INTRODUCTION:

The drug delivery field has advanced for more than 60 years. Two generations have passed since the introduction of the first controlled drug delivery system (the Spansule technology) in the early 1950s.Controlled release formulations were developed to increase patient compliance and convenience. Decades ago it was common to take a drug 3–4 times a day by oral administration.

Over the past 30 years, as the expense and complications involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of novel drug delivery, greater attention has been focused on development of controlled release drug delivery system. The role of drug delivery today is to take a therapeutically effective molecule with sub-optimal physiochemical optimized product that will still be therapeutically effective with added benefits. New drug delivery systems have been developed or are being developed to overcome the limitation of the conventional drug delivery systems to meet the need of the health care system. These systems can be characterized as controlled drug release systems and targeted drug delivery systems. The term “controlled release” has a meaning that goes beyond the scope of sustained drug action.^[1] It also implies predictability and reproducibility in the release rate kinetics, which mean that the release of drug ingredients from a controlled release drug delivery system proceeds at a rate profile that is not only predictable kinetically but also reproducible from one unit to another. Controlled release drug delivery systems provide uniform concentration of drug to the absorption site and thus allows the maintenance of plasma concentration within the therapeutic range which minimizes not only the side effects but also the frequency of administration.^[2]

Classification of rate controlled drug delivery systems: ^[3]

Based on their technical sophistication – controlled drug delivery systems can be classified into

Ÿ Rate – pre programmed drug delivery systems

Ÿ Activation modulated drug delivery systems

Ÿ Feed back regulated drug delivery systems

Ÿ Site-targeting drug delivery systems.

Advantages of Controlled Release Dosage Forms

Ÿ Avoid patient compliance problems

Ÿ Employ less total drug

Ÿ Minimization or elimination of local or systemic side effects.

Ÿ Minimal drug accumulation on chronic usage.

Ÿ Improve efficiency of treatment.

Ÿ Cure or control the condition more promptly.

Ÿ Reduce the fluctuation in drug level. Improves the bioavailability of some drugs.

E.g. Sustained release Aspirin for morning relief of arthritis by dosing before bed times.

Disadvantages.^[4]

Ÿ The physician has less flexibility in adjusting the dosage regimen.

Ÿ This is fixed by dosage form design. Administration of this type of dosage form does not permit the prompt termination of therapy.

Ÿ Economic factors include more costly processes and equipments that are involved in manufacturing many controlled release dosage forms.

Ÿ All drugs are not suitable candidates for controlled release medication.

Ÿ Drugs with long biological half life (e.g.Digoxin-34 hours) are inherently long acting and thus are viewed as questionable candidates for sustained release formulations.

Ÿ Drugs with narrow requirements for absorption (e.g.: drugs which depend on position of G1T for optimum absorption are also poor candidates).

Ÿ Drugs like Riboflavin and ferrous salt, which are not effectively absorbed in lower intestine are poor candidates.

Ÿ Drugs which are having very short half life (<1 hour) e.g.: Penicillin, Furosemide are poor candidates for SR formulations.

Oral drug delivery system:

Oral route is one of the most extensively used routes of drug administration because of its obvious advantages of ease of administration, improved patient compliance and convenience. By definition oral controlled release products refer to those formulations in which a “controlling technology or component” is incorporated that is critical to modulate the drug release pattern in a predictable fashion or that controls the timing and subsequently the location of drug release within GIT. All the pharmaceutical products formulated for systemic delivery via oral route of administration, irrespective of the mode of delivery – (immediate, sustained or controlled release) and the design of dosage forms (either solid, liquid or dispersion) must be developed within the intrinsic characters of GI physiology. Therefore a fundamental understanding of various disciplines including GI physiology, pharmacokinetics, pharmacodynamics and formulation design, is essential to achieve a systemic approach to the successful development of an oral pharmaceutical dosage form.^[5,6] The scientific frame work required for the successful develelopment of an oral delivery system consist of basic understanding of following 3 aspects:

1 Physiochemical, pharmacokinetic and pharmacodynamic characteristic of the drug.

2 The anatomic and physiologic characters of GIT (surface area, length and transit time).

3 Physiochemical characteristics and drug delivery mode of dosage form design. Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit.^[7,8]

Areas of potential

Ÿ Development of a drug delivery system.

Ÿ Modulation of GI transit time.

Ÿ Minimization of hepatic first pass elimination.

Rationale for modifying drug release in the GIT

Ÿ To provide a location specific action within the GIT.

Ÿ To avoid an undesirable local action within the GIT.

Ÿ To provide programmed delivery pattern.

Ÿ To increase the extend of absorption/ bioavailability.

Ÿ To extend the time of action of drug after administration.

MODIFIED-RELEASE DELIVERY SYSTEMS MAY BE DIVIDED CONVENIENTLY IN TO FOUR CATAGORIES

Ÿ Delayed release.

Ÿ Sustained release.

Ÿ Site-specific targeting.

Ÿ Receptor targeting.

Ÿ Sustained-release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the systems can provide some control, whether this is of a temporal or spatial nature, or both, of drug release in the body, or in other words; the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered a controlled-release system.^[9,10]

Sustained Release Preparation^[11]

These preparations may provide an immediate dose required for the normal therapeutic response, followed by the gradual release of drug in amounts sufficient to maintain the therapeutic response for a specific extended period of time usually 8-12 hrs. The major advantage of this category is that, in addition to the convenience of reduced frequency of administration, it provides blood levels that are devoid of the peak and valley effect which are characteristics of the conventional intermittent dosage regimen Sustained release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action.

Controlled Release Preparations^[12]

Although this term has been interchanged widely with sustained release preparation in the past, recently it has become customary to restrict the latter term to formulations where the mechanism of prolonged action is dependent on one or more of the environmental factors in the GI tract such as pH, enzymes concentration, gastric motility etc. On the other hand, the term controlled release dosage form usually applies to preparations that are designed for all routes of administration and where the mechanism of prolonged action is inherent and determined totally by the delivery system itself. Consequently, this category offers the current state of the art products where the drug release profile is controlled accurately, following zero order kinetics and often can be targeted to a special body site or a particular organ.

Advantages of Sustained Release Products^[12]

1. Decreased local and systemic side effects:

Ÿ Reduced gastrointestinal irritation.

2. Better drug utilization:

Ÿ Minimum drug accumulation on chronic dosing.

3. Improved efficiency in the treatment:

Ÿ More uniform blood concentration.

Ÿ Reduction in fluctuation in drug level and hence more uniform pharmacological response.

4. Improved patient compliance:

Ÿ Less frequent dosing.

Ÿ Reduced night-time dosing.

5. Economy

Ÿ Although the initial unit cost of sustained release products is usually greater than that of the conventional dosage form because of the special nature of these products, the average cost of treatment over an extended time period may be less.

Disadvantages^[12]

1. Dose dumping:

Ÿ Dose dumping may occur with faulty formulations.

2. Need for additional patient education:

Ÿ Patients may need substantial additional information as to the proper use of sustained release products e.g. “Do not crush or chew the dosage unit. Tablet residue may appear in the stools”. In some instances, patients must be started on an immediate release product and then switched over to the sustained release products.

3. Possible reduction in systemic availability:

Ÿ Reduced systemic availability has been shown for some sustained release formulations of Theophylline, Procainamide and Vitamin combinations.

BIOLOGICAL FACTORS INFLUENCING ORAL SUSTAINED-RELEASE DOSAGE FORM DESIGN^[13]

1. Biological Half-life:

Drug molecules with short half-life are excellent candidate for sustained-release formulation, since this can reduce dosing frequency. However, this is limited, in that drugs with very short half-lives may require excessive large amounts of drug in each dosage unit to maintain sustained effects, forcing the dosage form itself to become limitingly large. In general drugs with half-lives shorter than 2 hr such as furosemide or levodopa are poor candidates for sustained release preparations.

2. Absorption:

The absorption rate constant is an apparent rate constant, and should, in actuality, be the release rate constant of the drug from the dosage form. Compounds that demonstrate the absorption rate constant will probably be poor candidates for sustaining systems. If a drug is absorbed by active transport, or transport is limited to a specific region of intestine, sustained-release preparations may be disadvantageous to absorption.

3. Metabolism:

Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period, allowing more complete conversion of the drug to its metabolite.

PHYSIOLOGICAL FACTORS INFLUENCING ORAL SUSTAINED-RELEASE DOSAGE FORMS ^[13,14]

1. Dosage Size:

In general, single dose of 500-1000 mg is considered maximal for a conventional dosage form. This also holds true for sustained-release dosage forms. Another consideration is the margin of safety involved in administration of large amounts of drug with a narrow therapeutic range.

2. Ionization, pKa, and Aqueous Solubility:

Most drugs are weak acids or bases. Since the unchanged form of a drug preferentially permeates across lipid membranes, it is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. For dissolution or diffusion sustaining forms, much of the drug will arrive in the small intestine in solid form, meaning that the solubility of the drug may change several orders of magnitude during its release. The lower limit for the solubility of a drug to be formulated in a release system has been reported to be 0.1mg/ml.

3. Partition Co-efficient:

Compounds with a relative high partition coefficient are predominantly lipid soluble and consequently, have very low aqueous solubility. Furthermore these compounds can usually persist in the body for long period, because they can localize in the lipid membranes of cells.

4. Stability:

Orally administered drugs can be subjected to both acid-base hydrolysis and enzymatic

Degradation.

CONCLUSION:

Development of oral sustained release oral dosage form which will prolong the drug release leading to minimize the peak and valley effect in plasma and provide patient convenience. The advantages of sustained-release tablets or capsules are that they can often be taken less frequently than instant formulations of the same drug, By several approaches the residence time of drug delivery system in the gastrointestinal tract can be prolonged. Difference between controlled release and sustain release or sustained release is that controlled release is perfectly zero order release that is, the drug releases with time irrespective of concentration Oral Sustained release (SR) products provide an advantage over conventional dosage forms by optimizing bio-pharmaceutic, pharmacokinetic and pharmacodynamics properties of drugs in such a way that it reduces dosing frequency to an extent that once daily dose is sufficient for therapeutic management through uniform plasma concentration providing maximum utility of drug with reduction in local and systemic side effects and cure or control condition in shortest possible time by smallest quantity of drug tom assure greater patient compliance.

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Received on 12.05.2018 Accepted on 13.07.2018

Asian J. Pharm. Tech. 2018; 8 (3):161-164.

DOI: 10.5958/2231-5713.2018.00026.0