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Manisha Gahlyan*, Saroj Jain
Hindu college of pharmacy
Near Panchayat Bhawan, Gohana Road, Sonepat, Haryana

Oral route has been the most popular and successfully route for controlled delivery of drugs because of the flexibility in the designing of dosage form than other routes. The immidiate release conventional dosage form lack in the efficiency of controlling the proper plasma drug concentration. This factor as well as factors such as repetitive dosing ++and unpredictable absorption leads to the concept of oral controlled release drug delivery systems. A desirable characteristic of controlled release delivery system is that the duration of drug action should be dictated by the design property of drug molecules. There are different mechanistic aspects for design of oral controlled release drug delivery systems such as matrix, reservoir, osmotic pressure, ion exchange resins, altered density etc. This article contains brief review on currently existing oral controlled system and various formulation approaches for the controlled release system.


PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 8

Received On: 29/05/2014; Accepted On: 03/06/2014; Published On: 01/08/2014

How to cite this article: M Gahlyan, S Jain; Oral Controlled Release Drug Delivery System- A Review; PharmaTutor; 2014; 2(8); 170-178

Controlled release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or locally to specified target organ. Greater attention is paid on development of oral controlled release drug delivery systems due to flexibility in designing of dosage form. The main challenges to oral drug delivery systems are to deliver a drug at therapeutically effective rate to desirable site, modulation of GI transit time and minimization of first pass elimination. Control release dosage form provides better maintenance of optimal and effective drug level for prolonged duration with less dosing frequency and side effects1, 2. The modified release oral drug delivery systems classified as are:

* Controlled release-
- Sustained release
- Extended release
- Prolonged release

* Delayed release

The basic rationale of a controlled release drug delivery system is to optimize the biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of disease condition in the shortest possible time by using smallest quantity of drug, administered by most suitable route. The immediate release drug delivery system lacks some features like dose maintenance, controlled release rate and site targeting. An ideal drug delivery system should deliver the drug at a rate dictated by the need of body over a specified period of treatment.

A controlled release drug delivery system is capable of achieving the following benefits over conventional dosage forms4:
· Total dose is low.
· Reduced GI side effects and other toxic effects.
· Reduced dosing frequency.
· Better patient acceptance and compliance.
· Less fluctuation in plasma drug levels.
· More uniform drug effect.
· Better stability of drug.

Factor Influencing the Formulation of Oral Controlled Release Drug Delivery System 2, 3, 5,13
Physicochemical Factors

Low aqueous solubility drugs have low oral bioavailability5. Drugs having good solubility in stomach are poor choice for controlled/sustained oral dosage forms. The water solubility limits the loading efficiency of drug into a variety of carrier systems such as liposome and micro particles, where highly water-soluble drug tend to leach fast from the carrier. The pH dependent solubility particularly in the physiological pH rangewould be another problem for controlled release formulation because of the variation in pH throughout the gastrointestinal tract and variation in the dissolution rate. The biopharmaceutical classification system allow to estimate contribution of three major factors Solubility, Dissolution and Intestinal Permeability which affect oral absorption.

Class III (High solubility-Low permeability) and Class IV (Low solubility-Low permeability) drugs is poor candidate for controlled release dosage form.

Drug Stability
A drug in a solid state undergoes degradation at a much slower rate than a drug in suspension or solution6,7. Drugs that are unstable in gastric pH can be developed as slow release dosage form and the drugs can be delayed till the dosage form reaches the intestine. Drugs that undergo gut-wall metabolism and show instability in small intestine are not suitable for oral controlled drug delivery systems.

Molecular Size and Diffusivity5,8, 9, 10
Diffusivity defined as the ability of a drug to diffuse through membrane, is inversely related to molecular size. Diffusivity depends on size and shape of the cavities of the membrane. More than 95% of drugs are absorbed by passive diffusion. The upper limit of drug molecular size for passive diffusion is 600 Dalton. The examples of the drugs which are difficult to control release rate of medicament from dosage form are proteins and peptides.

Partition coefficients9, 10
Partition coefficient id defined as the fraction of drug in an oil phase to that of an aqueous phase.

It governs the permeation of drug particles through biological membrane. Drugs with high partition coefficient value easily permeate through biological membrane. The diffusion of drug molecules across rate controlling membrane or through the matrix system essentially relies on partition coefficient. Drugs that have lower partition coefficient are not suitable for oral controlled release drug delivery system and drugs that have higher partition coefficient are also not suitable for oral controlled drug delivery system because they will not partition out of the lipid membrane once it gets in the membrane.

Drug pKa and ionization at physiological pH5, 11
Drugs existing largely in ionized form are poor candidate for oral controlled release drug delivery system because absorption rate of ionized drug is 3-4 times less than that of unionized form. The pKa range for acidic drug whose ionization is pH sensitive is around 3.0-7.5 and for basic drug whose ionization is pH sensitive is around 7.0-11.0 are ideal for optimum positive absorption.

Biological factors
Absorption1, 4

The aim of formulating controlled release product is to place a control on delivery system. The desirable quality of oral controlled delivery system is that it should release complete drug and the release drug should be completely absorbed. The fraction of drug absorbed from the system can be lower than the expected due to degradation of drug, protein binding, site-specific, dose-dependent absorption, poor water solubility and  small partition coefficient.

Distribution1, 4, 11
Drugs with high apparent volume of distribution, which influence the rate of elimination of drug, are poor candidate for oral drug delivery system.  The apparent volume of distribution is one of the important parameter of drugs that describes the magnitude of distribution as well as protein binding within the body. The distribution of drug can be determined by the volume of distribution at steady state and T/P ratio.

T/P=K12/ (K21-b)

T=Amount of drug in peripheral compartment, P=Amount of drug in central compartment, K12=Constant for distribution of drug from central to peripheral compartment, K21=Constant for distribution of drug from peripheral to central compartment, b=Slow disposition constant.

Metabolism4, 12
Metabolism of a drug is either an inactivation, of an active drug or conversion of an inactive drug to an active metabolite. There are two factors related to metabolism of drug which restrict the design of sustained/controlled drug delivery.

For chronic administration, drugs that are capable of either inducing or inhibiting enzyme synthesis, they are poor candidates for controlled delivery systems due to difficulty in maintaining uniform blood levels.

Drugs possessing variations in bioavailability due to first-pass effect or intestinal metabolism are not suitable for sustained/controlled drug delivery.

Half- life4, 5
The duration of action is dependent on the biological half- life.  Drugs with short half-life (greater than 2 hrs) are most suitable for controlled drug delivery system. Factors influencing the half-life of a drug are elimination, metabolism, and distribution.

Therapeutic index5
Margin of safety can be described by considering therapeutics index, which is the ratio of median toxic dose and median effective dose.    Therapeutic index = TD50/ED50. Drugs with low therapeutics index are unsuitable for drug incorporation in controlled release formulation.The side effects can be minimized by controlling the concentration within therapeutic range.

Size of dose5
If the dose of a drug in conventional dosage form is high, then it is less suitable candidate for CRDDS. This is because the size of a unit dose controlled release oral formulation would become too big to administer without difficulty.

Absorption window5, 11
Certain drugs when administered orally are absorbed only from a specific part of GI tract. This part is known as ‘absorptionwindow’. These kinds of drugs are not suitable for CRDDS.


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