Sr or cr formulations

DRUG DELIVERY SYSTEM

1. SUSTAINED RELEASE / CONTROLLED RELEASE FORMULATIONS Presented by, Pratiksha C Chandragirivar M pharma 1 st sem Dept. of pharmaceutics HSK COP Bagalkot Facilitated by, Dr. Anita Desai HOD and professor Dept. of pharmaceutics HSK COP Bagalkot SR/CR FORMULATIONS 1

2. CONTENT 1. INTRODUCTION 2. BASIC CONCEPT OF SR OR CR FORMULATIONS 3. ADVANTAGES 4. DISADVANTAGES 5. FACTORS INFLUENCING SRDF’S 6. PHYSICAL APPROACHES SR/CR FORMULATIONS 2

3. INTRODUCTION WHAT IS DRUG DELIVERY SYSTEM? ANS : The term “drug delivery systems” refers to the technology utilized to present the drug to the desired body site for drug release and absorption HISTORY : The history of controlled release and sustained formulations involves three time periods viz., From 1950 to 1970 was the period of sustained drug release From 1970 to 1990 was involved in the determinations of the needs of the control drug delivery Post 1990 modern era of controlled release technology. SR/CR FORMULATIONS 3

4. In recent years, considerable attention has been focused on the development of new drug delivery systems. This is evidenced by the spate of books [1-8] and review articles [9-18] published on this subject. There are a number of reasons for the intense interest in new systems. First, recognition of the possibility of re patenting successful drugs by applying the concepts and techniques of controlled release drug delivery systems, coupled with the increasing expense in bringing new drug entities to market, has encouraged the development of new drug delivery systems. Second, new systems are needed to deliver the novel, genetically engineered pharmaceuticals, i.e., peptides and proteins, to their sites of action without incurring significant immunogenicity or biological inactivation. Third, treating enzyme deficient diseases and cancer therapies can be improved by better targeting. Finally, therapeutic efficacy and safety of drugs, administered by conventional methods, can be improved by more precise spatial and temporal placement within the body, thereby reducing both the size and number of doses. SR/CR FORMULATIONS 4

5. For the concepts of drug delivery system or dosage forms two criterias should be kept in mind viz,. 1. First, It should deliver drug at a rate dictated by the needs of the body over the period of treatment. This may necessitate delivery at a constant rate for drugs that have a clear relationship between steady state plasma levels and the resultant therapeutic response. Second, It should channel the active entity solely to the site of action. This may necessitate delivery to specific receptors, as in the case of H1 and H2 antagonists, localization to tumor cells, as required by most cancer treatments, or to specific areas of the body as for arthritis or gout. . SR/CR FORMULATIONS 5

6. Before ,initiating a discussion of sustained release and controlled release dosage forms , It is necessary to study some terminologies viz., CONTROLLED RELEASE DOSAGE FORMS : Dosage form which release drug at a constant rate and provide plasma concentration that remains invariant with time. REPEAT ACTION DOASAGE FORMS : An individual dose is released fairly soon after administration , and second or third doses are subsequently released at intermittent intervals. SUSTAINED RELEASE DOASAGE FORMS : An initial release of drug sufficient to provide a therapeutic dose soon after administration and then a gradual release over a extended period. SR/CR FORMULATIONS 6

7. EXTENDED RELEASE DOSAGE FORMS : These are the dosage forms which release the drug slowly , so that the plasma concentration are maintained at a therapeutic level for a prolonged period of time usually between 8-12 hours. MODIFIED RELEASE DOSAGE FORMS : According to USP these are those dosage forms whose drug release characteristics of time course and or chosen to accomplish therapeutic or conveniences objectives not offered by conventional dosage forms. SR/CR FORMULATIONS 7

8. WHAT IS SUSTAINED RELEASE FORMULATIONS? SRF ‘S describes the slow release of a drug Substance from a dosage form to maintain therapeutic response for extended period i.e. for about 8-12 hrs. of time. Time depends on the dosage form viz., in oral form = it is in hours in parenteral form = it is in days and months Examples : Aspirin SR, Dextrin SR. SR/CR FORMULATIONS 8

9. WHAT IS CONTROLLED RELEASE FORMULATIONS? These are the formulations which delivers the drug at a predetermined rate, for locally or systematically , for a specified period of time. Example : GITS - Prazosin (mini press) Morphine sulphate ( Roxonal SR) SR/CR FORMULATIONS 9

10. Difference between controlled release and sustained release formulations SR/CR FORMULATIONS 10 Sustained release formulations Controlled release formulations 1. Constitutes dosage form that provides medication over a extended period of time. 1 .Constitutes dosage form that maintains constant drug levels in blood or tissue. 2.SRF’S generally do not follows zero order kinetic pattern. 2.Maintains constant drug levels in the blood in the target tissue usually by releasing the drug in a zero order kinetic pattern. 3.Usually do not contain mechanisms to promote localization of the drug at active site. 3. It contains methods to promote localization of the drug at active site.

11. CONCEPT OF SUSTAINED RELEASE FORMULATIONS The of concept of sustained release formulation can be divided into two considerations i.e., Release rate Dose consideration RELEASE RATE: Here , K r = Drug release , K a = Drug absorption K e = Drug elimination. SR/CR FORMULATIONS 11

12. In conventional dosage form K r >K a in this, the release of drug from dosage form is not rate limiting step. The above criteria i.e.( K r > K a ) in case of immediate release, where as in non immediate ( K r < K a ) I.e. release is rate limiting step. So that effort of developing S.R.F. must be directed primarily altering the release rate. The rate should be independent of drug removing in the dosage from over constant time. The release rate should follow zero order kinetics, K r = rate in = rate out = K e V d . C d K e = overall elimination (first order kinetics). V d = total volume of distribution. C d = desired drug concentration. SR/CR FORMULATIONS 12

13. B. DOSE CONSIDERATIONS: To achieve the therapeutic level and sustain for a given period of time for the dosage form generally consists of 2 part a. Initial (primary)dose b. Maintenance dose Therefore the total dose ‘W’ can be W = D i + D m In a system ,the therapeutic dose release follows zero order process for a specified period of time. W = D i + K r. T d T d = time required for sustained release from one dose . SR/CR FORMULATIONS 13

14. If maintenance dose begins to release the drug during dosing t = 0 then, W = D i + K r. T d - K r. T p where, T p = time of peak drug level However a constant drug can be obtained by suitable combination of D i and D m that release the drug by first order process, then W = D i + K r. T d + (K e . C d / K r ) V d . Sustained release, sustained action, prolonged action, controlled release , extended action , time release dosage forms are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect continuously releasing medication over an extended period of time after administration of single dose. SR/CR FORMULATIONS 14

15. ADVANTAGES Reduction in dosing frequency. Enhanced patient convenience and compliance due to less frequent drug administration. Reduction in adverse effects (both systematic and local) of potent drugs in patients. Reduction in health care costs. Improved efficiency of treatment. Reduces nursing and hospitalizing time. Reduction in blood level fluctuations of the drug ,thus the better management of disease. Maximum bioavailability with minimum dose. Minimizes the accumulation of drug with chronic dosing. Cure or controlled condition promptly. Makes use of special effects. E.g. treatment of arthritis. SR/CR FORMULATIONS 15

16. DISADVANTAGES Possibility of dose dumping due to food , physiologic or formulation variables or grinding of oral formulations by patients and thus increased risk of toxicity. Reduced potential for dose adjustment of drugs normally administered in varying strengths. Cost of single unit dosage form is higher than that of conventional dosage form. Increase potential for first pass metabolism. Requirement of additional patient education for proper medication. Decreased systemic availability in comparison to immediate release conventional dosage form , this may be due to incomplete release , increased first metabolism, increased instability, insufficient resident time for complete release, site specific absorption, P H dependent solubility etc,. Poor in vitro and in vivo correlation. Retrieval of drug is difficult in case of toxicity, poisoning and hypersensitivity reaction. SR/CR FORMULATIONS 16

17. FACTORS INFLUENCING SUSTAINED OR CONTROLLED RELEASED FORMULATIONS There are mainly six factors influences the performances of sr or cr formulations those are as follows : 1. Drug properties 2. Route of drug delivery 3. Target sites 4. Acute or chronic therapy 5. The disease 6. Patients SR/CR FORMULATIONS 17

18. Drug properties : The physiochemical properties of a drug , Including stability, solubility, partitioning characteristics, charge, and protein binding propensity, play a dominant role in the design and performance of controlled release systems. Route of drug delivery : The area of the body in which drugs will be applied or administered can be restrictive on the basis of technological achievement of a suitable controlled release mechanism or device. At times, the drug delivery system, in certain routes of administration, can exert a negative influence on drug efficacy, particularly during chronic administration, and hence other routes of administration should be considered. Performance of the controlled release systems may also be influenced by physiological constraints imposed by the particular route, such as first-pass metabolism, GI motility, blood supply, and sequestration of small foreign particles by the liver and spleen. SR/CR FORMULATIONS 18

19. 3. Target sites : In order to minimize unwanted side effects, it is desirable to maximize the fraction of applied dose reaching the target organ or tissue. This can be partially achieved by local administration or by the use of carriers. However, the absorptive surfaces of most routes are impermeable to macromolecules or other targeted delivery systems, thereby necessitating either intravascular or intra arterial administration. 4. Acute or chronic therapy: Consideration of whether one expects to achieve cure or control of a condition and the expected length of drug therapy are important factors in designing controlled release systems. Attempts to generate a one year contraceptive implant presents significantly different problems in design than does an antibiotic for acute infection. Moreover, long term toxicity of rate-controlled drug delivery systems is usually different from that of conventional dosage forms. SR/CR FORMULATIONS 19

20. 5. The disease : Pathological changes during the course of a disease can play a significant role in the design of a suitable drug delivery system. Example: In attempting to design an ocular controlled-release product for an external inflammation, the time course of changes in protein content in ocular fluids and in the integrity of the ocular barriers would have to taken into consideration. Sometimes, one can take advantage of the unique manifestations of the disease state. Example: The higher plasminogen activator levels in some tumor cells can lead to preferential bioconversion of peptidyl prodrugs in these cells. Similarly, the higher tyrosinase level in melanoma cells has been demonstrated to allow targeting to and preferential bioconversion of 2, 4-dihydroxphenylalanine in them. SR/CR FORMULATIONS 20

21. 6. The patient : Whether the patient is ambulatory or bedridden , young or old, obese or gaunt, etc., can influence the design of a controlled release product. An implant or intramuscular injection of a drug to a bedridden patient with little muscle movement may perform in a manner significantly different from that of an ambulatory patient. Some of these factors represent individual patient variation and cannot be controlled by the research scientist while others must be considered. Example: single unit controlled release products are particularly prone to intra- and inter-subject variation because of variabilities in individual GI motility . SR/CR FORMULATIONS 21

22. PHYSICOCHEMICAL APPROACHES FOR THE SR/CR RELEASE FORMULATIONS SR/CR FORMULATIONS 22

23. Aqueous Solubility As we know that for the better absorption the drug must be in solution form, compounds with very low aqueous solubility results in oral bioavailability problems because of limited gastrointestinal transit time of the un dissolved drug particles and limited solubility at the absorption site. A drug with good aqueous solubility , especially if Ph independent , serves as a good candidates. Drug to be absorbed first must dissolve in aqueous phase surrounding the site of administration and then partition into absorbing membrane. SR/CR FORMULATIONS 23

24. For many compounds, the site of maximum absorption will also be the area in which the drug is least soluble. Example: Tetracycline dissolves to a greater extent in the stomach than in the intestine, although it is best absorbed in the intestine. Such drugs may be poor candidate for sustained/controlled release systems, unless the system is capable of retaining the drug in the stomach and gradually releasing it to the small intestine or unless the solubility is made higher and independent of the external environment by encapsulating the drug with an acid (if the drug is a weak base) or a base (if the drug is a weak acid) in a membrane system. SR/CR FORMULATIONS 24

25. Examples of other drugs which are limited in absorption by their dissolution rate are digoxin , warfarin , griseofulvin , and salicylamide . Although the action of a drug can be prolonged by making it less soluble, this may occur at the expense of inconsistent and incomplete bioavailability. The choice of mechanism for oral sustained/controlled release systems is limited by aqueous solubility of the drug. If the mechanism is of dissolution, it must give some extent of dissolution rate. The dissolution rate must be clearly depicted by the equation called “ Noyes Whitney equation ” dc/dt = Kd A Cs where, dc/dt = Dissolution rate Kd = Dissolution rate constant A = Total surface area of a drug Cs = aqueous saturation solubility SR/CR FORMULATIONS 25

26. Diffusional systems will be poor choices for slightly soluble drugs because the driving force for diffusion, the concentration in aqueous solution, will be low. Prevention: In contrast, such drugs may be effectively incorporated in matrix systems. On the positive side for dissolution concept for the sr formulations, the slow dissolution rate of compounds can be utilized to achieve sustained/controlled drug release by incorporation in a matrix system. On the negative side, dissolution-limited bioavailability may occur.   SR/CR FORMULATIONS 26

27. PKA (dissociation constant): The aqueous solubility of weak acids and weak bases is governed by the pKa value of the compound and pH of the medium. weakly acidic drug exist as unionized form in the stomach absorption is favored by acidic medium. For weak acid, St = So (1+ Ka \[H]) = So (1+10 pH - pKa) where , St = Total solubility Of the weak acid So = Solubility of the unionized form Ka = Acid dissociation constant H = Hydrogen ion concentratio n SR/CR FORMULATIONS 27

28. For weak bases, Weakly basic drugs exists as ionized form in the stomach hence absorption of this type is poor in this medium. St = So + (1+[H]\Ka) = So (1+ 10 pKa - pH) Where, St =Total solubility of both conjugate and free base form of weak base. So = Solubility of the free base SR/CR FORMULATIONS 28

29. B. PARTITION CO-EEFICIENT AND MOLECULAR SIZE   Partition coefficient and molecular size influence not only the permeation of a drug across biological membranes, but also diffusion across or through a rate-controlling membrane or matrix. Following administration, the drug must traverse a variety of membranes to gain access to the target area. Drugs with extremely high partition coefficient (i.e., very oil-soluble) readily penetrate the membranes but are unable to proceed further, while drugs with excessive aqueous solubility i.e., low oil/water partition coefficients cannot penetrate the membranes. A balance in the partition coefficient is needed to give an optimum flux for permeation through the biological and rate controlling membranes. Hansen and Dunn as well as Fujita et al. have shown that, for many body tissues, such as the gastrointestinal tract, skin, and blood-aqueous barrier of the eye, the optimum n- octanol/water partition coefficient at which maximum flux occurs is approximately 1000. SR/CR FORMULATIONS 29

30. The ability of a drug to diffuse through membranes, its so called diffusivity, is related to its molecular size by the following equation: Log D = -Sv log V + kv = -Sm log M + Km Where, D = Diffusivity M = molecular weight V = molecular volume, and Sv, sM, kv, and Km are constants in a particular medium. In general, the denser the medium, the smaller the diffusivity. For drugs of intermediate molecular weight (150-400), diffusivities through flexible polymers are typically of the order of 10"^-8 cm2 sec-1. SR/CR FORMULATIONS 30

31. C. DRUG STABILITY : The stability of a drug in the environment to which it is exposed is another physicochemical factor to be considered in the design of sustained/controlled release systems. Drugs that are unstable in the stomach can be placed in a slowly soluble form or have their release delayed until they reach the small intestine. However, such a strategy would be detrimental for drugs that either are unstable in the small intestine or undergo extensive gut-wall metabolism, as evidenced by decreased bioavailability when these drugs are administered from a sustained release dosage form. To achieve better bioavailability and controlled release of drugs that are unstable in the small intestine, a different route of administration should be chosen. Controlled release of nitroglycerin is a good example. On the positive side, the presence of metabolizing enzymes at the site of administration or along the pathway to the target area can sometimes be utilized in controlled drug delivery SR/CR FORMULATIONS 31

32. D . Protein Binding It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re circulated and not eliminated, drug protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug-binding occurs. SR/CR FORMULATIONS 32

33. Levine has shown that quaternary ammonium compounds bind to mucin in the GI tract. i.e., Drugs bound to mucin may increase absorption, if the bound drug act as a depot. However, if degradation and/or washing of the drug further down the GI tract occurs, binding of drug to mucin may result in a reduction of free drug available for absorption. The issue of drug and vehicle interaction with the mucin layer and its influence on extent and duration of drug absorption has been reviewed. Main forces for binding proteins are Vander Waal forces , Hydrogen bonding, electrostatic forces.  Charged compounds has greater tendency to bind proteins than uncharged one. SR/CR FORMULATIONS 33

34. REFERENCES Robinson, J. R., Lee V. H. L, Controlled Drug Delivery Systems, Marcel Dekker,Inc., New York, 1992. Biopharmaceutics and pharmacokinetics a treatise by D.M. BRAHMANKAR, SUNIL.B. JAISWAL. WWW.GOOGLE.COM SR/CR FORMULATIONS 34

35. SR/CR FORMULATIONS 35 THANK YOU