Modified Release Drug Delivery System PDF
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This document discusses modified release drug delivery systems, including pharmaceutical concepts and conventional drug therapy. It details principles of obtaining prolonged-action preparations. Key topics cover drug release mechanisms and different types of dosage forms.
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MODIFIED RELEASE DRUG DELIVERY SYSTEM Pharmaceutical concepts: For many disease states, the ideal dose regimen of a drug delivery system is: To provide a therapeutic concentration of the drug at the site of action. Maintained constant for the desired duration of the treatment. Therefo...
MODIFIED RELEASE DRUG DELIVERY SYSTEM Pharmaceutical concepts: For many disease states, the ideal dose regimen of a drug delivery system is: To provide a therapeutic concentration of the drug at the site of action. Maintained constant for the desired duration of the treatment. Therefore, therapeutic "steady-state" plasma concentration of drug can be achieved promptly and maintained by the repetitive administration of conventional dosage forms, provided that the dose size and frequency of administration are correct. CONVENTIONAL DRUG THERAPY Conventional dosage forms are generally designed not only to produce maximum physical and chemical stability, but also to give maximal drug bioavailability by optimizing the rate and extent of drug absorption. Whilst such dosage forms have been useful, they often give rise to several potential problems: 1. Poor patient compliance is a problem with conventional dosage forms, especially if the contained drug has a short biological half life, is that the drug has to be given more frequently, for example 2 or 3 or 4 times a day to obtain the desired therapeutic response. This will cause great inconvenience to the patient. 2. The frequency of administration of any drug increased the chances of missing the dose of a drug. 3. Big fluctuations in peak and trough plasma drug level when given repeatedly. High peak drug levels may give rise to undesirable side effects. Excessively low trough levels may cause loss of therapeutic levels. Thus, maintenance of steady state drug levels with minimal fluctuations has become an important issue in drug delivery, especially with drugs of relatively narrow therapeutic indices. To overcome these problems, several technical advancements have been made in the development of new drug delivery systems 1 capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue. There are two ways to overcome such a situation: Development of new drugs with long half lives, thus no need for multiple dosing. Effective and safer use of existing drugs through concepts and techniques of controlled delivery systems. The first approach has many disadvantages which therefore resulted in increased interest in the second approach. Fig: - Typical drug blood level versus time profile following oral multiple –dose therapy A modified release product: is a system in which a portion of the drug (initial priming dose) is released immediately in order to achieve the desired therapeutic response promptly. The remaining dose of drug (the maintenance dose) is then released slowly, therefore resulting in a therapeutic drug concentration which is prolonged but not maintained constant. It is interesting to note that the USP considers that the terms controlled release; sustained release and prolonged release are interchangeably with extended release. 2 The term modified release used to describe dosage forms that continuously release drugs at rates which are sufficiently controlled to provide periods of prolonged therapeutic action following each administration of a single dose. Principles of obtaining prolonged-action preparations: A. Utilization of pharmacokinetic phase. 1. Prolongation of absorption, e.g. addition of vasoconstrictors to local anaesthetic prolongs their local action. 2. Prolongation of metabolism, e.g. enzyme induction (acetyl cholinesterase inhibitor like neostigmine or pyridostigmine prolongs the action of acetylcholine due to inhibition of its hydrolysis in the organism. 3. Prolongation of excretion, e.g. competitive interaction in renal tubules (penicillin and probencide). B. Utilization of chemical reactions. 1. Preparation of slightly soluble salts, esters, or complexes (prodrugs). 2. Chemical modifications of a molecule which are aimed at achieving, among others, extension of mass, alteration of solubility or partition coefficient, and degree of protein binding. 3. Binding on ion-exchange resins: weak acids on cationic exchangers and weak bases on anionic exchangers. C. Utilization of technological processes for dosage-form formulation. 1. Change in solvent type, e.g. water replaced by oil. 2. Addition of viscosity- increasing substances which lead to extended diffusions rate. 3. Drug adsorptions on insoluble adsorbents. 4. Enclosure of a drug within multilayer emulsions W/O/W with an oil phase functioning as liquid membrane, controlling the rate of release. 5. Replacement of a solution by a suspension; the factor controlling rate of release is a crystallographic form and size of particles. 6. Coating a drug, drug pellets, or whole dosage form by a film-forming substance. 3 7. A drug embedded matrix by embedding a drug into insoluble, soluble, or eroding (hydrolytic break-down) excipients which control the rate of release. 8. Using osmotic pressure. 9. Combined application of the above mentioned procedures. TERMINOLOGY: There are several terms used inter changeably viz. controlled release: Sustained, Prolonged, Extended Release: - Slowly release of drug from the dosage form for extended period of time. Extended-Release dosage form: A dosage form which, due to special technology of preparation provides, soon after a single dose administration, therapeutic drug level maintained for 8 to 12 hours. Extended-Release dosage form indicates merely a dosage form that has its dissolution profile extended in time rather than designed and characterized to achieve a desired drug delivery profile (example, wax matrix). Controlled- Release dosage form: A dosage form which, due to its special technological construction, provides for drug release having kinetics of zero order in an amount sufficient to maintain the therapeutic drug level over extended time (24 hr or more). i.e. the drug released at a constant rate and the plasma remains invariant with time. Sustained-Release drug product: is designed to deliver an initial dose of the drug (loading dose) immediately in order to achieve the desired therapeutic response promptly followed by a slower and constant release of the remaining dose (maintenance dose) of the drug. The rate of release of the maintenance dose is designed so that the amount of drug loss from the body by elimination is constantly replaced. Delayed-Release systems: are either those that use repetitive, intermittent dosing of a drug from one or more immediate-release units incorporated into a single dosage form or an enteric delayed release systems. Examples, of delayed release systems include repeat-action tablets and capsules, and enteric-coated tablets where timed release is achieved by a barrier coating, or by means of enteric coat. Long-acting or Prolonged- action: A dosage form containing a therapeutic substance modified chemically in order to prolong biological half life (mostly prevented very rapid absorption of the drug). 4 Targeted -Release dosage forms: are those releases drug, at or near the intended physiologic site of action or biological location and they can be site specific or receptor targeting. An enteric-coated tablet: is an example of a modified-release dosage form, designed to protect the tablet core from disintegration in the acid environment of the stomach and release in the small intestine for one or more of the following reasons: Prevention of acid attack on active constituents which unstable at lower PH. Protect the stomach from irritant drugs. Facilitate absorption of some drugs. Advantages of modified release drug delivery system: Modified-release formulations have attained medical acceptance and gained popularity due to several therapeutic advantages. 5 1. More uniform plasma levels of drug can be maintained at steady state over an extended period of time through the reduction in fluctuations between peak and trough plasma concentrations. 2. The need for frequent drug administration can be minimized to once or twice daily, which is particularly advantageous for drugs used in treatment of chronic diseases, leading to improved patient compliance and convenience. 3. The reduced fluctuations in plasma drug levels can help to reduce the incidence of adverse side effects, which are common in conventional drug administration. 4. Local irritation of the gastrointestinal tract due to exposure to high concentration of certain drugs can be minimized. 5. Modified-release formulations are useful for delivering drug with narrow therapeutic index, in which fluctuation in blood level may induce supra therapeutic levels resulting in systemic toxicity, or sub-therapeutic levels characterized by loss in therapeutic efficacy. 6. The overall administration of modified-release products enables increased reliability of therapy. DISADVANTAGES OF ORAL CONTROLLED-RELEASE DOSAGE FORM 1. Prompt termination of therapy if significant adverse effects are observed is impossible after administration of the dosage form. 2. The physician has less flexibility in regulating dosage regimens as the dose has been fixed by the dosage form design. 3. The formulation of modified-release drug products for drugs usually administered in large doses in conventional dosage forms may not be practical or useful. 4. The high cost employed in the processes and equipment for manufacturing of controlled-release formulations results in more expensive products compared to conventional preparations. 5. The upscale manufacturing procedure sometimes causes unpredictable release profile and often reduces the drug bioavailability due to relatively poor understanding of in vitro and in vivo correlation. 6 6. Furthermore, there are other disadvantages such as possible dose dumping, increased first-pass metabolism of certain drugs, and the effective drug release period is limited and affected by gastrointestinal transit time. Dose dumping may be defined as the release of more than the usual fraction of drug at greater rate, in such case adverse plasma levels may be reached. RATE CONTROLLED DELIVERY SYSTEMS (MECHANISMS OF RELEASE) All sustain release formulations employ a barrier to provide a slow release of maintenance dose. I. DISSOLUTION SYSTEMS: The releases of certain drugs are inherently sustained due to their intrinsic low aqueous solubility and thus these drugs are natural sustained release products. Thus, in principle, it would seem possible to prepare sustained release preparations for highly water soluble drugs by controlling their dissolution rate in gastrointestinal medium. Generally, either matrix dissolution systems or barrier membrane based controlled- release systems are applied to slow down, delay, or control the delivery and release rate of drugs. It is well comprehended that the dissolution process includes two steps that is: The initial detachment of drug molecules from the surface of their solid structure to the adjacent liquid interface. Followed by their diffusion from the interface into the bulk liquid medium. Therefore, this process can be manipulated to design controlled-release delivery systems with desired release rate and profile. 7 a. Dissolution controlled matrix system: In the dissolution controlled matrix system, the drug is uniformly dispersed within a tablet core consisting of a slowly dissolving polymer which forms the matrix, in which the polymer can be: Hydrophobic in nature (e.g. wax, polyethylene, polypropylene and ethylcellulose). Hydrophilic matrix (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxy methyl cellulose). Methods of preparing drug-wax particles: CONGEALING: in this method drug is mixed with a molten wax material, congealed and screened. AQUEOUS DISPERSION: In aqueous dispersion method, the drug-wax mixture is simply sprayed in water and the resulting particles are collected. DIRECT COMPRESSION: Matrix tablets are also made by direct compression of a mixture of drug, polymer and excipients. The rate of drug release is controlled by the rate of penetration of the dissolution medium into the matrix. This in turn, can be controlled by the porosity of the tablet matrix, the presence of hydrophobic additives, as well as wettability of the tablet and the particle surface. b. Dissolution controlled barrier system: In the dissolution controlled barrier system, the drug particles or granules can first be coated with slowly dissolving polymeric materials and subsequently be directly 8 compressed into tablets or put into capsules. One of the principal methods of coating a drug is through micro encapsulation. Once the polymeric membrane has dissolved, the drug contained inside the membrane is immediately available for dissolution and absorption. Thus, the drug release can be controlled by adjusting the thickness and the dissolution rate of the polymeric membrane. A more uniformed controlled-release can be obtained via application of a spectrum of different thicknesses. Drug release from the coated beads occurs in a progressive manner. Beads with the thinnest layers will provide the initial dose, while the maintenance of drug level at a later timeframe will be achieved with beads of thicker coatings. The coating materials can be selected from a wide variety of natural and synthetic polymers, depending on the characteristic of the drug to be coated and the desired release pattern. The commonly used coating materials include: gelatin, carnauba wax, shellac, cellulose acetate phthalate and cellulose acetate butyrate. There are several factors affecting the rate of drug dissolution, which include: The aqueous solubility of the drug. The surface area of the dissolving particles or tablet. The diffusivity of the drug. The thickness of the boundary layer. One of the major setbacks of the dissolution controlled barrier system is the difficulty in maintaining a constant drug release. The reasons for such difficulty are the surface area changes with time, and the solubility of drugs that are weak acids or bases is affected by the variation in pH of the gastrointestinal tract. II. DIFFUSION SYSTEMS: Diffusion can be defined as a process by which molecules transfer spontaneously from one region to another in order to equalize chemical potential gradient. It is a result of random molecular motion with a wide spectrum of physico-chemical properties occurring in various conditions and situations. In the pharmaceutical dosage form is the movement of drug molecules from a region of high concentration in the dosage form to one of a lower concentration in the gastro intestinal fluid. 9 In diffusion controlled mechanism, the control of drug release to the environment is achieved by diffusion of drug molecules embedded within a polymeric carrier through an inert membrane barrier as a result of concentration gradient. Therefore, it is very common for diffusion controlled devices to exhibit non zero-order release due to an increase in diffusional resistance and decrease in diffusion area as the release proceeds. In these systems, the release rate of drug is determined by its diffusion through an inert membrane barrier, usually an insoluble polymer. There are basically two types of diffusion controlled systems, namely, reservoir and matrix systems: A. RESERVOIR DEVICES In which a core of drug is surrounded by a polymeric membrane. B. MATRIX DEVICES In which dissolved or dispersed drug is distributed uniformly in an inert insoluble polymeric matrix. A. RESERVOIR DEVICES: The reservoir type of device is generally spherical, cylindrical or disk-like in shape and consists of a compact drug core surrounded by a non-biodegradable permeable membrane through which the drug slowly diffuses. The rate at which the drug is released is determined by the thickness and the permeability of the membrane. Several factors affect the rate of drug release from reservoir type of diffusion controlled device. They include: The surface area. Diffusion coefficient. Partition coefficient of the drug between the drug core and the membrane. The diffusional pathlength. The concentration gradient across the membrane. The release kinetics of this type of system suggests that: 10 If the concentration of the drug within the reservoir is in constant equilibrium with the inner surface of the enclosed membrane, the driving force for diffusional release of the drug is constant, and zero-order release kinetics of the drug is obtained. If a constant drug concentration cannot be maintained then the rate of drug release would decline with a decline in the drug concentration in the reservoir. However, there is also a possibility of the reservoir membrane to accidentally rupturing, causing a sudden large amount of drug to be released following administration (known as drug dumping), resulting in toxic side effects if plasma drug concentration exceeds maximum safety level. Reservoir diffusional systems have several advantages over conventional dosage forms, the former can offer zero-order release kinetics of drug and the kinetics can be controlled by changing the characteristics of the polymer to suit a particular drug as well as therapy conditions. The inherent disadvantage is that, unless the polymer used is biodegradable, the system must somehow be removed from the body after the drug has been released. Diffusion reservoir devices have been some of the widely used and most successful oral systems. Common methods used to develop reservoir type devices include microencapsulation of drug particles and film coating of tablets. If the encapsulating material is selected properly, diffusion will be the controlling process. Some materials used as the membrane barrier coat, alone or in combination, are: Methyl cellulose, ethylcellulose. Polyhydroxymethacrylate. polyvinylacetate, Eudragit L and S. Hydroxy Propyl cellulose, cellulose nitrate. Various waxes Etc. B. MATRIX DEVICES 11 In the matrix system, also referred to as the monolithic system, the drug is dispersed homogenously throughout the polymer matrix, which can be either hydrophobic or hydrophilic. Slow diffusion of the drug through the matrix provides sustained release of the drug from the delivery system. Higuchi has provided the theoretical basis for defining drug release from such matrices. In this model, Drug particles dispersed in the outer layer of the matrix which is exposed to the bathing solution will dissolve and then diffuse out of the matrix. This process continues with penetration of the dissolution medium into the matrix to further dissolve the contained drug. Thereby, creating channels through which diffusion of the dispersed drug in the inner core can take place. It is therefore obvious that for matrix system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of dissolved drug leaving the matrix. Drug release from a matrix system can be influenced by porosity and tortuosity of the matrix. The release rate is directly proportional to the: 1. Concentration of the dispersed drug in the tablet matrix. 2. The diffusion coefficient and the solubility of the drug in the release media. Drug particles that are physically embedded in the polymer matrix should be at concentrations high enough to create a series of interconnected pores through which the drug can subsequently diffuse. However, the release kinetics of the drug from this matrix system will not be constant and it depends on the volume fraction of the drug within the matrix. The greater the concentration of dissolved drug within the matrix, the greater will be its release rate from the matrix system. As such, a first order release kinetics is obtained from such matrix systems. Thus, unlike the reservoir device, there is minimal risk of drug dumping in case of accidental rupture of the membrane. The three major types of materials used in the preparation of matrix devices are: 12 1. Insoluble Plastics: - Methyl acrylate, Methyl methacrylate, Polyvinyl chloride, Polyethylene 2. Hydrophillic Polymers:- Methyl cellulose, Hydroxy-propylmethylcellulose, Sodium carboxymethyl cellulose 3. Various waxes: - carhauba wax, Beeswax etc. III. EROSION-CONTROLLED MECHANISM: In erosion controlled drug delivery system, the drug particles are distributed uniformly throughout the polymer matrix and the rate of drug release depends on the erosion rate of the polymer. When erosion is faster than drug diffusion, the drug release is controlled by erosion. The difference between erodible systems and non-erodible systems is that the structure/mass in a non-erodible system remains unchanged with time and the drug is released by diffusion, while the structure or mass in an erodible system decreases with time which makes zero-order release unlikely. Erosion can take place through the whole matrix, referred to as bulk erosion, or be limited to the matrix surface, termed as surface erosion. a. Bulk erosion: Bulk erosion is very complex because water penetration through the matrix is much faster than polymer degradation, leading to a rapid hydration of the internal core of matrix and digestion throughout the whole matrix. This results in concurrent drug diffusion and matrix erosion. Subsequently, the weight of the polymer decreases steadily and the matrix permeability increases as a function of time. However, the matrix maintains its original shape and mass until up to approximately 90% is degraded, then only matrix dissolution and mass loss starts. In bulk erosion release system, the kinetics of the drug is difficult to determine, especially when the matrix disintegrates before drug is completely released. b. Surface erosion: In surface erosion, degradation takes place only at the matrix boundaries and not in the core of the polymer, thus except for the matrix at the boundaries, the physical integrity of the matrix is preserved and a consistent degradation rate of the polymer is obtained. Surface erosion can be achieved when the degradation rate of the polymer at the matrix surface is much faster than the rate of water penetration into the matrix bulk. As the drug is dispersed throughout the matrix but only a minimal 13 diffusion takes place, the drug release rate is determined by the rate of erosion of the matrix surface. Therefore, surface erosion is often preferred over bulk erosion because the former is highly reproducible, the drug release rate is proportional to the rate of polymer erosion, and can be controlled by varying system thickness and the total drug content. Also, surface erosion eliminates the possibility of dose dumping, thus improving the safe use of the delivery system. IV. SWELLING-CONTROLLED MECHANISM: Swelling-controlled matrices utilize a combination of both diffusion and dissolution mechanisms. The drug is dispersed in the polymer, but instead of using an insoluble or erodible polymer, a swellable polymer is employed. When the polymer loaded with the drug comes into contact with the gastrointestinal fluids: It absorbs water and swells without being dissolved. The swelling further increases the entrance of water, causing dissolution of the contained drug. Followed by diffusion of the dissolved drug out of the swollen networks to the external environment. This system usually minimizes the bursting effect as a rapid polymer swelling takes place before the drug is being released. In swelling controlled delivery systems, the absorption of water causes changes in dimensions and physical properties of the matrix, therefore, the changes in the rate of drug release is correlated with the degree of swelling. The diffusion coefficient of the drug in the matrix is initially very low but increases as the gel absorbs more fluids. Thus, the gel layer formation and consequently the rate of drug release are highly dependent on the: 1. Rate of liquid penetration. 2. Polymer swelling rate. 3. Drug solubility. 14 4. Diffusion as well as matrix erosion. The swelling composition of the swellable matrices is divided into three components: a. The first component is the swelling front which clearly separates the rubbery region from the glassy region. b. The second component is the erosion front which separates the matrix from the solvent. c. The last component is the diffusion front located between the swelling and erosion fronts during drug release. The position of the diffusion front in the gel phase is dependent on the drug solubility and loading. For swellable matrix delivery systems, the essential element of the drug release mechanism is the formation of gel around the matrix which assists water penetration and protects matrix disintegration. V. ION EXCHANGE RESINS OR (DRUG COMPEXES): Ion exchange resin delivery systems generally use water-insoluble crosslinked polymers containing groups of exchanging ions to obtain sustained release of drug for ionizable drugs. Therefore, these polymers are also known as ion exchange resin. These resins contain salt-forming functional groups in repeating positions on the resin. They may contain acidic or basic-reacting groups, whereby these reacting groups can bind to drugs. Basic drugs are bound to acidic cation ion exchangers, while the acidic drugs are bound to basic anion ion exchangers. A general mechanism for the formulation of: i. Cationic drug is: H+ +Resin – So3-drug+ Resin – So3- H+ + drug+. Insoluble drug complex soluble drug ii. For anionic drug is: 15 Cl- + Resin – N+ (CH3)3 drug- Resin – N+ (CH3)3 Cl- + drug-. Insoluble drug complex soluble drug Drug molecules attached to the resins are exchanged for release by appropriately charged ions in contact with the ion-exchange groups and the released drug molecules diffuse out of the resin. Drug release from the resins depends on properties of the resin and the ionic environment, such as pH or electrolyte concentration within the gastrointestinal tract. The rate of sustained release of the drug is a result of slow diffusion of drug molecules through the resin complex. The release rate can be controlled by: The diffusion area. Diffusional pathlength. Chemical composition. The rigidity of the resin. The release rate can even be further controlled by coating the drug-resin-complex with a hydrophobic polymer such as ethyl cellulose or waxes, using micro encapsulation processes. Resin-drug complex is advantageous for drugs that are highly susceptible to hydrolysis or degradation by enzymatic process, since it offers a protective mechanism by temporarily altering the substrate. Like all other systems, this approach also has a limitation that the release rate is proportional to the concentration of the ions present in the environment, indicating that there is a maximum release rate which cannot be further increased. Also the release rate of drug can be affected by variability in diet, and water intake as well as the individual intestinal content. VI. OSMOTIC PUMP SYSTEM: Osmosis can be defined as the spontaneous movement of a solvent from a region of lower solute concentration to a region of higher solute concentration across an ideal semi-permeable membrane, which is permeable only to the solvent but impermeable to the solute. 16 In recent years, this mechanism was employed for controlling the rate of drug release. An oral osmotic pump, popularly called Oros, works on the principle of osmotic pressure to release the drug at a constant zero-order rate. In this approach, the unit consists of an osmotic core containing an osmotically active drug or a combination of an osmotically inactive drug with an osmotically active salt or agent such as NaCl, coated with a rigid semi-permeable membrane. The uptake of water across the semi-permeable membrane is at a controlled rate that causes the device to deliver an equal volume of saturated drug solution out of the core through a drilled orifice on the coat (an orifice of 0.4 mm diameter is produced by laser beam). Considering a semi-permeable membrane that is permeable to water but not drug, the osmotic and hydrostatic pressure differences on either side of the semi-permeable membrane will provide the driving force to generate controlled-release of the contained drug. The osmotic delivery systems generally classified into two different forms: a. The first form contains the drug in a solid core together with the electrolyte. Both the drug and the electrolyte are dissolved by the incoming water, in which the electrolyte provides a high osmotic pressure difference. The built-up hydrostatic pressure due to the imbibed water can only be relieved by pumping the drug solution out of the drilled hole. b. The second form contains the drug (in solution) in an impermeable membrane within the device. The electrolyte surrounding the impermeable membrane yields high osmotic pressure to draw water into the device. This in turn causes compression of the membrane and drug is pumped out of the core through a drilled hole. Both systems have either single or multiple holes bored through the membrane to allow drug release. In general, the system can assume any shape or size, depending on the dosage requirements. 17 Osmotic systems as oral MRDD: The elementary osmotic pump (EOP) or oral osmotic pump (OROS) is a dosage form for dispensing drugs to GIT at a rate independent on the GIT pH, and GIT motility. The semi-permeable membrane exhibits sufficient strength and rigidity to maintain a constant volume during pump operation. Working mechanism of EOP: 1. The water passes through the membrane. The influx is constant, and its rate is controlled by membrane permeability and osmotic pressure of the reservoirs content. 2. The water dissolves the osmotic active agent creating an osmotic pressure and the solution in the reservoir becomes saturated. 3. Continuous influx of water into the device causes an increase in hydrostatic pressure which produces and maintains the release of saturated drug solution through the delivery orifice. 4. When solid drug depleted, the delivery rate declines to zero 5. Unlike membrane controlled systems the membrane in osmotic system allows one diffusion process (water in). 18 Since the release mechanism is based on osmotic pressure, the rate of drug release is essentially independent of agitation speed, orifice size, variation in pH and hydrodynamic conditions. The elementary osmotic pump benefits from its simple functional design and it is well suited for the formulation and delivery of drugs with intermediate water solubility. Besides the typical osmotic pump delivery system described earlier, a controlled porosity osmotic pump was described. In this system, an osmotically active core was coated with a mixture of polymers with differing degrees of water solubility. In the presence of water, the soluble components of the coating will dissolve, leaving a micro porous film. Subsequently, water can diffuse into the core creating an osmotic gradient, which controls the release of drug. Delivery rate of the drug is dependent on: Membrane permeability. The osmotic pressure of the core. The solubility of drug in the tablet core. The coating thickness. The solubility of the coating component. Diameter of the orifice. Membrane area. HYDRODYNAMIC PRESSURE CONTROLLED SYSTEMS OR PUSH- PULL OSMOTIC PUMPS. Modifications have been developed to the EOP, in these systems; the hydrodynamic pressure generated by swelling of a hydrophilic gum can also be used to activate the delivery of drugs. The device comprises of a rigid, shape retaining housing enclosing a collapsible, impermeable compartment contain a liquid drug. The space between the external housing and the drug compartment contains a layer of swellable, hydrophilic gum such as polyhydroxyalkyl methacrylate. In the GIT, the Gum Imbibes water through the opening present in at the lower side of external housing and swells creating a hydrodynamic pressure. 19 The pressure thus created squeezes the collapsible drug reservoir to release the medicament through the delivery orifice at a zero-order release. Such systems are also called as PUSH-PULL osmotic pumps. Rate controlling factors: Surface area of wall with opening Nature of the gum Fluid permeability DRUG PROPERTIES IN THE DESIGN OF CONTROLLED RELEASE SYSTEM The desired properties of a drug to be used in a controlled delivery system are as follows: I. Physico-chemical properties A. Aqueous Solubility and pKa:- Extremes in aqueous solubility are undesirable in the preparation of sustained release products. For drugs with low water solubility they will be difficult to incorporate into a sustained release mechanism. 20 Drugs with very high water solubility and rapid dissolution rate are equally difficult to incorporate into a sustained release system because it is quite difficult to decrease its dissolution rate and slow its absorption. PH-dependent solubility particularly in the physiological pH range, would be another problem because of the variation in the pH throughout the GI tract and hence variation in the dissolution rate. Since weakly acidic drugs exist primarily in the unionized form in the stomach (pH = 1 to 2), their absorption will be excellent in acidic environment on the other hand, weakly basic drug exist primarily in the ionized form at the same site and their absorption will be poor. In the upper portion of the small intestine, the pH = 5 to 7 (Basic) and the reverse will be expected for weak acids and bases. For optimum passive absorption, the drugs with good aqueous solubility, especially if pH independent, and remain unionized at the site of absorption, serves as a good candidate for controlled release dosage form (Example:-Diclofenac Sodium). Preparing a slightly soluble form of a drug with normally high solubility is one possible method for producing extended release dosage forms (Example:-Aspirin). B. DRUG STABILITY Drugs that are unstable in the stomach the most appropriate controlling unit would be one that releases its contents only in the intestine. The reverse is the case for those drugs that are unstable in the environment of intestine. However, it is very difficult for a delivery system to release its contents in a specific region of the G.I.T. Thus, drugs with significant stability problems in any particular area of the G.I.T. are less suitable for formulation into C.D.D.S. that delivers their contents uniformly over the length of the G.I.T. C. MOLECULAR SIZE AND DIFFUSIVITY More than 95% of drugs are absorbed by passive diffusion. Diffusivity defined as the ability of a drug to diffuse through the membranes, is inversely related to molecular size. Thus drugs with large molecular weight show small diffusion coefficients and may be difficult to place into a suitable sustained 21 release system. Drugs of molecular weight up to 500-700 should present no difficulty in this regard. D. SITE OF ABSORPTION Drugs absorbed by carrier-mediated transport processes are poor candidate for controlled release systems. Example: several B-vitamins. E. PROTEIN BINDING Extensive binding to Plasma proteins (ex: albumin) may result in a long half life for the drug; such drugs generally do not require an extended-release dosage form. Some drugs that exhibit greater than 95% protein binding at therapeutic levels are Diazepam, Diazoxide and Novabiocin. II. PHARMACOKINETIC CONSIDERATIONS (BIOLOGICAL PROPERTIES) A. ABSORPTION RATE AND ABSORPTION Drugs that are slowly absorbed or absorbed with a variable absorption rate are poor candidate for sustained release system since continuous release will result in a pool of unabsorbed drug. Example: Iron. For a drug to be administered as controlled release formulation, its absorption must be efficient since the rate limiting step is the rate of drug release Kr i.e. Kr