Unit 5 MODIFIED-RELEASE DRUG PRODUCTS adv biopharm

Immediate-release tablets & capsules are formulated to release the API immediately, which shows rapid drug absorption.
Modified release drug product are those that alter the timing and/or the rate of release drug substance.
• Types of modified release drug products are:
Delayed release
Extended release
Orally disintegrating tablet
Target release Drug product
EXTENDED RELEASE DRUG PRODUCTS: Two fold release in dosage frequency, examples include controlled release, sustained release and long acting drug products.
DELAYED RELEASE DRUG PRODUCTS: Releases a discrete portion of drug at a time other than promptly after administration. e.g: enteric coated dosage forms like enteric coated aspirin, other NSAIDS, etc.
ORALLY DISINTEGRATING TABLETS: Disintegrate rapidly in saliva after oral administration. Can be used without addition of water. Drug dispersed in saliva and swallowed.
TARGET RELEASE DRUG PRODUCT: A dosage form that releases drug at or near the intended physiologic site of action.

1. MODIFIED-RELEASE DRUG PRODUCTS

2. Introduction Immediate-release tablets & capsules are formulated to release the API immediately, which shows rapid drug absorption. Modified release drug product are those that alter the timing and/or the rate of release drug substance. • Types of modified release drug products are: Delayed release Extended release Orally disintegrating tablet Target release Drug product

3. Types: EXTENDED RELEASE DRUG PRODUCTS: Two fold release in dosage frequency, examples include controlled release, sustained release and long acting drug products. DELAYED RELEASE DRUG PRODUCTS: Releases a discrete portion of drug at a time other than promptly after administration. e.g : enteric coated dosage forms like enteric coated aspirin, other NSAIDS, etc. ORALLY DISINTEGRATING TABLETS: Disintegrate rapidly in saliva after oral administration. Can be used without addition of water. Drug dispersed in saliva and swallowed. TARGET RELEASE DRUG PRODUCT: A dosage form that releases drug at or near the intended physiologic site of action.

4. Immediate release vs Modified release IMMEDIATE RELEASE MODIFIED RELEASE Drugs that release their API quickly after ingestion. Drugs which are modified to release their API slowly for extended period or in controlled manner. Requires more frequent dosing. Reduced dosing frequency. Fluctuations in drug levels. Stable drug levels. Patient compliance is less. Patient compliance is more. These formulations are suitable for acute conditions which needs quick relief. Ideal for chronic conditions requiring consistent medication levels.

5. Advantages: Reduction in fluctuation of plasma levels. Reduction in dosing frequency Patient compliance Reduced adverse side effect Reduction in health care cost

6. Disadvantages: Dose Dumping Less flexibility in accurate dose adjustment Less flexibility for high dosage

7. DOSAGE FORM SELECTION Drug with low aqueous solubility not formulated into a non-disintegrating tablet, because the risk of incomplete drug dissolution is high. Drug with low solubility at neutral pH should be formulated, so that most of drug is released before it reaches the colon. A drug with high water solubility in acidic pH in stomach but insoluble at intestinal pH may be difficult to formulate into ER drug product. With too much coating, bioavailability gets reduced.

8. CHARACTERISTICS OF EXTENDED RELEASE ORAL DOSAGE FORMS The drugs best suited for incorporation into an extended release product have the following characteristics- They exhibit neither very slow nor very fast rates of absorption and excretion. They should uniformly absorbed from the gastrointestinal tract. They are administered in relatively small doses. Possess a good margin of safety. They are used in the treatment of chronic rather than acute conditions.

9. TYPES OF EXTENDED-RELEASE PRODUCTS: DRUG RELEASE FROM MATRIX: A matrix is an inert solid vehicle in which a drug is uniformly suspended. A variety of excipients based on wax, lipid, as well as natural and synthetic polymers have been used as carrier material in the preparation of such matrix type of drug delivery systems. The drug release from such matrix systems is mainly controlled by the diffusion process, concomitant swelling, and/or erosion process.

10. CLASSIFICATION OF MATRIX TABLETS Based on the retarded materials used, matrix tablets can be divided into five types: Hydrophobic matrix (plastic matrix) Lipid matrix Hydrophilic matrix Biodegradable matrix Mineral matrix

11. Matrix system can also be classified according to their porosity situation, including microporous, and nonporous system. By the usage frequency, matrix tablets can also be categorized as follows: GUM TYPE MATRIX TABLETS Some excipients have a remarkable ability to swell in the presence of water and form a substance with a gel-like consistency. When this happens, the gel provides a natural barrier to drug diffusion from the tablet. Drug excipients such as methylcellulose, gum tragacanth, Veegum, and alginic acid form a viscous mass and provide a useful matrix for controlling drug release and dissolution.

12. POLYMERIC TYPE MATRIX TABLETS The most important characteristic of this type of preparation is that the prolonged release may last for days or weeks rather than for a shorter duration (as with other techniques). Example of an oral polymeric matrix tablet was Gradumet (Abbott Laboratories), which was marketed as an iron preparation. The non-biodegradable plastic matrix provides a rigid geometric surface for drug diffusion, so that a relatively constant rate of drug release is obtained.

13. SLOW RELEASE COATED BEADS, GRANULES OR MICROSPHERES In these systems, the drug is distributed onto beads, pellets, granules, or other particulate systems. The size of these beads can be very small (microencapsulation) for injections or larger for oral drug delivery. Several approaches have been used to manufacture beaded formulations including pan coating, spray drying, fluid-bed drying, and extrusion- spheronization . Pan coating is a modified method adopted from candy manufacturing. Cores of a given mesh size are slowly added to known amount of fine drug powder and coating solution and rounded for hours to become coated drug beads. The drug-coated beads are then coated with a polymeric layer, which regulates drug release rate by changing either the thickness of the film or the composition of the polymeric material.

14. MICROENCAPSULATED DRUG Microencapsulation is a process of encapsulating microscopic drug particles with a special coating material, therefore making the drug particles more desirable in terms of physical and chemical characteristics. It is a process by which solids, liquids, or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material around the substance. The typical encapsulation process usually begins with dissolving the wall material, say gelatin, in water. The material to be encapsulated is added and the two-phase mixture thoroughly stirred. With the material to be encapsulated broken up to the desired particle size, a solution of a second material, usually acacia, is added. This additive material concentrates the gelatin into tiny liquid droplets One of the advantages of microencapsulation is that the administered dose of a drug is subdivided into small units that are spread over a large area of the gastrointestinal tract, which may enhance absorption by diminishing localized drug concentration. A common drug that has been encapsulated is aspirin. Aspirin has been microencapsulated with ethyl cellulose, making the drug superior in its flow.

15. ION-EXCHANGE PRODUCTS lon -exchange technique has been popularly applied in water purification and chemical extraction, Ion-exchange preparations usually involve an insoluble resin capable of reacting with either an anionic or a cationic drug. An anionic resin is negatively charged so that a positively charged cationic drag may attach the resin to form an insoluble non-absorbable resin-drug complex. lon exchange has been combining with a coating to obtain a more effective sustained release product.

16. PROCESS A solution of a cationic drug may be passed through a column containing an ion-exchange resin, forming a complex by the replacement of hydrogen atoms. The resin-drug complex is then washed and may be tableted, encapsulated, or suspended in an aqueous vehicle. The release of the drug is dependent upon the pH and the electrolyte concentration in the GI tract. Release is greater in the acidity environment of the stomach than in the less acidic environment of the small intestine.

17. The insoluble drug complex containing the resin and drug dissociates in the GIT in the presence of the appropriate counter ions. The released drug dissolves in the fluids and is rapidly absorbed.

18. OSMOTIC DRUG DELIVERY SYSTEMS Osmotic drug delivery systems have been developed for both oral extended-release products known as gastrointestinal therapeutic systems (GITS) and for parenteral drug delivery as an implantable drug delivery ( eg , osmotic minipump). Drug delivery is controlled by the use of an osmotically controlled device in which a constant amount of water flows into the system causing the dissolution and releasing of a constant amount of drug per unit time. PROCESS IN OSMOTIC MINIPUMP The oral osmotic pump drug delivery system is the Oros system, developed by Alza . The system is composed of a core tablet surrounded by a semi permeable membrane coating have a 0.4 mm diameter hole produced by laser beam. The system is designed such that only a few drops of water are drawn into the tablet each hour. The rate of inflow of water and the function of the tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and the fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant.

19. Here, The drug release rate may be altered by, Changing the surface area, The thickness or composition of the membrane, Changing the diameter of the drug release orifice. The drug-release rate is not affected by gastrointestinal acidity, alkalinity, fed conditions, or Gl motility.

20. GASTRORETENTIVE SYSTEMS The extended-release drug product should release the drug completely within the region in the GI tract in which the drug is optimally absorbed. Due to GI transit, the extended-release drug product continuously moves down the Gl tract. In some cases, the extended-release drug product containing residual drug may exit from the body. Pharmaceutical formulation developers have used various approaches to retain the dosage form in the desired area of the GI tract. One such approach is a gastro-retentive system that can remain in the gastric region for several hours and prolong the gastric residence time of drugs. Usually, the gastro-retentive systems can be classified into several types based on the mechanism applied such as High-density systems Floating systems Expandable systems Super porous hydrogels Mucoadhesive or bioadhesive systems Magnetic systems Dual working systems

21. TRANSDERMAL DRUG DELIVERY SYSTEMS Skin represents the largest and most easily accessible organ of the body. A transdermal drug delivery system (patch) is a dosage form intended for delivering drug across the skin for systemic drug absorption. Transdermal drug absorption also avoids presystemic metabolism or "first-pass" effects. It deliver the drug through the skin in a controlled rate over an extended period of time.

22. CORE TABLETS A core tablet is a tablet within a tablet, the inner core is usually used for the slow-drug-release component, and the outside shell contains a rapid-release dose of drug Formulation of a core tablet requires two granulations. The core granulation is usually compressed lightly to form a loose core and then transferred to a second die cavity, where a second granulation containing additional ingredients is compressed further to form the final tablet. The core material may be surrounded by hydrophobic excipients so that the drug leaches out over a prolonged period of time. This type of preparation is sometimes called a slow-erosion core tablet, because the core generally contains either no disintegrant or insufficient disintegrant to fragment the tablet.

23. Modified-Release Parenteral Dosage Forms Modified-release parenteral dosage forms are parenteral dosage forms that maintain plasma drug concentrations through rate-controlled drug release from the formulation over a prolonged period of time. Some examples of modified-release parenteral dosage forms include microspheres, liposomes, drug implants, inserts and nanoparticles. These formulations are designed by entrapment or microencapsulation of the drug into inert polymeric or lipophilic matrices that slowly release the drug, in vivo, for the duration of several days or up to several years. Modified-release parenteral dosage forms may be biodegradable or nonbiodegradable. Nonbiodegradable implants need to be surgically removed at the end of therapy.

24. Liposomes A liposome is a microvesicle composed of a bilayer of lipid amphipathic molecules enclosing an aqueous compartment. Liposomes may be nanoparticle size or larger. Liposome drug products are formed when a liposome is used to encapsulate a drug substance within the lipid bilayer or in the interior aqueous space of the liposome depending on the physicochemical characteristics of the drug. Liposomes can be composed of naturally derived phospholipids with mixed lipid chains (like egg phosphatidylethanolamine) or other surfactants. Liposome drug products exhibit a different pharmacokinetic and/or tissue distribution profile from the same drug substance (or active moiety) in a nonliposomal formulation given by the same route of administration

25. KINETICS OF EXTENDED-RELEASE DOSAGE FORMS The amount of drug required in an extended-release dosage form to provide a sustained drug level in the body is determined by the pharmacokinetics of the drug, the desired therapeutic level of the drug, and the intended duration of action. In general, the total dose required (D) is the sum of the maintenance dose (D m ) and the initial dose (D I ) released immediately to provide a therapeutic blood level. D total = D I +D m D m (mg) released over a period of time and is equal to the product of t d (the duration of drug release ) and the zero-order rate k r (mg/h). Therefore, can be expressed as: D total = D I +k r t d

26. Ideally, the maintenance dose (D) is released after D I has produced a blood level equal to the therapeutic drug level C P. However, due to the limits of formulations, D I actually starts to release at t=0. For a drug that follows a one-compartment open model, the rate of elimination (R) needed to maintain the drug at a therapeutic level is C P R = k V D C P The above equation may also be written as R = C P Cl T where a Cl T is the clearance of the drug. In designing an extended-release product, D I would be the loading dose that would raise the drug concentration in the body to Cp, and the total dose needed to maintain therapeutic concentration in the body would be simply D total = D I + C P Cl T τ where, τ = dosing interval.

27. EVALUATION OF MODIFIED-RELEASE DRUG PRODUCTS

28. IN VITRO/IN VIVO CORRELATIONS (IVIVCs) IVIVCs is critical to the development of oral-extended release products. Assessing IVIVCs is important throughout the periods of product development, clinical evaluation, submitting of an application for FDA-approval for marketing, and during post approval for any formulation or manufacturing changes which are taking place.

29. Three categories of IVIVCs included in the document are as follows: Level A A predictive mathematical model for the relationship between the entire in vitro dissolution/ release time course. E.g. : The time course for plasma drug concentration or amount of drug absorbed. Level B A predictive mathematical model of the relationship between summary parameters that characterize in vitro and in vivo, time courses.

30. Level C A predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time ( or T 50 % ) and a summary parameter that characterizes the in vivo time course. E.g. C max and AUC

31. Suggested dissolution/drug release studies Reproducibility of the method Proper choice of the medium Maintenance of sink condition Control of solution hydrodynamics Dissolution rate as function of pH, ranging from 1-8.

32. Evaluation of in-vivo bioavailability data Pharmacokinetic Profile Plasma drug concentration-time curve should adequately define bioavailability of drug from dosage form. The bioavailability data should demonstrate the extended release characteristics of the dosage form compared to reference/immediate release product.

33. 2. Steady state plasma drug concentration Fluctuation C ∞ max - C ∞ min / C ∞ av where C ∞ av is equal to [ AUC ]/ T 3. Rate of drug absorption For an extended release drug product to claim zero-order drug absorption, Wagner Nelson method is used.

34. 4. Occupancy Time For drugs whose therapeutic window are known, plasma drug concentration maintained above the minimum effective drug concentration. The time required to obtain plasma drug levels within therapeutic window is known as occupancy time.

35. 5. Bioequivalence studies It includes the study of: A fasting study A food intervention study A multiple dose study

36. 6. Statistical Evaluation Variables subject to statistical analysis generally include plasma drug concentrations at each collection time, AUC (from zero to last sampling time), AUC (from zero to time infinity), C max , t max , and elimination half-life t 1/2 . Statistical testing may include an analysis of variance (ANOVA), computation of 90% and 95% confidence intervals on the difference in formulation means, and the power of ANOVA to detect a 20% difference from the reference mean.