Bio-pharmaceutics of Sustained Release Dosage Forms

1. Bio-pharmaceutics of Sustained Release Dosage Forms

2. INTRODUCTION DEFINITIONS:- • SRF’s describes the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-12hrs)of time. Time depends on the dosage form. In oral form it is in hours, and in parenteral’s it is in days and months. Ex: Aspirin SR, Dextrim SR. • Controlled release dosage form: In this the rate or speed at which the drug is released is controlled. Ex: Adalat CR (Nifidipine), Dynacirc CR (Isradipine.)

3. CONCEPT The of SRDF’s is to obtain Zero order release from the dosage form. • Zero order release is a release which is independent of the amount of drug present in the dosage form. • Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion. • Pharmacological action is seen as long as the drug is in therapeutic range, problems occur when drug concentration is above/below therapeutic range. GOALS

4. ORAL suspensions Pellets Solutions Suspensions Ion exchange resin Slightly soluble salts complexes Mixed release granules Porous inert carrier Repeat action Multilayer granules Osmotic system SUSTAINED RELEASE DOSAGE FORMS PARENTRALS Capsules Tablets Slow release

5. ADVANTAGES • Improved patient compliance: • Less frequent dosing • Allows whole day coverage. • Decreased local and systemic side effects. • Decreased GIT irritation. • Decreased local inflammation. • Better drug utilisation. • Decreased total amount of drug used. • Minimum drug accumulation on chronic dosing. • Improved efficiency in treatment. • Uniform blood and plasma concentration. • Decreased fluctuation in drug level i.e uniform pharmacological response. • Increased bioavailability of some drugs • Special effects: SR Aspirin gives symptomatic relief in Arthritis after waking • Economy

6. DISADVANTAGES • DOSE DUMPING :Increase quantity of drug release causes dumping of drug which in turn leads to toxicity. • REDUCED POTENTIAL FOR ACCURATE DOSE ADJUSTMENT: Administrating a fraction of drug is not possible. • NEED FOR ADDITIONAL PATIENT EDUCATION: “Do not Crush or Chew the dosage unit”. “ Tablet residue may appear in stools”. • STABILITY PROBLEMS: The complexity of SRF’s will lead to stability problem. • REDUCTION IN SYSTEMIC AVAILABILITY: Example Theophylline, Procainamide and vitamin combinations.

7. DISADVANTAGES continued.. • Retrieval of the drug is difficult in case of toxicity / poisoning / hypersensitive reaction. • Higher cost of the formulation. • Half life: Drugs having shorter half life (less than one hour) and drugs having longer half life (More than twelve hrs) cannot be formulated as SRDF’s. • If a dosage form contains more than 500mgs., of active ingredient formulation of SRDF’s is difficult. • If CRDF is required (With New polymers) cost of government approval is very high.

8. FACTORS TO BE CONSIDERED WHILE FORMULATING A SRDF’s • DRUG PROPERTIES: Stability, solubility, partition coefficient and protein binding are to be considered. • ROUTE OF DRUG DELIVERY: Area of the body where drugs are applied or administered play a vital role. • TARGET SITES: To minimize side effects, its desired to maximize the fraction of dose applied. • ACUTE OR CHRONIC DOSING: Cure, Control and length of drug therapy must be considered. • THE DISEASE: Pathological conditions play a significant role. • THE PATIENT: Ambulatory/ bedridden, young or old, etc., must be considered.

9. PHYSICOCHEMICAL PROPERTIES • AQUEOUS SOLUBILITY & pKa • PARTITION COEFFICIENT • DRUG STABILITY • PROTEIN BINDING • MOLECULAR SIZE & DIFFUSIVITY • DOSE SIZE

10. AQUEOUS SOLUBILITY For a drug to be absorbed, it must first dissolve in the aqueous phase surrounding the site of administration. • AqS of a drug influences its dissolution rate which in turn establishes its concentration in solution. • Dissolution rate is related to AqS solubility as shown by Noyes Whitney equation under sink condition( CGIT»C) dc/ dt= KD ACS dc/ dt- dissolution rate KD - dissolution rate constant A- Total surface area of drug particles. CS-Aqueous saturation solubility.

11. Drugs with low aqueous solubility have low dissolution rate and have oral bioavailability problems. E.g.: Tetracycline. • Drugs with high aqueous solubility are undesirable to formulate SRDF’s. E.g.: Aspirin.

12. The aqueous solubility of weak acids & weak bases is governed by the pKa of the compound and pH of the medium. FOR WEAK ACID St = So(1+Ka\[H ] =So(1+10pH-pKa) St – Total solubility of the weak acid So – Solubility of the un-ionized form Ka – Acid dissociation constant H - Hydrogen ion concentration Weakly acidic drug exist as unionized form in the stomach absorption is favored by acidic medium pKa

13. FOR WEAK BASES: St = So(1+[H ] \Ka) =So(1+pKa-pH) St– Total solubility of both conjugate and free base form of weak base. So– Solubility of the free base. Weakly basic drug exists as ionized form in the stomach hence absorption of this type is poor in this medium.

14. PARTITION COEFFICIENT • Between the time of drug administration & elimination it diffuse through several membranes ( Lipid barrier’s) • Oil/Water partition coefficient plays a major role in evaluating the drug penetration. K=Co/Cs Where.. Co= Equilibrium concentration in organic phase. Cs= Equilibrium concentration in aqueous phase. • Drugs with extremely high partition coefficient are very oil soluble and penetrates in to various membranes very easily.

15. Contd……….. Log activity Log K • The relationship between tissue penetration and partition coefficient for the drug is known as Hansch Correlation. • The activity of the drug is a function of its ability to cross membranes and interact with receptors. The more effectively the drug crosses the membrane the greater is the activity

16. Contd…….. • There is an optimum partition coefficient for a drug in which it permeates membrane effectively and shows greater activity. • Partition coefficient with higher or lower than the optimum are poorer candidates for the formulation • Unionized water soluble are highly absorbed from the intestine and lipid soluble drugs are absorbed from the tissue.

17. Contd…….. • Values of partition coefficient below optimum result in the decreased lipid solubility and remain localized in the first aqueous phase it contacts. • Values larger than the optimum , result in poor aqueous solubility but enhanced lipid solubility and the drug will not partition out of the lipid membrane once it gets in.

18. Solid state undergoes degradation at much slower rate than in the suspension or solution etc.. • Drugs stable in stomach gets released in stomach and which are unstable gets released in intestine. • Drugs with stability problems in any particular area of G.I.T are less suitable for the formulation. • Drugs may be protected from enzymatic degradation by incorporation in to a polymeric matrix. DRUG STABILITY

19. Drug binding to plasma proteins (albumins) & resulting retention of the drug in the vascular space. • Drug-protein complex can serve as a reservoir in vascular space. • Main forces for binding are Vander Waal forces, hydrogen bonding , electrostatic forces. • Charged compounds has greater tendency to bind proteins than uncharged ones. • Extensive binding of plasma proteins results in longer half-life of elimination for the drug • E.x..95% binding in Amitriptyline , diazepam , diazepoxide. PROTIEN BINDING

20. The ability of the drug to diffuse through a membrane is called diffusivity (Diffusion coefficient). It is the function of its molecular size (molecular weight). In most polymers it is possible to relate log D to some function of molecular size as, Log D = -Svlog V + Kv = -Smlog M+ Km MOLECULAR SIZE & DIFFUSIVITY

21. Contd..., V – Molecular volume. M – Molecular weight. Sv, Sm, Kv & Km are constants The value of D is related to the size and shape of the cavities, as well as the drugs. The drugs with high molecular weight show very slow kinetics.

22. For those drugs requiring large conventional doses, the volume of sustained dose may be too large to be practical. • The compounds that require large dose are given in multiple amounts or formulated into liquid systems. • For oral route the volume of product is limited by patients. For IM,IV or SC routes its tolerated. DOSE SIZE

23. ABSORPTION • DISTRIBUTION • METABOLISM • ELIMINATION & HALF LIFE • SIDE EFFECTS & MARGIN OF SAFETY • ROLE OF DISEASED STATE • ROLE OF CIRCADIAN RHYTHM BIOLOGICAL PROPERTIES

24. The release of a drug from a dosage form is important than its absorption. • The reason of poor absorption are poor water solubility, low partition coefficient, acid hydrolysis and metabolism. • For SRDF’s rate of release is much slower than the rate of absorption. • Transit time of drug is between 9-12hrs. • Maximum absorption half-life should be 3-4hr. ABSORPTION

25. Continued.. • Low density pellets, capsules or tablets are formulated which float on top of gastric juice and delay their transfer out of stomach e.g. PABA • GI retention for drugs with poor absorption can be increased by enhancers. • Bioadhesive materials is made which has high affinity to the mucin coat. • A drug that is slowly absorbed is poor candidate for SRDF eg.,Gentamycin, Hexamethonium

26. Distribution of drugs in to vascular & extra vascular spaces is an important factor. • Apparent volume of distribution & drug concentration in tissue to that of plasma at steady state are important parameters for distribution. It is called T\P ratio. • Calculation of this distribution is mainly based on one compartment pharmacokinetic models. It is given by.. • V= Dose\Co • Co–Initial concentration immediately after i.v bolus injection DISTRIBUTION

27. For two compartment models, the total volume of distribution is given by the apparent volume of the distribution at steady state • Vss = (1+K12\K21)V1 • Where. • V1 - Volume of the central compartment • K12-Rate constant for distribution of the drug • from central compartment to peripheral • K21 - Peripheral to the central compartment • blood or plasma to the total volume.

28. Metabolic conversion of drug to another chemical form. • Factors associated with metabolism are; • Ability of drug to induce or inhibit enzyme synthesis. This results in fluctuating drug blood level with chronic dosing. • Fluctuating drug blood level due to intestinal metabolism or through a hepatic first pass effect. Ex.., intestinal metabolism upon oral dosing are hydralazine , salicylamide , nitroglycerine. METABOLISM

29. Rate of elimination of the drug is described quantitatively by its biological half life i.e.. T1/2. • The half life of the drug is related to its apparent volume of distribution and its systemic clearance. • t1/2 = 0.693V/CLs = 0.693 AUC/dose ELIMINATION & BIOLOGICAL HALF-LIFE

30. Contd... • A drug with shorter half life requires frequent dosing. • Drugs with half life 2hr should not be used ,since such system requires unexpectedly large release rate and large doses. E.x.., Ampicillin , Cephalosporin • Drugs with half life greater than 8 hrs should not be used, formulation of such drugs is unnecessary. E.x.., Diazepam, Digitoxin , Digoxin

31. SRDF is useful in minimizing the side effects of the drug. • Slow release potassium – SR of potassium to prevent gastric irritation. Timed release of aspirin – to prevent gastric irritation. • Measure of margin of safety of the drug is THERAPEUTIC INDEX(TI). • TI = TD50\ED50 • TD50 = median toxic dose • ED50 = median effective dose. • For potent drugs TI value is small. Larger the value of TI safer the drug. • Drugs with small value of TI are poor candidates for the formulation. • A drug is considered to be relatively safe if TI exceeds 10. • Some drugs of TI less than 10 are Digitoxin, Digoxin and Phenobarbitone. SIDE EFFECTS

32. Text book of Sustained release dosage form by Y.S.Robinson, Decker Series. • Controlled release dosage form by Y.W.Chien. • Ansel’s Pharmaceutical Dosage forms and Drug delivery Systems. • Tutorial Pharmacy by Cooper and Gunns. • Remington’s Pharmaceutical Sciences • Text book of Pharmaceutics by Bentley and Drivers. • www.google.co.in (CRDF design- google book result- cherng-jukin). • Text book of Pharmaceutical Sciences by Aulton. REFERENCES

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