INTRODUCTION^{15 17}:

Controlled-release systems also offer a sustained-release profile but, in contrast to sustained-release forms, controlled-release systems are designed to lead to predictably constant plasma concentrations, independently of the biological environment of the application site. This means that they are actually controlling the drug concentration in the body, not just the release of the drug from the dosage form, as is the case in a sustained-release system. Another difference between sustained- and controlled-release dosage forms is that the former are basically restricted to oral dosage forms whilst controlled-release systems are used in a variety of administration routes, including transdermal,

oral and vaginal administration. Controlled release of drugs from a dosage form may be achieved by the use of so-called therapeutic systems. These are drug delivery systems in which the drug is released in a predetermined pattern over a fixed period of time.

The release kinetics is usually zero-order. In contrast to sustained-release systems, the dose in the therapeutic systems is of less importance than the release rate from the therapeutic system. Ideally the release rate from the dosage form should be the rate-determining step for the absorption of the drug and in fact for the drug concentration in the plasma and target site. However, controlled-release systems are not necessarily target-specific, which means that they do not ‘exclusively’ deliver the drug to the target organ. This may be achieved by so-called targeted delivery systems which aim to exploit the characteristics of the drug carrier and the drug target to control the bio distribution of the drug. The figure shows an idealized plasma concentration versus time profile of a controlled-release dosage form.

Fig 1 Ideal used plasma concentration versus time profile of a controlled-release dosage form

ADVANTAGES ¹

1. Maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuations.

2. Predictable and reproducible release rates for extended duration.

3. Enhancement of therapeutic activity duration for drugs having short biological half - life

4. Elimination of side effects, frequent dosing and wastage of drugs.

5. Optimized therapy and better patient compliance.

6. To mask the unpleasant taste and odour of drugs.

7. Prevention of vaporization of volatile drugs.

8. Alteration of site of absorption.

9. Elimination of incompatibilities among the drugs.

DISADVANTAGES¹

1. Administration of this type of dosage form does not permit the prompt termination of therapy.

2. 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

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

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

5. The physician has less flexibility in adjusting the dosage regimen. This is fixed by dosage form design

CLASSIFICATION²

1. Rate – preprogrammed drug delivery systems

2. Activation modulated drug delivery systems

3. Feedback regulated drug delivery systems

4. Site-targeting drug delivery systems.

FACTORS AFFECTING THE DESIGN AND PERFORMANCE OF CONTROLLED DRUG DELIVERY SYSTEM³

Physicochemical factors

· Aqueous solubility

· Biological factor

· Drug solubility

· Partition coefficient

· Drug pKa and ionization at physiological pH

· Molecular size and diffusivity

· Half life

· Therapeutic Index

· Dose size

· Absorption window

· Plasma concentration

· Diffusion sustained system

· Concentration dependency

· Diffusion reservoir system

· Diffusion matrix system

DIFFERENT TYPES OF CONTROLLED RELEASE SYSTEM INTENDED FOR ORAL USE^2,3,4,11

1. Matrix tablets

2. Mucoadhesive tablets

3. Microcapsules and microspheres

4. Ion-exchange resins

5. Film coated tablets

6. Swellable tablets

7. Floating tablets

8. Osmotic tablets

9. Micro and multiple emulsions

10. Electrically stimulated release devices

11. Bioadhesive systems

Matrix tablets:

Matrix systems are widely used for the purpose of sustained release. It is the release system which prolongs and controls the release of the drug that is dissolved or dispersed. In fact, a matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e. hydrophilic polymers. 12 By the sustained release method therapeutically effective concentration can be achieved in the systemic circulation over an extended period of time, thus achieving better compliance of patients. Numerous SR oral dosage forms such as membrane controlled system, matrices with water soluble/insoluble polymers or waxes and osmotic systems have been developed, intense research has recently focused on the designation of SR systems for poorly water soluble drugs.

Mucoadhesive tablets:

Bio adhesion is the mechanism by which two biological materials are held together by interfacial forces. When relating this mechanism to the pharmaceutical sciences, mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucus membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water (approximately 95%) within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or Nano sized drug particles into the body.

Microcapsules and microspheres:

Microencapsulation is a process in which very tiny droplets or particles of liquid or solid material are surrounded or coated with polymeric, waxy or protective material. The product obtained by this process is called as micro particles, microcapsules. Particles having diameter between 3 - 800µm are known as micro particles or microcapsules or microspheres. Particles larger than 1000µm are known as Macroparticles. Generally Micro particles consist of two components a) Core material b) Coat or wall or shell material. Microcapsules: micrometric reservoir systems Microspheres: micrometric matrix systems

Ion-exchange resins:

An ion-exchange resin or ion-exchange polymer is a resin or polymer that acts as a medium for ion exchange. It is an insoluble matrix (or support structure) normally in the form of small (0.25–0.5 mm radius) microbeads, usually white or yellowish, fabricated from an organic polymer substrate. The beads are typically porous, providing a large surface area on and inside them. The trapping of ions occurs along with the accompanying release of other ions, and thus the process is called ion exchange. There are multiple types of ion-exchange resin. Most commercial resins are made of polystyrene sulfonate.

Ion-exchange resin beads:

Ion-exchange resins are widely used in different separation, purification, and decontamination processes. The most common examples are water softening and water purification. In many cases ion-exchange resins were introduced in such processes as a more flexible alternative to the use of natural or artificial zeolites. Also, ion-exchange resins are highly effective in the biodiesel filtration process.

Film coated tablets:

In pharmaceutical drug delivery of solid oral dosage forms film coatings are frequently applied. The motivation for coating dosage forms range from cosmetic considerations (colour, gloss), improving the stability (light protection, moisture and gas barrier) and making it easier to swallow the tablet. In addition, functional coatings can be used to modify the drug release behaviour from the dosage form. Depending on the polymers used it is possible either delay the release of the drug (such as in enteric coatings) or use the coating to sustain the release of the drug from the dosage form over extended periods of time. A film coating is a thin polymer-based coat applied to a solid dosage form such as a tablet. The thickness of such a coating is usually between 20-100 µm. It is possible to follow the dynamic curing effect on tablet coating structure by using non-destructive analytical methodologies.

Film coating formulations usually contain the following components:

· Polymer

· Plasticizer

· Colourant

· Opacifier

· Solvent

· Vehicle

Swellable tablets:

Swellable tablets are developed in a size, which can be swallowed and when they reach stomach fluid, swell quickly and attain considerably larger size. The dosage form is larger than the pylorus opening; it cannot pass through pylorus, thereby, the residence time in stomach increases. The gastric emptying of the swellable tablets is affected by their physical properties such as size, shape and flexibility. In addition to the swelling, the gel forming property of the polymer can retain the drug molecules within dosage form, there by sustaining the release of drug from the formulations. Swellable tablets are prepared in various shapes such as disk, string, pellet and tetrahedron. The tetrahedron shaped tablets showed an increased residence time in stomach than tablets of other shapes. The commonly used materials are gum karaya, guar gum, hydroxyl ethyl methacrylate and polyethylene glycol.

Floating tablets:

Increased gastro intestinal transit time is the consequent property of floating tablets. Floating tablets are used for local action in the proximal g.i. tract. These systems are designed to have lesser specific gravity than the gastric contents, thereby float on the gastro intestinal fluid for extended period. Poorly soluble and unstable as well as poorly absorbable (in intestine) drugs are suitable for floating dosage units. Hydrodynamically balanced systems are the typical examples of floating tablets.

Osmotic tablets:

The osmotic tablets are comprised of a drug contained in a rigid, semi permeable membrane in which an aperture (300 μm approx.) is created by a mechanical drill or a laser beam. These systems are suitable for the controlled release of water soluble drugs. The dispersion of drug molecules in the hydrogel with in the tablet leads to controlled release. When water penetrates through the semi-permeable membrane into the tablet mass by osmosis, osmotic pressure is developed with in the tablet and as a result saturated solution of drug is forced out of the tablet through the aperture. The two major factors, which control the release, are the membrane permeability and the quality and quantity of hydrogel polymer. Semi-permeable polymers such as cellulose acetate, ethyl carbamate, polyamide and polyurethane are widely used.

Micro and multiple emulsions:

Micro or sub-micron emulsions are having the dispersed phase diameter less than 0.1μm and appear translucent or transparent and they are thermodynamically stable compared to conventional emulsions. Multiple emulsions are containing three phases either o/w/o or w/o/w type. The selection of type of emulsion depends on the hydrophilic or lipophilic nature of the drugs. Lipid soluble drugs are more suitable to these systems for improved absorption

Electrically stimulated release devices:

Electrical muscle stimulation (EMS), also known as neuromuscular electrical stimulation (NMES) or electromyostimulation, is the elicitation of muscle contraction using electric impulses. EMS has received an increasing amount of attention in the last few years for many reasons: it can be utilized as a strength training tool for healthy subjects and athletes; it could be used as a rehabilitation and preventive tool for partially or totally immobilized patients; it could be utilized as a testing tool for evaluating the neural and/or muscular function in vivo; it could be used as a post-exercise recovery tool for athletes.[1] The impulses are generated by a device and are delivered through electrodes on the skin near to the muscles being stimulated. The electrodes are generally pads that adhere to the skin. The impulses mimic the action potential that comes from the central nervous system, causing the muscles to contract. The use of EMS has been cited by sports scientists[2] as a complementary technique for sports training, and published research is available on the results obtained.[3] In the United States, EMS devices are regulated by the U.S. Food and Drug Administration (FDA).

Bioadhesive systems:

Bioadhesive can be defined as any substance that can adhere to a biological membrane and remain there for an extended period of time. If the membrane substrate is then the polymer is referred to as mucoadhesive3. The bioadhesives increase the residence time and contact time at the area of absorption and provide a high concentration gradient across the membrane.

CUNCLUSION:

Now a day’s modern technologies including target concept have work for successful oral controlled drug delivery. The oral controlled release drug or product provides advantages over conventional dosage form. Therapeutic efficacy and safety of drugs, administrated by conventional methods, can be improved by more precise spatial and temporal placement within the body, thereby reducing both the size and number of doses by using controlled drug delivery system. An ideal controlled drug delivery system is the one which delivers the drug at predetermined rate, locally or systemically for a specified period of time. An ideal targeted drug delivery system deliver the drug only to its site of action. From the above discussion it is concluded that the oral controlled release drug delivery system has been commonly adopted and most convenient route for drug delivery

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Received on 12.06.2018 Modified on 18.07.2018

Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 215-219.

DOI: 10.5958/0975-4377.2018.00033.2