From membrane-reservoir systems

Cumulative Release from Membrane-Reservoir Systems... 

Membrane-reservoir systems based on solution-diffusion mechanism have been utilized in different forms for the controlled delivery of therapeutic agents. These systems including membrane devices, microcapsules, liposomes, and hollow fibres have been applied to a number of areas ranging from birth control, transdermal delivery, to cancer therapy. Various polymeric materials including silicone rubber, ethylene vinylacetate copolymers, polyurethanes, and hydrogels have been employed in the fabrication of such membrane-reservoir systems (13). 

Mechanisms of Release. In Figure 3, Line A represents release from a reservoir system with a large core relative to the wall mass. This could be a microcapsule releasing by steady-state diffiision through a uniform nonerodible wall. Transport through the polymer membrane (or matrix) occurs by a dissolution-diffusion process, where the active ingredient first dissolves in the polymer and then diffuses across the polymer to the external surface where the concentration is lower. The diflfiision is in accordance with Fick s first law ... 

Membra.ne Diffusiona.1 Systems. Membrane diffusional systems are not as simple to formulate as matrix systems, but they offer much more precisely controlled and uniform dmg release. In membrane-controlled dmg deUvery, the dmg reservoir is intimately surrounded by a polymeric membrane that controls the dmg release rate. Dmg release is governed by the thermodynamic energy derived from the concentration gradient between the saturated dmg solution in the system s reservoir and the lower concentration in the receptor. The dmg moves toward the lower concentration at a nearly constant rate determined by the concentration gradient and diffusivity in the membrane (33). 

The hormone-releasing devices have a closer resemblance to standard methods of sustained release because they involve the release of a steroid compound by diffusion [198,199]. The Progestasert, a reservoir system, is shown in Fig. 16. Progesterone, the active ingredient, is dispersed in the inner reservoir, surrounded by an ethylene/vinyl acetate copolymer membrane. The release of progesterone from this system is maintained almost constant for 1 year. The effects of release are local, with none of the systematic side effects observed with orally administered contraceptives [200-207]. 

A typical reservoir system consists of a core (the reservoir) and a coating membrane (the diffusion barrier). The core contains the active ingredients and excipients, whereas the membrane is made primarily of rate-controlling polymer(s). The governing release mechanism is diffusion from the reservoir across the membrane to the bulk solution, and the one-dimensional release rate is described by Eqs. (4.4), (4.17), and (4.22).10,14 In addition,... 

Scopolamine was the first drug to be marketed as a transdermal delivery system (Transderm-Scop) to alleviate the discomfort of motion sickness. After oral administration, scopolamine has a short duration of action because of a high first-pass effect. In addition, several side-effects are associated with the peak plasma levels obtained. Transderm-Scop is a reservoir system that incorporates two types of release mechanims a rapid, short-term release of drag from the adhesive layer, superimposed on an essentially zero-order input profile metered by the microporous membrane separating the reservoir from the skin surface. The scopolamine patch is able to maintain plasma levels in the therapeutic window for extended periods of time, delivering 0.5 mg over 3 days with few of the side-effects associated with (for example) oral administration. 

The second system was developed by the Hereon Division of Health Chem Corporation and consists of a laminated plastic chip. Figure 2. The chip is composed of a pheromone saturated polymer reservoir with a semi-permeable plastic membrane on either side. The pheromone is thus released by diffusion from the reservoir through the membrane. The rate is controlled by the membrane composition and thickness(2,). The two systems are applied in a polybutene sticker to facilitate adhesion to the plant surface. 

The microsealed delivery device is a variation of the matrix-type transdermal system in which the drug is dispersed in a reservoir phase which is then immobilized as discrete droplets in a cross-linked polymeric matrix. Release can be further controlled by inclusion of a polymeric microporous membrane. This system therefore combines the principles of both the liquid reservoir and matrix-type devices. Rate of release of a drug from a microsealed delivery system is dependent on the partition coefficient between the reservoir droplets and the polymeric matrix the diffusivity of the drug in the reservoir, the matrix and the controlling membrane and on the solubility of the drug in the various phases. There are, obviously, many ways to achieve the desired zero-order release rate, but only nitroglycerin has been commercially formulated into this type of delivery device (Karim 1983). 

The insoluble cellulose derivatives utilized for permeation control of various species (e.g. oxygen and water vapor transport in coated pharmaceuticals, contact lenses, packaging, or water and solute transport through semi-permeable membranes in reverse osmosis, as well as drug release from reservoir systems) differ considerably in their permeability characteristics according to the type and extent of substitution, as well as their molar mass. However, very few comparative data are available from the literature on the polymers actually used in biological applications. Recently, new results have been published. Thus, Sprockel et al. [142] determined the water vapor transmission through various CA, CAT, CAB and CAPr films at different relative humidities (Table 22). 

As in the case of hydrophilic (swelling) matrix systems and reservoir (membrane) systems, drug release profiles from insoluble (porous or non porous) systems are most of the time described on a basis of the diffusion theory. This is not true for every situation and we have for example shown that the release from porous matrix systems is dissolution-controlled above the solubility limit of the drug [150]. A simplified equation for the model proposed and for values of kd t > 4, is ... 

In most reservoir and transdermal systems (Figure 9.2), release of drug from the reservoir into the external solution occurs in three steps (1) dissolution of the drug in the polymer, (2) diffusion of drug across the polymer membrane, and (3) dissolution of the drug into the external phase. Assuming that the rate of diffusion across the membrane is much slower than the rate of dissolution/... 

Figure 9.3 Drug release from a planar membrane-reservoir drug delivery system.

In membrane diffusion systems the polymer membrane with a given pore size or pore size distribution controls the diffusion of the active substance from the drug reservoir. Dosage forms with membrane-controlled drug delivery can be coated tablets, coated granules or pellets, or so-called multiparticulate systems on which various coats are applied. One possibility for transdermal drug administration is the transdermal patch controlled with a membrane [4-7,34-39]. 

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