Polymers in Controlled Release Delivery System - Drug Delivery

Currently available polymers for controlled release can be classified into three major categories: Diffusion-controlled systems. Solvent-activated systems. Chemically controlled systems. Diffusion Controlled Systems These systems involve two types: reservoir and matrix. A res...

Currently available polymers for controlled release can be classified into three major categories: Diffusion-controlled systems. Solvent-activated systems. Chemically controlled systems. Diffusion Controlled Systems These systems involve two types: reservoir and matrix. A reservoir consists of a core of drug, which is surrounded by a layer of nonbiodegradable polymer through which the drug slowly diffuses (Figure 1). A reservoir can provide nearly uniform delivery of the drug. However, to maintain uniformity, the thickness of the polymer should remain constant. The major problem with the reservoir system is that if the polymer membrane accidentally ruptures, a large amount of drug may be released suddenly. In the matrix type of diffusion control system, the drug is uniformly distributed throughout the polymer matrix and is released from the matrix at a uniform rate as drug particles dislodge from the polymer network. In such a system, unlike the reservoir, there is no danger of dose dumping. Fig. (1): Drug Delivery from a Reservoir System.  Solvent-activated Systems Solvent activated systems are subdivided into two types; osmotically controlled systems and swelling-controlled systems. In the osmotically controlled systems, an external fluid containing a very low concentration of the drug moves across a semipermeable membrane to a region inside the device where the drug is in high concentration. Osmotic pressure tends to decrease the difference in concentration between one side of the membrane and the other. The inward  Fig. (2): Drug Delivery from a Swelling Controlled System In the swelling-controlled systems: the polymer holds a large quantity of water without dissolving (Figure 2). The system consists of hydrophilic macromolecules crosslinked to form a three-dimensional network (hydrogel). Chemically Controlled Systems This type of system has two classes; one class is the pendant chain system and the other is the bioerodible system. A “pendant chain system” is one in which the drug molecule is chemically linked to the backbone of the polymer. In the body, in presence of enzymes, or fluids, chemical hydrolysis or enzymatic cleavage occurs with concomitant release of drug at a controlled rate. The drug may be linked directly to the polymer or via a “spacer group”. In the bioerodible system, the controlled release of drugs involves polymers that gradually decompose. The drug is dispersed uniformly throughout the polymer and is slowly There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release system. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale—as through pores in the polymer matrix—or on a molecular level, by passing between polymer chains. In Figure 3, a polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Fig. (3): Drug Delivery from a Typical Matrix Drug Delivery System. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to be released. For the reservoir systems, the drug delivery rate can remain fairly constant. In this design, a reservoir—whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix —is surrounded by a film or membrane of a rate- controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a non changing thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure 4a is representative of an implantable or oral reservoir delivery system, whereas the system shown in Figure 4b illustrates a transdermal drug delivery system, in which only one side of the device will actually be delivering the drug Fig. (4): Drug Delivery from a Typical Reservoir System a) Implantable or Oral b) Transdermal.  TDDS Design Membrane Monolithic controlled Systems Transdermal Systems Drug in Adhesive Transdermal Systems  Components of Transdermal Drug Delivery System Liner : Protects the patch during storage. The liner is removed before use. Adhesive : Serves to adhere the components of the patch together along with adhering the patch to the skin (Polybutyl acrylate) Membrane : Controls the release of the drug from the reservoir (Polyethylene with microporous structure) Drug Backing : Protects the patch from the outer environment (Transparent or pigmented films of polypropylene, polyethylene) Monolithic Systems Incorporate a drug matrix layer between backing and frontal layers. The drug matrix layer is composed of a polymeric material in which the drug is uniformly dispersed. Polymeric matrix controls the rate at which drug is released for percutaneous absorption. Membrane Controlled Transdermal Systems They are designed to contain: Protective layers (Liner) Adhesive A rate controlling membrane A drug reservoir usually in liquid or gel form Backing Membrane Controlled Transdermal Systems  Examples: Catapress TDDS Estraderm (Clonidine) TDDS (Estradiol) Product name = Product name = Catapress- Estraderm-TDDS® TDDS® (Clonidine) (Estradiol) used to treat used to treat  Examples: Catapress TDDS (Clonidine), Estraderm TDDS (Estradiol). The device artificial membrane is the rate limiting barrier. Rupturing of the rate- limiting membrane may result in drug dumping. Drug-in-Adhesive Transdermal Drug Delivery System  It is an easier transdermal drug delivery system.  In this type, the adhesive layer also contains the drug. The adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin but is also responsible for releasing the drug.  B. Osmotic pumps consists of a flexible, impermeable diaphragm surrounded by a sealed layer containing an osmotic agent at a particular concentration, which, in turn, is contained within a cellulose ester semipermeable membrane. When the filled pump is placed in an aqueous environment, water diffuses into the osmotic agent chamber The absorbed water generates a hydrostatic pressure that acts on the flexible lining to force drug through the pump outlet III. Implants for contraception Biodegradab le Nonbiodegrad able  Nonbiodegradable: One of the methods of steroid release involves the use of a nondegradable polymer, silastic. The polymer is shaped into capsules or rods, which are implanted subdermally. i) Polymeric Matrix system (sometimes referred to as monolithic system): the drug is dispersed, homogeneously, inside the matrix material. Slow diffusion of the drug through the polymeric matrix material provides sustained release of the drug from the delivery system. ii) Reservoir system: consists of a compact drug core surrounded by a permeable non-degradable membrane whose thickness and permeability properties can control the diffusion of the drug into the body. Biodegradable: they can provide a programmed rate of release of steroids The primary mechanisms of steroid release are erosion, diffusion, cleavage of covalent linkage, or a combination of these processes The most investigated polymer materials are poly(lactic acid), poly(glycolic acid), and poly-(e-caprolactone  Application for Non-biodegradable implants Norplant®: is a set of small contraceptive capsules that release levonorgestrol for five years. It is an example of the reservoir non-degradable system. The capsules are made of Silastic® which is a dimethylsiloxane/ methylvinylsiloxane copolymer. The capsules are placed under the skin of the arm.  Solvent Controlled Devices: Osmosis is the movement of a solvent through a semi- permeable membrane from a region of low-solute concentration to a region of high-solute concentration  Zoladex®: is an implantable biodegradable lactide/ glycolide polymeric delivery system of goserelin acetate used to treat prostate cancer that is injected through a wide pore needle and can provide medication for one or three months.  Solvent Controlled Devices: The system consists of an outer cylindrical titanium alloy reservoir which protects the drug molecules from enzymes, body moisture, and cellular components. At one end of the reservoir is positioned the membrane, from a polyurethane polymer. The membrane is permeable to water but impermeable to ions. Positioned next to the membrane is the osmotic engine. Next to the engine is the piston. The piston is made from elastomeric materials and serves to separate the osmotic engine from the drug formulation (may be either a solution or suspension). At the distal end of the titanium cylinder is the exit port. Radiation sterilization (gamma) may be utilized to sterilize the final drug product.  When implanted, a large, constant osmotic gradient is established between the tissue water and the osmotic engine which provides a region of high NaCl concentration. In response to the osmotic gradient, water is drawn across the membrane into the osmotic engine. The water imbibed into the osmotic engine expands its volume, thereby displacing the piston at a controlled, steady rate. This displacement pumps drug formulation from the drug reservoir through the exit port and into the patient. Targeted Drug Delivery With Catheterized Osmotic Pumps: Catheters of different designs can be attached to the exit port of an osmotic pump for targeted drug delivery. B- swelling In swelling controlled systems, a polymer which can hold a large volume of water is employed. When the device is placed in an aqueous environment water penetrates the matrix and the polymer consequently swells and the drug is able to diffuse through. It is nondegradable. Erodible devices: Combination of polymer breakdown and drug diffusion through matrix releases cargo Advantage: being injectable and resorbable (no retrieval surgery) Disadvantage: therapy difficult to stop once injected due to difficult recovery of particles Example: Lupron depot One month injectable implant containing leuprolide acetate for treatment of endometriosis and prostatic cancer.  NALTREXONE PELLETS Naltrexone pellets block the effects of heroin and other opiates when inserted under the skin. They gradually release their medication over time. 500 mg naltrexone pellets that are replaced every two months, and 800 mg naltrexone pellets that are replaced every three months DISULFIRAM PELLETS treat alcoholism  Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate. The rate of drug diffusion is controlled by: - The polymer composition - The membrane thickness - The solubility of the drug e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system - Designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release pilocarpine continuously at a steady rate for 7 days for treatment of glucoma. -consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.  Soluble Ocular inserts: Types a) Based on natural polymers e.g. collagen. b) Based on synthetic or semi synthetic polymers e.g. Cellulose derivatives –Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl acetate copolymer. The system soften in 10-15 sec after introduction into the upper conjuctivall sac, gradually dissolves within 1 h, while releasing the drug.