Sustained release delivery system: Sustained release delivery system By: Sai Kishan Dept: Industrial Pharmacy Biological factors influencing design and performance of sustained release products: Biological factors influencing design and performance of sustained release products Every biological response parameter gives a useful information to design a sustained release dosage form, without which design of a product becomes difficult. Absorption Distribution Metabolism Duration of action Side effects Margin of safety Role of disease Slide 3: Absorption : Drug is to be uniformly absorbed and released from the dosage form to maintain constant blood level. Placement of a liable drug in a sustained release drug delivery system can sometimes improve the fraction of dose absorbed. In case of oral route, the absorptive character of the different segments of GI tract varies, which also influences the amount and rate of absorption of certain drugs. Ex: Anticoagulant dicumarol, Quaternary ammonium compounds hexamethonium & decamethonium, Aminoglycosides such as gentamicin & kanamycin, When we consider large intestinal absorption variation to this route of administration are due to muscle mobility, water content, tissue integrity….. To design a sustained release dosage form, the minimum absorption rate constant should be lower than 0.25 hr -1 to 0.35 hr -1 is necessary for 95% of the administered dose to be absorbed . Slide 4: Distribution: The distribution of drug is into tissue is an important factor since it not only lowers the concentration of circulating drug but also can be rate limiting with blood and extracellular fluid. One aspect to the distribution is binding of drug to tissue & to proteins. Apparent volume of distribution of a drug is used to determine magnitude of distribution, including binding, within the body. V d = Therefore the dose required to be given can be determined if V d of the drug is known, it is a reflection of how a drug will distribute through out the body depending upon several physiochemical factors ex: solubility, charge, particle size……… The V d may also be used to determine how readily a drug will displace into body tissue compartments relative to the blood: V d = v p + v t Slide 5: Where; V p = plasma volume v t = apparent tissue volume f u = fraction unbound in plasma f ut = fraction unbound in tissue In the beaker the concentration is same and the apparent volume of distribution is same throughout the beaker. In second beaker after a rapid equilibrium, distribution between the solution and charcoal may be complete. However, drug concentration within the beaker are not uniform. Much of the drug is left within the charcoal leaving less drug in the solution. Apparent volume of distribution Slide 7: Metabolism: This process is to inactivate an active drug or convert an inactive drug to an active metabolite. Alteration of drug can occur in variety of tissues. The most responsible organ for metabolism is liver and thus most of the metabolic conversion occurs after a drug is absorbed into the general circulation. Metabolism will be reflected in the elimination constant of a drug or by the appearance of metabolite. It is possible to incorporate this pharmacokinetic parameter into the design of sustained release product, provided the rate and extent of metabolism are predictable and the rate constant(s) for the process are not too large. we need to concentrate on 2 areas relative to metabolism that restrict sustained release product design: on chronic administration whether the drug is capable of inducing or inhibiting enzyme synthesis, this kind of drug will be poor candidate for sustained release product because it will be difficult to attain uniform blood levels of drugs. If variable blood level of drug either through first pass metabolism or intestinal metabolism, it will also make preparation of a sustained release product difficult. Slide 9: Example : Hydralazine is metabolized by the intestinal wall and/or the liver during absorption, although it is well absorbed. Dose- dependent bioavailability behavior for salicylamide when seen, is metabolized during its passage through intestinal wall. When formulated into sustained release dosage forms it showed more passage through intestinal wall. Sustained release systems for the drugs which are extensively metabolized is possible as long as rate of absorption is not too great . Duration of action: The biological half life and duration of action plays a major role in the process of considering a drug for sustained release. Factors influencing the biological half life of a drug include its elimination, metabolism & distribution patterns. Drugs with short life will require frequent dosing to reduce fluctuations in blood levels. Therefore, sustained release dosage forms would be desirable for these kind of drugs. For a given steady state drug concentration, the drug should follow up zero order kinetics. Slide 10: Example: The dose of procaniamide must be given every 3hrs to prevent fluctuations in plasma level by more than 50%. Sustained release formulations of the drug has showed up good benefits by maintaining the plasma level for more than 8 hrs. For drugs like phenylbutazone with a biological half life of 72 hrs its unnecessary to prepare sustained release dosage form. Side effects: Incidence of side effects can be minimized by controlling the concentration at which the drug exists in plasma at any given time, and hence sustained release dosage forms may solve this problem. Example: Brocadopa Temtabs , a sustained release form of levadopa, lowered the incidence of drug induced dykinesis. The technique of sustained release has been more widely used to lower the incidence of GI side effects than that of systemic side effects. The specific sustained release mechanism employed depends on the drug property inducing side effects. Slide 11: Margin of safety: Therapeutic index is to be considered when we go for formulating a sustained release dosage form which can be given by Eq : Therapeutic index= median toxic dose/ median effective dose = TD 50 /ED 50 But, this ratios doesn't provide information on The nature of distribution of toxicity and its effectiveness. The amount of dose producing therapeutic and toxic effects Plasma or serum drug concentrations with respect to toxic and therapeutic levels. In formulating sustained release systems for drugs with narrow therapeutic index, it is imperative that the drug release pattern should concern the plasma concentration achieved is within the therapeutically safe and effective range . There are other factors, such as patient variability , drug accumulation upon multiple dosing , that can alter plasma levels. So, we need to consider all these factors while designing a sustained release dosage system. Slide 12: Role of diseased state: It may not be drug property but in few instances it is equally important as drug properties in considering a drug for controlled release. As in case of rheumatoid arthritis , Aspirin can be formulated into a sustained release delivery system to maintain therapeutic concentrations, particularly throughout the night, thus altering morning stiffness. Physicochemical properties of a drug influencing drug product design and performance Aqueous solubility Partition coefficient Molecular size Drug stability Protein binding Ionization Slide 13: Aqueous solubility: Drug must be in solution before it can be absorbed, compounds with low solubility will not have good absorption . The drugs having poor solubility can be designed into sustained release if the system is capable of retaining the drug in the stomach and gradually releasing it to the small intestine or unless the solubility of the drug is increased. Example: Tetracycline In selecting polymer coatings for sustained system the dissolution rate of a drug must be considered. The slow dissolution rate of compound like antibiotics can be utilized to develop sustained release delivery system. Partition coefficient and Molecular size : Partition coefficient and molecular size influence not only permeation of a drug across biological membranes, but also diffusion across or through a rate controlling membranes or matrix Drugs with extremely high partition coefficient readily penetrate the membranes but cannot proceed further, while drugs with excessive aqueous solubility i.e., low oil/water partition coefficient 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. Slide 14: Drug stability: The stability of the drugs at the site of its release and drug release can be delayed till the dosage form reaches the exposure bio-milieu one more drug property that can influence the design of oral sustained drug delivery. Drugs that are unstable in gastric pH can be developed as sustained release dosage forms and drug release can be delayed till the dosage form reach the intestine. Drugs that undergo gut wall metabolism and show instability are not suitable for sustained drug delivery systems. Protein binding: As drug tend to bind to protein plasma proteins, have an greater effect on duration of action. Drug protein serve as a depot for producing a prolonged release, especially if a high degree of drug-binding occurs. Drugs bound to mucin may increase absorption, by acting as drug depot. However, if drugs reaches down GIT, binding to mucin may cause reduction of free drug available for absorption. Slide 16: Ionization: The essential fact to know is that highly ionized drugs cannnot cross lipid membranes (basically they can't go anywhere) and unionised drugs can cross freely. According to the Henderson- Hasselbalch equation, the difference between the pH of the solution and the pKa of the drug is the common logarithm of the ratio of ionized to unionized forms of the drug. For acid drugs log(ionized/unionized) = pH - pKa , or ratio of ionized to unionized is 10 X / 1, where X = pH – pKa The degree of ionisation depends on the pKa of the drug and the pH of the local environment. The pKa is the the pH at which the drug is 50% ionised. Most drugs are either weak acids or weak bases. Acids are most highly ionised at a high pH (i.e. in an alkaline environment). Bases are most highly ionised in an acidic environment (low pH). Slide 18: References: Controlled drug delivery fundamentals and applications, by Joseph R. Robinson & Vincent H. Lee, Ed- 1987, pg no: 12-36 Controlled and novel drug delivery, by S.N. Sharma, Ed: 1987, pg no: 6-16 http://www. 4um.com/tutorial/science/pharmak.htm http://www.drugdeliverytech.com/ME2/dirmod.asp?sid=&nm=&type=Publishing&mod=Publications%3A%3AArticle&mid=8F3A7027421841978F18BE895F87F791&tier=4&id=7DA76504CDEB49A99B13B4603220A39C http:// campus.houghton.edu/orgs/psychology/principles%20of%20drug%20action.ppt Slide 19: Thank you !