polymer from the surface eventually the entire matrix may break down and most of the remaining drug could be released in a burst. On he other hand if the polymer is hydrophobic and water does not penetrate inside the device, erosion occurs only on the surface; these devices can be called surface eroding. The drug release rate from a surface eroding polymeric matrix with uniform drug distribution is given by eq.
dM/dt = KS………………..(2)
Where, K is a constant related to the drug concentration in the matrix and the rate of polymer erosion and S is the surface area of the system. In general, due to erosion of
polymer, the surface area of devices of the most common shapes decreases over time, rate of this decrease is geometry dependent. For systems with a high initial surface are to-volume ratio such as a slab the surface area and hence the release rate, decreases only slightly. On the other hand with devices of spherical geometry where the surface area-to-volume ratio is the lowest the surface area and hence release rate decreases rapidly with time. Therefore, matrix drug-release devices with shapes of slab geometry may provide less deviation in drug release over time than those with spherical geometry.

In practice because of imperfections such as pin holes, the presence of water-soluble drugs and polymer hydrophilicity, bioerodible delivery systems are most commonly bulk-erosion controlled. The drug release from these systems depends on a combination of diffusion bulk erosion and surface erosion, making a theoretical prediction of drug release rate much more difficult. An important advantage of this type of system is that the drug-release profile may be controlled by manipulation of the size and shape of the device amount of drug loading addition of other excipients and the intrinsic degradation rate and molecular weight of the polymer.

Pendent chain
The other mechanism for chemically controlled release of drug is known as the pendent-chain system where the drug is attached to the polymer backbone by a labile chemical linkage. In the presence of water or enzymes the labile linkage breads to release the drug. The pendent chain may be water soluble or insoluble; a water-soluble backbone may serve as a drug carrier to a specific cell or organ where the drug is released by metabolism. Insoluble pendent chains on the other hand serve as a depot from which the drug is slowly released. In either case after completion of the drug release the polymer-drug linkage. Varying the hydrophilicity of the polymer backbone and the device geometry can control the rate of linkage degradation and therefore the drug release. An important disadvantage of this system compared to bioerosion-controlled systems is that
since the drug is covalently linked to the polymer the drug-polymer conjugate may be viewed as a new chemical entity by the regulatory agencies and extensive safety testing may be needed.

Solvent activated
Solvent-activated systems release active agents because of controlled penetration of a solvent into the device; they may be controlled by swelling or osmotic pressure.

Swelling controlled
Swelling-controlled systems are similar to matrix-type devices except that the dispersed drug is immobilized inside a glassy polymer and therefore there is no diffusion of drug. When this device is placed in water the outer polymer region begins to swell, resulting in relaxation of the polymer chains. This allows the otherwise locked drug to diffuse outward. Therefore two fronts are observed: one moving inward, separating the polymer in the glassy stare from the rubbery state and the second moving outward separating the swollen rubbery polymer from the surrounding aqueous medium. The drug release is determined by the rate of relaxation of the chains that unlock the drug.

Osmotically controlled
In one example of an osmotically controlled system an osmotically active agent such as water-soluble salt is placed inside a rigid semi permeable polymer housing, which is separated from the drug compartment by a movable partition. The semi permeable housing draws water inside by osmosis, leading to an increase in volume and exertion of pressure on the movable partition. The partition, in turn pushes the drug out of the compartment through a delivery orifice or cannula. Thus, the drug delivery rate is controlled by the mass movement of water across the semi permeable membrane.

Osmotic pump provide a predictable, zero-order release rate independent of the physicochemical properties of the drug and therefore afford an excellent means of
evaluating effects of long-term, zero-order administration into animals. Alza corp. markets several implantable osmotic pump devices. Alzet osmotic pumps have been extensively evaluated for local as well as systemic drug delivery in may animal models. Delivery rates from these pumps range from 1 to 10 L/h, and a release duration from three days to four weeks. The smallest of these osmotic pump, model 10003d, weighs about 350 mg and is designed for small research animals, weighing about 20 g. although these pumps are very useful in providing constant drug release in animals, they have found minimal therapeutic application in humans because of the need for surgical implantation and removal lack of external regulation and in situ refillability. However a variation of the osmotic pumps where a drug or and osmotically active agent is surrounded by a semi permeable membrane containing a single laser-drilled hole (the OROS system is being used for oral delivery of drugs such as phenylpropanolamine (Acutrim, Ciba0 and nifedipine (pericardia-XL, Pfizer)

Externally regulated
These systems have the important advantage that the drug-delivery rate cat be externally increased on demand even after the device has been implanted. Four predominant techniques have been evaluated with externally modulated implant: magnetically controlled ultrasonically activated thermally activated and electrically controlled.

Magnetically controlled
In magnetically controlled drug-delivery systems the drug and magnetic beads are uniformly dispersed inside semi elastic polymer matrix made of a nonbiodegradable polymer such as ethylene-vinyl acetate copolymer (EV Ac). When the device is placed in a dissolution medium the drug release follows matrix diffusion control. However, when the device is placed in a magnetic field, the magnetic beads attempt to a align with the applied magnetic field including a torque on the magnet and a slight rearrangement of the polymer. In an oscillating magnetic field, the beads tend to oscillate compressing and expanding the polymer in the process. This is proposed to result in a pulsatile flow of the
dissolution medium through the pores in the elastic polymer and along the concentration gradient of the drug resulting in an increase in the drug-release rate. This effect of the oscillating magnetic field is further enhanced by an increase in polymer elasticity (e.g., by increasing the vinyl acetate content) and the frequency and strength of the magnetic field.

Ultrasonically activated
In these systems the drug is uniformly distributed inside a polymer and an external ultrasonic field is applied to activate drug release. They have been evaluated for both nonbiodegradable polymers (EVAc) and biodegradable polymers [polyesters, polyanhydrides, polyglycolides, polylactides and sebacic acid]. In the case of biodegradable polymers application of ultrasound increased the drug release as well as the polymer degradation rate. It is believed that the cavitation induced by the ultrasonic waves may be partially responsible for this effect as reduced polymer degradation and drug release was observed in a degassed buffer. In both the biodegradable and nonbiodegradable polymer systems the drug release rate was controlled by the intensity frequency and duration of the ultrasound.
For in vivo evaluation devices made of EVAc and insulin or polyanhydrides and p-amminohippurate were implanted in rats and an ultrasonic applicator head was placed over the treated area for the delivery of ultrasonic waves to the implant. The rate of drug delivery was increased with no histologically detectable damage to the rat skin.

Thermally activated
A series of thermosensitive hydrogels that show significant swelling changes in water in response to temperature have been prepared and evaluated. These polymers respond to temperature change based on the Flory-Huggins theory that a change in temperature affects hydrogen bonding which, in turn, affects swelling. A linear correlation is observed between the diffusion coefficient for entrapped drug and polymer swelling. Based on their origin by thermosinsitive interaction these polymers can be classified into those base on polymer-water interactions and those based on polymer-polymer interactions.
In the first group, a series of poly (N-alkyl substituted acrylamides) have been evaluated for the effect of cross-linking density on the temperature dependence of swilling. At low temperatures the polymer is in an unswollen state due to the increased hydrogen bonding interaction. This swilling leads to increased solute diffusion and hence drug release. Thus thermosensitivity of the polymer network has been shown to primarily due to polymer-water interactions and hydrophobic interactions of the side groups.

In the second group two interacting polymers with repulsive or attractive polymer-polymer interaction are combined to form a hydrogel. With an increase in temperature, swilling increases as the polymer responds not only to the polymer-water interactions but also to increased polymer-polymer interactions.

Hoffman demonstrated the applicability of hydrogels based on N-isopropylacrylamide (NIPAAm) or N-isopropylacrylamide-methacrylic copolymers with methylenebis (acrylamide) (MBAAm) in providing temperature-responsive release of vitamin B12. By manipulation of temperature, pulsatile release of Indomethacin and insulin has been reported.

Electrically controlled
Electrically controlled systems provide drug release by the action of an applied electric field on a rate-limiting barrier membrane or a solute thus modulating its transport across it. Grimshaw reported four different mechanisms for the transport of proteins and neutral solutes across hydrogel membranes:
Electrically and chemically induced swelling of a membrane to alter the effective pore size and permeability
Electrophoretic augmentation of solute flux within a membrane
Electroosmotic augmentation of solute flux within the membrane and
Electrostatic partitioning of charged solutes into charged membranes.

Propanolol hydrochloride delivery devices containing a drug reservoir with a pair of electrodes placed across a poly (2-hydroxyethyl methacrylate) (PHEMA) membrane, cross-linked with ethylene glycol (1 % v/v) have been evaluated for modulated drug delivery. Controlled and predictable propranolol hydrochloride release in response to the electric field was observed with a linear relationship between current and propranolol hydrochloride permeability. Variables for this mechanism have been extensively evaluated for Transdermal delivery (iontophoresis) systems.

Self-regulated
These are biofeedback-controlled system, where the drug release rate is dependent on the body’s need for the drug at a given time. From a therapeutic viewpoint these systems may come closest to duplicating the release from a gland such as the pancreas. A variety of mechanisms have been employed to obtain self-regulated delivery.

Ionic strength and pH responsive
These devices take advantage of the fact that polymers containing weakly acidic or basic side groups develop a charge in alkaline or acidic pH respectively. In a cross-linked water-insoluble polymer, this results in water uptake and corresponding swelling of the polymeric membrane with opening of molecular pores and increased drug release rate. Siegel demonstrated the application of cross-linked polymeric gels (methyl methacrylate-N, N-dimethylaminoethl methacrylate co polymer) in drug delivery. IN this case, the polymer is unionized and hydrophobic in neutral pH. A reduction in the pH of the gel leads to ionization of the gel-forming polymer with subsequent swelling which results in molecular pores for release of drug.Thus,this system has shown to effectively control caffeine release at different pH.In terms of practical usefulness.This concept has been extended to glucose sensitive release of insulin as describe below. 

Glucose responsive
Immobilized Glucose Oxidase. Glucose Oxidase catalyses a reaction between glucose and oxygen in the body fluids to form gluconic acid, which reduces the pH of the microenvironment. This is related to the concentration of gluconic acid and hence glucose. The insulin-release systems based on glucose Oxidase utilize this drop in pH to trigger an increased release.
Heller reported on application of Ph-sensitive biodegradable polyorthoesters in which insulin is immobilized. The biodegradable polymer matrix is coated with a hydrogen containing immobilized glucose Oxidase. Glucose diffusing into the hydrogel is oxidized to gluconic acid causing a drop in pH. This increases the erosion rate of the polymer releasing entrapped insulin. Thus, insulin release in modulated by the concentration of glucose in the surrounding fluids.
Langer took advantage of the fact that like many other insulin has a pH of minimum solubility around its isoelectric point. They used modified insulin (with three additional lysine molecules) change the isoelectric point of insulin from around 5.0 to 7.4 thus at physiological pH insulin has the lowest solubility. In the presence of glucose and immobilized glucose Oxidase the resultant drop in pH leads to an increase in insulin solubility with an increase in release rate.
Another such system employs drug encapsulated in special phospholipids vesicles that change structure and permeability with changes in ph temperature or glucose concentration.

Competitive binding
Brownlee and Cerami discovered the principle of competitive binding. It involves the preparation of glycosylated insulin which combines with Concavalin A (Con A), a
Carbohydrate- binding protein. Con A is immobilized on sepharose beads and the glycosylated insulin is bound to it. The beads are encapsulated in a suitable membrane which is permeable to both glucose and insulin. Blood glucose diffuses into the device and replaces insulin from the con a-insulin complex by competitive binding. The free insulin diffuse out of the rate-controlling membrane and is thus released in an active and more stable against aggregation than commercial insulin. This device has been shown to produce glucose-dependent insulin release both in vitro and in vivo. However, the release of insulin has been found to be nonlinearly dependent on glucose.
The device was implanted intraperitoneally in dogs whose pancreas had been removed and blood-glucose levels were compared with those of normal and diabetic dogs after administration of 500-mg/kg dextrose bolus dose. The implanted dogs responded to blood-glucose levels in a manner similar to that of normal dogs. The levels were maintained in the dog for the two days of in vivo evaluation.


Urea responsive
Heller was first to demonstrate the feasibility of a self-regulated hydrocortisone delivery system responding to the presence of urea. The device of disks containing hydrocortisone incorporated into a biodegradable polymer (n-hexyl half-easer of methyl vinyl ether and maleic anhydride) with pH dependent degradation. This disk is coated with a hydrogen containing immobilized urease. In physiological-buffer base line hydrocortisone release is obtained by the hydrolysis of the polymer and diffusion of drug. In the presence of urea the enzyme urease increases the ph of the microenvironment by converting urea into ammonium bicarbonate and ammonium hydroxide. This increase in pH results in increased hydrolysis of the biodegradable polymer and increased hydrocortisone release. The latter was shown to be proportional to the concentration of urea present.


1.3 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.

1.4 THERAPEUTIC APPLICATIONS
Ocular disease
Several different implantable systems have been evaluated to provide prolonged oclular delivery. These include membrane-controlled devices implantable silicone devices, and implantable infusion systems. An example of the membrane-controlled system is the ocusert containing pilocarpine base and alginic acid in a drug reservoir surrounded by a release-rate controlling ethylene-vinyl acetate membrane. The ocusert system provides an initial burst followed by a near zero order delivery of pilocarpine at 20 or 40 g/h for a period of seven days. The device is well tolerated in adults, with satisfactory control of intraocular pressure and minimal side effects. However it appears to be poorly tolerated in the geriatric population where most of the therapeutic need exists.
Implantable devices evaluated for ocular cancer treatment include silicone rubber balloon containing an antineoplastic agent. BCNU. The device consists of two sheets of silicon rubber glued at the edges with silicon adhesive to form a balloon like sac through which a silicone tube is inserted. By a diffusional process, the BCNU solution is
slowly released through the silicone tube. Upon completion of delivery, the device is refilled with drug solution.
The implantable infusion pump system evaluated consists of a miniaturized and computerized pumping device with silastic tubing leading to the site for infusion so drug.

Contraception
Norplant a subdermal implant for long-term delivery of the contraceptive agent levonorgestrel gas recently been approved for marketing by the FDA. The device consists of six silicone membrane capsules each containing about 36 mg of levonorgestrel. The capsules are piaced subdermally on the inside of the upper arm or the forearm in a fan-shaped pattern through a trocar from a single trocar entry point. Cumulatively the six capsules deliver about 70 g/day in vitro and 90 g/day in vivo for the first 100 days with a gradual decrease to about 30 g/day at about 800 days. This rate of delivery appears to continue for over five years. Clinically, Norplant users have a net pregnancy rate of below 1.5 in 100 women at four years. At the end of four years 42 % of the women continued with the method indicating acceptability comparable with that of other methods. Other polymer-based systems under study for contraception include vaginal rings generally composed of silicon rubber used for 3 to 76 months often with a removal period of one week monthly to allow for menstruation; the progestasert an ethylenevinyl acetate copolymer intrauterine drug-releasing device which lasts for one year: and suspensions of injectable microspheres or rods composed of biodegradable polymers.

Dental application
Polymeric implants have been evaluated for several dental applications involving local prolonged administration of fluoride antibacterials and antibiotics. For sustained-release fluoride delivery stannous fluoride was incorporated into different dental cements. Another dispersed in the hydroxyethyl methacrylate and methyl methacrylate copolymer hydrogel coated with an outer layer of the same copolymers in  different proportion so as to be rate limiting in drug release. The device, about 8 mm long and containing 42 mg
of fluoride in the core was attached to the buccal surface of the maxillary first molar and designed to release 0.5 mg of fluoride per day for 30 days. Although increased fluoride concentration were found in the saliva of the subjects erythema or small ulcers were also detected on the buccal mucosal opposite to the device. A modification of this system containing only 17.5 mg of fluoride in a nylon suture system providing 0.15 mg of fluoride per day resulted in 63% fewer carious enamel lesions than in rats without any treatment.
Ethycellulose slabs containing polyethylene glycol and chlorhexidine as an antibacterial agent gave also been evaluated. The slabs have the additional advantage that they can be cut to fit the periodontal pocket and can be inserted quickly with minimal discomfort to the patient. Acrylic polymers have also been evaluated for such a system. Sustained-release implants made of hollow cellulose fibers have also been extensively evaluated. Hollow gibers containing 20% solution of chlorhexidine gluconate and placed in periodontal pockets resulted in significant clinical improvement with relief of discomfort, reduced gingival flow, and less bleeding on probe. Finally matrix systems composed of ethylene-vinyl acetate copolymer and releasing tetracycline (on site therapeutic system) are being tested clinically to treat periodontal disease. Although all these systems led to a reduction of microbial count one of their major disadvantages is the need to remove the device at the end of the 3 to 5 days release period.
The localized nature of dental diseases and the ease of implantation make sustained-release systems of resorbable and biodegradable polymers highly suitable. Research is on going in the area but for commercialization any such delivery system would need to overcome obstacles such as ease of application and patient acceptability and have to complete with conventional delivery systems such as a mouthwash.

Immunization
Polymeric implants are being evaluated for enhanced immune response to antigens. The concept here is to provide pulsatile or continuous administration of the antigen over a prolonged time period. Wise et al. evaluated immunization efficacy of ethylene-vinyl acetate copolymer pellets containing bovine serum albumin as model antigen. The immune response was comparable to that achieved by two injections of bovine serum albumin in complete Freund’s adjuvant (Freund’s adjuvant is an oil-in-water suspension containing bacteria).

Cancer
Silicone rod implants similar to those used for delivery of levonorgestrone have been evaluated for delivery of testosterone propionate or ethinyl estradiol in patients  with prostate cancer. Lupron depot manufactured by Takeda chemical industries is an implantation system providing one – month depot release of leuprolide acetate. a synthetic analogue of the gonadotropin-releasing hormone (GhRH).  The implat consists of biodegradable microspheres prepared from polylactic – glycolic copolymer at 50:50 composition. Containing 10% leuprolide acetate for the treatment of prostate cancer sanders et al. reported on a similar delivery system for nafarelin acetate. an agonistic analogue of lutenizing hormone releasing hormone (LHRH). Zoladex manufactured buy ICI Pharma provides one – month depot release of goserelin acetate from a biodegradable implantable rod . For the treatment of prostate cancer. Biodegradable implants Containing polyanhydrides.  P (CPP:SA) 20:80 ( copolymer of carboxyphenoxy propane and sebacic acid) and BCNU for the treatment of glioblastoma multiform. A form of brain cancer have also been evaluated. Microsphere formulations containing the same polyanhydrides have been evaluated for 24 to 36 delivery of methotrexate .

Narcotic antagonists
Naltrexone  has been extensively evaluated in implant from long- term delivery of narcotic antagonists. Natrexone  freebase. Its hydrochloride. Or the pamoate acid salt has been prepared in a variety of polymers and dosage forma for prolonged narcotic antaginist activity . Though in vitro delivery of up to 50 day has been achieved by some of the systems. in vivo duration of release has been shorter .
Nuwayser et al. reported on biodegradable polymer-coated microspheres  containing naltrexone base. The polymers  evaluated were poly lactide. poly lactic glycolide 65:35 and polycaprolactone-co-lactide 90:10. Diffusion controlled, linear naltrexone release was observed from the coated microspheres lasting for about 50 days. The microspheres produced about 60 day s of morphine antagonist response in implanted rats.

Other applications
Numerous insulin - delivery systems have been prepared and evaluated for a biofeedback approach and have been described previously.
Biodegradable implantable delivery systems have been developed to provide prolonged release of antibiotic to wou Self-regulated
These are biofeedback-controlled system, where the drug release rate is dependent on the body’s need for the drug at a given time. From a therapeutic viewpoint these systems may come closest to duplicating the release from a gland such as the pancreas. A variety of mechanisms have been employed to obtain self-regulated delivery.


2. REVIEW OF WORK DONE
Loss of Sagittal Plane Correction after Removal of Spinal Implants
Deckey J.E. et al (13) studied retrospective review of a clinical series. To evaluate the incidence of adult patients who experienced spinal collapse after spinal implant removal after a long spinal arthrodesis, and to assess the various factors that may influences the likelihood of collapse after implant removal. Publishes reports describing the benefits or complications of spinal implant removal do not exist. Spinal implant removal. Often considered a benign procedure, is even required by the Food and drug Administration (FDA) for certain implants. The medical records and radiographs of 116 consecutive adult patients with long posterior  instrumented fusions (>5 segments) were reviewed. The information obtained included original diagnosis, patient a few, number of previous surgeries before implant removal, levels of anterior and posterior fusion, time from fusion to implant removal time from implant removal to failure and reason for hardware removal. Radiographs also were assessed including scoliosis. Lordosis, and kyphosis measurements before implant removal, after hardware removal, after failure and after revision surgery, of 116 patients, 14  underwent spinal implant removal, Most of these patients reported prominent implants either proximally in the thoracic spine or distally in the ileum (Galveston technique) Of these 14 patients 4 experienced increased pain and collapse after implant removal despite through intraoperative explorations demonstrating solid fusion. Spinal implant remover after long posterior fusion in adults may lead to spinal collapse and further surgery. Removal of instrumentation should be avoided or should involve partial removal of the prominent implant.

Does long term exposure to get-filled silicone implants increase the risk of relapse after breast cancer?
Petit JY et al(14) studied that an increased risk of cancer and autoimmune diseases associated with gel-filled silicone implants debated by FDA expert since 1991 has given rise to a profusion of literature on the subject. However, such effects have not been adequately investigated in patients with breast cancer, In a previous report compared 146 breast cancer patients with gel-filled silicone implants for breast reconstruction to 146 control patients in whom no reconstructions had been performed. The observed results were reassuring, as the evolution of the disease after 10 years was better in the reconstruction group than in the control group. WE now report that end results of this study with a median follow-up of 13 years after the breast reconstruction (range 10-20 years) the relative risks of detrimental events were estimated with Cox’s Proportional Hazards Model, with stratification according to age t at diagnosis. The risks of loco regional recurrences and distant metastasis were significantly lower in the BR group than in the control group. The risks of death, of a second breast cancer and of a second primary cancer at a site other than the breast were not significantly different between the two groups of patients. Long-term follow-up of patients exposed to gel-filled silicone implants confirmed the absence of detrimental effects after breast cancer. The power of our study is, however below that required to detect a very slight increase in the risks studied.

A Case-Control Study to Asses Possible Triggers And Cofactors In Chronic Fatigue Syndromes
Petit JY et al(15) studied to assess possible triggers and cofactors for chronic fatigue syndrome (CFS) and to compare levels of selected cytokines between cases and an appropriately matched control group. Conducted a case-control study of 47 cases of CFS obtained through a regional CFS research program maintained at tertiary care medical center, One age-gender- and neighborhood-matched control was identified for each case through systematic community telephone sampling. Standardized questionnaires were administered to cases and controls. Sera were assayed for transforming growth factor-beta (TGF_beta) nterleukin-1 beta, interleukin-6 tumor necrosis factor-alpha, and antibody to Borrelia burgdorferi and Babesia microti. Cases were more likely to have exercised regularly before illness onset than controls (67% versus 40% matched odds ratio (MOR) = 3.4; 95% CI=1.2 to 11.8: P-0.02). Female cases were more likely to be nulliparous prior to onset of CFS than controls (51% versus 31% MOR= 8.0:95% CI=1.03 to 170;P= 0.05). History of other major factors, including silicon-gel breast implants (one female case and one female control) pre- morbid history of depression (15% of cases 11% of controls) and history of allergies (66% of cases, 51% of controls) were similar for cases and controls. However, causes were more likely to have a diagnosis of depression.
Subsequent to their diagnosis of CFS compared to a similar time frame for controls MOR= undefined; 95% CL lower bound = 2.5 P<0.001). Positive antibody titers to B burgdorferi (one case and one control) ad B miscroti (zero cases and two controls) were also similar, further investigation into the role of prior routine exercise as a cofactor for CFS is warranted. This study supports the concurrence of CFS and depression, although pre-morbid history of depression was similar for both groups.

Safety and Efficacy of levonorgesterel Implant, Intrauterine Device, and Sterilization.
Olav MD et al (16) studied to evaluate safety and efficacy of levonorgestrel releasing contraceptive implants (Norplant) in developing countries. They used controlled cohort methodology, Women attending family planning clinics in eight developing countries selecting Norplant were enrolled, together with women of similar age choosing intrauterine devices (IUDs) or surgical sterilization. Participants were interviewed and examined at semi-annual visits and followed-up for 5 years regardless of change of contraceptive methods. Incidence rate ratios of health events were estimated for initial and current method use, Altogether 7977 women initiated Norplant, 6625 IUD, and 1419 sterilization. The overall follow-up rate was 94.6% and 78.323 woman-years of observation were accumulated. Pregnancy rats for Norplant, copper IUDs and sterilization each averaged less than 1 per 100 woman-years. With two exceptions. No significant excess risk of serious morbidity was detected for Norplant users compared with controls. The incidence of gallbladder disease was higher in women who initiated Norplant use than in controls (rate ratio 1.52 95% confidence interval (CI) 1.02.2.27) as was the incidence of hypertension and borderline hypertension in current implant users (rate ratio 1.81;CI 1.12.2.92) Other new findings were increased risks of respiratory diseases and decreased risks of inflammatory disease of the genital tract in Norplant users compared with IUD users and sterilized women. The study confirms the safety with respect to serious disease and the high contraceptive efficacy of Nor-plant copper IUD, and sterilization.

Immediate placement and immediate provisionalization of ITI implants in maxillary non-restorable single teeth. A preliminary report.
Amin U R et al (17) studied to examine the outcome of Sandblasted Large Grit Acid Etched (SLA) surface, solid screw implants placed immediately into extraction sockets and loaded within one hours of implant placement to achieve immediate replacement of non restorable single maxillary teeth. Thirty five ITI implants in thirty-one patients were placed and immediately restored with a non-occluding provisional acrylic crown.  Porcelain fused to metal crowns were cemented six weeks later by all 35 implants achieved osseointegration as demonstrated by stability and function at the placement of the final un-splinted crown. The healing process was uneventful and without adverse events. There were no reported peri-implant mucosal complications. The prosthetic procedures occurred without intervening incident of abutment loosening of fracture. Considerable advantages exist to immediate placement and provisiolanization after tooth extraction. Soft tissue profiles can remain stable and alveolar bone can be avoided. The rationale for replacing maxillary molars is debatable. Immediate placement of ITI dental implants following tooth extractions and immediately provisionalized is a viable treatment option.

Mechanisms and State of the Arts of Vagus Nerve Stimulation.
Kosal M.D. et al (18) studied that Vagus nerve stimulation (VNS) is an established treatment of medically refractory partial-onset seizures. Recent data from an open-lable multicenter pilot also suggested a potential clinical usefulness in the acute and maintenance treatment of drug resistant depressive disorder. Despite the fact that surgery  is needed to implant the stimulating  device, the option of long-term use  largely devoid of severe side effects would give this treatment modality a privileged place in the management of drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large placebo-controlled trials. Besides the potential clinical usefulness VNS can be used as a research toll in epilepsy patient implanted for clinical reasons, allowing neurophysiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.

Update on Deep Brain stimulation
Benjamin D MD et al(19) studied that Deep brain stimulation (DBS) is an established therapy for movement disorders and an investigational treatment in other neurological conditions and in neuropsychiatry. DBS can target with precision neuroanatomical targets deep within the brain  that are proposed, on the basis of increasing evidence from functional neuroimaging and other methods, to be centrally involved in the pathophysiology of some neuropsychiatry illness. DBS is nonablative offering the advantages of reversibility 
And adjustability. In theory, this characteristic might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Although its mechanisms of action are unknown. Several possible effects have been proposed to underline the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. This issue is the subject of very active investigation in a number of clinical and preclinical laboratories. DBS may offer a degree of hope for patients with intractable neuropsychiatry illness. Research intended to realize this potential will required a very considerable commitment of resources; energy and time across disciplines including psychiatry, neurosurgery, neurology, neuropsychology, and bioethics, Investigations in this area should proceed cautiously.

Surgical Determinants of Clinical Success of Osseointegrated Oral Implants
Sennerby R et al (20) reviewed the current knowledge about the influence of surgical factors on implant failure in routine cases and in those where  implants have been used in conjunction with bone augmentation procedures. Clinical reports published in major scientific journals served as the basis for this review, with few exceptions, most clinical reports were on screw-shaped titanium implants. High failure rates are associated with per bone quality and the use of short implants in the athrophic maxilla, irradiation, and bone-grafting procedures of the athrophic maxilla. Evidence for high long-term failure rates of pres-fit cylinders was found: Moreover, limited clinical experience, lack of preoperative antibiotics, and smoking may lead to higher failure rates; there is a need for further research to increase the success rates in the severely resorbed maxilla. Because of a lack of proper documentation with respect to the great majority of currently used oral implant designs, the influence of different factors and their long-term results remain unknown.

The Implant-Mucosal Interface and Its Role in the long Term Success if Endosseous Oral Implants
Koka et al (21) reviewed the literature on the anatomy and the role of the implant-mucosal interface in the long-term success of oral endosseous implants .In vitro, in vivo animal and in vivo human studies are reviewed and discussed. The anatomy of the implant-mucosal interface is described. The interface shares, many feature with periodontal mucosa. A clinically healthy implant-mucosal interface is a routine and predictable occurrence. The validity of using traditional clinical periodontal parameters to indicate or predict changes in peri-implant marginal bone height is unproven; especially if inflamed mucosal tissues are present in general, the human host response of peri-implant mucosa to long-term functional challenges if favorable.

Imaging Techniques and Image Interpretation for Dental Implant Treatment
Wyantt P et al (22) reviewed the literature on radiographic imaging techniques and image interpretation for dental implant treatment MEDLINE was used to identify published peer-reviewed literature for this report. Radiographic images are indispensable in the evaluation of osseous structures when planning treatment for dental implants. Potential bone sites for implant placement can be assessed clinically by means of palpation or probing through the mucosa; however, diagnostic imaging provides the best means for indirectly measuring bone dimensions. After healing of the implant site, the application of radiology is useful to verify the amount of bone adjacent to the implant and that the transmucosal abetments fit the implant, upon completion of the implant and that the transmucosal abutments fit the implant upon completion of the implant prosthesis. Radiology may be used to monitor initial and long-term success of implant treatment Recommendations for the application of radiology over the course of treatment are made for various implant cases ranging from the overdenture to the single-tooth implant.

Effect of Hydrophobic Channel Modulators On Membrane Fluidity And Single Channel Kinetics Of Maxik Channels
Olaf S et al (23) has been shown that several potassium channel blockers including quinine inhibit lipopolyscaccharide (LPS) induced cell activation in human macrophages and LPS is capable of activating MaxiK channels in macrophages, Intrigued by the fact that the lipid moiety of the LPS is responsible for its biological activity we seek to investigate, what mechanisms underline the influence of hydrophobic channel blockers on ion channel kinetics. There are various hydrophobic compounds which have effects on ion channels, like quinine, the local anesthetic lidocaine, the antipsychotic fluphenazine and the non-narcotic sedativum chlorpromazine. While their blocking effect on shaker potassium channels and sodium channels are widely investigated. No information about their effects due to changes in the membrane environment or their influences on Maxik channels are known, yet as control compounds the hydrophilic channel blockers QX314(a hydrophilic quaternary lidocaine derivative). TEA Paxilline and charybdoxin were used. WE investigated in excised outside-out patch-clamp technique the single channel kinetics of MaxiK channels in human macrophages upon extracellular application of the various compounds. The effects on channel kinetics were obtained by direct fit of the time series to a hidden markov model (closed=open=gap; gap=flickering closed state). Furthermore, we determined the effect of the compounds on membrane fluidity using fourier-tranform infrared-spectroscopy (FTIR). The fluidity of the lipids was determined by evaluating the band position of the symmetric stretching vibration of the methylene group vs.)CH2), which lies around 2850 cm-1 in the gel phase and around 2852 cm-1 in the fluid phase above the lipid specific phase transition temperature TC As expected. The hydrophobic compounds show a significant effect on membrane fluidity showing (a ) a possible pathway to internal binding sites when applied from outside, and (b) the possibility of influencing the ion channels by altering the membrane environment. The blocking effect of all hydrophobic blockers caused a shift of the open+ gap transition towards the gap state in the closed=open=gap model. Additionally, the hydrophobic compounds lidocaine, quinine, chlorpromazine and fluephenazine influence the closed=open transition by shortening the closed times while the open-to-closed transition remained constant, thus, leading to an increased dwell time in the active state. This activation was not observed when the control compounds were applied. The combination of both effects (Shorter closed times but higher flickering rate) led to an overall decreased of the ion flux. The  increase in fluidity of the membrane correlates with the observed  modulation of the Maxik channel by the hydrophobic compounds and suggest either a modulation via the   membrane environment of the channel or an additional intracellular binding site for these compounds,

The Evaluation Of Methods Used To Determine The Efficacy Of Antimicrobial And Analgesic Coatings
Qlaf S et al (24) studied that according to the National Center for health Statistics approximately five millon Americans have hernias that are repaired using a permanent implant device such as polyester mesh or expanded polyterafluoroethlene (ePTFE). The efficacy of antimicrobial-coated polyester mesh to prevent infection by Staphylococcus aureus and biofilm formation on permanent implants was evaluated in this study, and the drug release kinetic of anti-inflammatory and analgesic agents was also observed. These were done using three testing methods including a zone of inhibition test, a respirometer test, and an elution test. All experiments performed were designed to emulate in vivo conditions for the intention of eventually implanting specific coated devices into humans. It was discovered that antimicrobial coatings on permanent implants are effective against bacterial growth reproduction and possibly respiration. It was also found that the elution of analgesic coatings from 3PTFE is difficult to determine, but when established, it will facilitate the formation of standardized methods for coating medical implants.

3. REFERENCES
1. Diffusion controlled systems in controlled release of  biologically active  agents. By john Wiley and sons 1987.
2. Implantable therapeutic systems  in controlled drug delivery systems by chein yiew. 1987
3. Microsealed drug delivery systems; theoretical aspects and biomedical assessments Recent advances in drug delivery systems by chein y.w. 1984.
4. Ophthalmic drug delivery systems in drug delivery devices. fundaments and applications by mitra a.k. 1988.
5. Controlled release systems for contraception in medical application of controlled release by Nash h.a. boca ranton fl, vol.2 1984.
6. Delivery of  contraceptive  by subdermal  implants. Fundamentals and applications by saxena b.b. and singh m. 1988.
7. Sustained release drug delivery devices for local treatment of dental diseases. By steinberg g.d. and  friedman m. 1988.
8. Membrane controlled reservoir drug delivery system medical application of controlled  release by good w.r. and lee p.i. vol. 1 1983.
9. Medical application of controlled release, matrix systems by cardinal j.r. vol.I 1984.
10. Electrically  and chemical controlled hydrogels for drug delivery pulsed and self  regulated drug delivery by grodzinsky a.j. and grimshaw p.e. 1990.
11. Biodegradable and delivery systems for contraception by skeins w.e. burton f.g. and Duncan g.w. Vol 1. 1980.
12. Microencapsulation by Florence at an Jenkins a.w. chap. 3. 1976.
13. Loss of Sagittal Plane Correction After Removal of Spinal Implants Deckey, Jeffrey E. MD : Court, Charles MD : Bradford David S. MD 25(19):2453-2460, October-1,2000.
14. Long-term exposure to gel-filled silicone implants after breast cancer Petti JY Le. M. Rietjens M. Contesso G. Lehmann A. Mouriesse H 84(5): 525-8 1998 UI : 99077326
15. A case control study to assess possible triggers and cofactors in chronic fatigue syndrome Petit JT le. M Riejens M. Contesso G. Lehmann A; Mourissee 11 84(5):525-81998 UI : 99077326

16. Immediate placement and immediate provisionalization of ITI  implants in maxillary non-restorable single teeth. A prelimenary report Amin Ur. Rahman. Konstantina Dedi, Zeerak, Samuel, Saqib Rashid. Oender Solakoglu, Fraukhe Beres. Lyndon F Cooper. Jun-2004-13(2):6671.
17. Mechanisms and State of the Art of Vagus Nerve Stimulation, Kosel, Markus MD :  Thomas E. M.D. Journal  of ECT,18(4):189-192, December-2002.
18. Update on Deep Brain Stimulation Greenberg, Benjamin D.MD Ph.D. Journal of ECT 18(4)193.196 December-2002.
19. Surgical Determinants of Clinical Success of Osseointegrated Oral Implants: The International Journal of Prosthodontics by Sennerby/roos Review of the Literature Vol.II No. 5 1998 Page : 408.
20. The Implant-Mucosal Interface and Its Role in the long-Term Success of Endosseous Oral Implants. The International journal of Prosthodontics by Koka A Review of the Literature Vol.I No: 5 1998 Page  421.

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