Modified Release Drug Delivery System PDF

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 sit...

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. Jt ;/,~ 2. The frequency of administration of any drug increased the chances of missing the dose of a drug. 3 \~ -:igH:::::::~: ~:::a::::::::s:~::i::::::::ne::::_r;eatedly. ~f Excessively low trough levels may cause loss of therapeutic levels. /: Thus, maintenance of steady state drug levels with minimal fluctuations has v(~, ~ become an important issue in drug delivery, especially with drugs of.relatively 1 ~ ~ narrow therapeutic indices. To overcome these problems, several technical advancements have been made in the development of new drug delivery systems capable of controlling. the rate of drug ,--~ ~ delivery, sustaining the duration of ~ ~ ~~ ~ t1,ii1"2. l!A)i, ~ 1~ ~' \f ' I J,,~ -' ' " y, ·  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. To ic RonQt.J LJ > w TMnJpt"flc.J Ran941 0 0 0 M-,,......,-,-,.-r-,...,....,,....,...,~,..,r-,...,...,.-Jll-r..,...,...,...,.-r-,,-,-,.-r-r-r-r...,....,..""'"7 ID ,.._._..__..........___..,.,_.~I"'-"-..__.__.____.___ _ _ _ ___..J 0 :, XMffectivt a: C Rang TIME (hra) 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) i_s 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. The term modified release used to describe dosage forms that continuously :r:elease drugs at rates which are sufficiently controlled to provide periods of prolonged therapeutic action following each administration of a single dose. 2 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. -=---====------ I. 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. 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. 3.., 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. , _~xtended-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 J-,Ac.,C\/and characterized to achieve a desired drug delivery profile (example, wax matrix). ontrolled- Release dosa e 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 ,J.,cVinvariant with time. y 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. ~ong-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 cA drug).. 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. 4  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..... Toxic leve, --MSC u ~ Zaro oRSer ~-+\ ➔ -f"°1 ~! - controlled f- rele e _ f:.- - MEC Sublherapeutic level , Multiple doalno of Su&talned release conventEonal dosage. T form·. ··.... Single do&o of a ·.... -····· c;onvendonal lebleUcapsule ---+ Time A h)"pCthctical plasma conccntro.tlon-Umc profile from conYcntio11al mullipJc do.sing and single dOlles of sustained end controlled deU ¥Cry !,---:-:nu lat ions A_