2. The uniform dispersion of a drug into small dosage units reduces the risk of high local drug concentration and their potentially irritating effect on gastric mucosa. Furthermore, drug absorption is maximized and peak plasma fluctuations are reduced .

3. In the case of coated multiparticulates, every pellet acts as a single drug reservoir with its own release mechanism. Any coating imperfection would therefore only affect the release of a small drug portion, in contrast to complete dose dumping from a single-unit drug reservoir.

4. Pellets offer the possibility of combining several active components, incompatible drugs or drugs with different release profiles in the same dosage unit.

5. Dosage forms with different doses can be produced from the same batch by adjusting the fill weight of the pellets.

6. Owing to their smooth surface morphology, narrow size distribution, spherical shape and low friability pellets can be easily coated.

7. Pellets have good flow properties which ensures reproducible die or capsule filling and consequently good content uniformity.

There are some sophisticated technologies by which pellets can be formulated such as:

5.1. Emulsion/Solvent Evaporation³:

Paracetamol/eudragit RS, Paracetamol/ Ethyl cellulose, pellets of different drug/polymer ratios(w/w) were prepared by Emulsion/solvent evaporation technique.

1. Extrusion and spheronization method⁵

Extrusion, a method of applying pressure to a mass until it flows through an orifice or defined opening, because the cross sectional geometry is defined by the orifice, extrude length is usually the only dimensional variable. Generally the extruder used is screw, sieve and basket, roll and ram extruder.

Spheronization the early trade name was Marumerizer, which means “round maker”. Extrudate is charged onto the rotating plate and broken into short segments by collision with the wall.

Fig. Schematic representation of screw-fed extruders: (A) axial extruder and (B) radial extruder⁶.

2. Solution and Suspension layering⁵

Layering a suspension or solution of drug onto a seed material (generally, a coarse crystal or nonpareil) can result in pellets that are uniform in size distribution and generally possess very good surface morphology.

3. Dry powder Layering⁵

This process involved layering a drug powder onto nonpareils using syrup as adhesive solution. In conventional coating pan process the basic component are the rotating pan ,air supply system ,spray system, powder addition system, and air exhaust system.

4. Melt pelletization process⁷:

Melt granulation is a solvent free process in which granulation is obtained through the addition of a binder, melting or softening at a relatively low temperature, after melting, the binder acts like a binding liquid. Polyethylene glycols ,waxes , stearic acid, fats, fatty acids, fatty alcohols and glycerides are typical examples of melt able binders (MBs). By selecting a melting binder, which is insoluble in water, melt granulation might be a way of producing sustained release granules or pellets.

6. Novel freeze pelletization technique⁸:

The freeze pelletization technique is a simple and novel technique for producing spherical matrix pellets containing active ingredients. In this technique, a molten solid carrier along with a dispersed active ingredient is introduced as droplets into an inert and immiscible column of liquid. These droplets can move either in upward or downward directions, depending on their density with respect to the liquid in the column and solidify into spherical pellets.

Fig. Schematics of the freeze pelletization apparatus II

CONTROLLED DRUG DELIVERY SYSTEMS:

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 controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug delivery system. There are several reasons for attractiveness of these dosage form, it is generally recognized for many disease state, a substantial number of therapeutically effective compound already exist. The goal in developing sustained or controlled release drug delivery system is to reduce frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery⁹.

The rationale for development and use of controlled dosage forms may include one or more of the following arguments¹⁰:

• Decrease the toxicity and occurrence of adverse drug reactions by controlling the level of drug and/or metabolites in the blood at the target sites.

• Improve drug utilization by applying a smaller drug dose in a controlled – release form to produce the same clinical effect as a larger dose in a conventional dosage form.

• Control the rate and site of release of a drug that acts locally so that the drug is released where the activity is needed rather than at other sites where it may cause adverse reactions.

• Provide a uniform blood concentration and/or provide a more predictable drug deliver.

• Provide greater patient convenience and better patient compliance by significantly prolonging the interval between administrations.

CLASSIFICATION OF RATE- CONTROLLED DRUG DELIVERY SYSTEMS¹¹:

Based on their technical sophistication controlled-release drug delivery systems that have recently been marketed or are under active development can be classified as¹¹

1. Rate-programmed drug delivery systems

2. Activation –modulated drug delivery systems

3. Feedback-regulated drug delivery systems

4. Site –targeting drug delivery systems

Various Sustained and Controlled Release Delivery Strategies¹²

Sustained or controlled release mechanism	Comments
Rate controlled mechanism^*	Drug is enclosed within device in such a way that the rate of drug release is controlled by its permeation through a membrane wall.
Diffusion controlled	Reservoir devices-diffusion through membrane Monolithic devices-diffusion through bulk polymer
Water penetration controlled	Osmotic systems-osmotic transport of water through semipermeable membrane Swelling systems-water penetration into glassy polymer
Chemically controlled	Monolithic system-Either pure polymer erosion (surface erosion)or combination of erosion and diffusion(bulk erosion) Pendent chain systems-combination of hydrolysis of pendent group and diffusion from bulk polymer.
Polymer matrix diffusion controlled Drug Delivery System	Active agent is homogeneously dispersed throughout a rate controlling polymer matrix and the rate of drug release is controlled by diffusion through the polymer matrix
Activation Modulated Drug Delivery System	In these systems the release of drug is activated by some physical, chemical or biochemical process, or facilited by energy supplied externally. Rate is then controlled by regulating the process applied or energy.
Physical means	Osmotic pressure, Hydrodynamic pressure, vapour pressure activated, Mechanically activated Sonophoresis activated, Iontophoresis activated, Hydration activated
Chemical means	pH, Ion activated, Hydrolysis activated
Biochemical means	Enzyme activated Small molecule activated
Regulated systems	Magnetic or ultrasound –External application of magnetic field or ultrasound to device Chemical –Use of competitive desorption or enzyme-substrate reaction. Rate control is built into the device Implantable infusion pump for long term applications Electrically activated-Iontophoresis pH –activated systems
Feedback-controlled Systems	Bio-responsive Drug delivery system-Glucose triggered insulin system

ORAL CONTROLLED RELEASE SYSTEM:

1. Dissolution controlled release system¹³:

a. Matrix dissolution controlled systems: They are very common and employ waxes such as beeswax, carnauba wax, hydrogenated castor oil, etc. which control drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of tablet,decreasing its wettability or by itself getting dissolved at a slower rate.

b. Encapsulation /coating dissolution controlled system:

Here, the drug particles are coated or encapsulated by one of the several microencapsulation techniques with slowly dissolving materials like cellulose, PEGs, polymethacrylates, waxes,etc.

2. Dissolution and diffusion controlled release systems:

In such systems , the drug core is encased in a partially soluble membrane which

-permit entry of aqueous medium into the core and hence drug dissolution and

-allow diffusion of dissolved drug out of the systems

Polymers used for this system: mixture of ethyl cellulose with PVP or ethyl cellulose.

3. diffusion controlled release systems¹³:

Diagrammatic representation of diffusion controlled system¹⁴:

Fig. Diffusion-controlled (a) reservoir and (b) matrix systems

a) reservoir devices: These systems are hollow containing an inner core of drug surrounded in a water insoluble polymer membrane. The polymer can be applied by coating or microencapsulation techniques.

Polymer used for reservoir devices: hydroxy propyl cellulose, ethyl cellulose and polyvinyl actate¹³ .

b) Matrix diffusion controlled systems: Here, the drug is dispersed in an insoluble matrix of rigid nonswellable hydrophobic materials or swellable hydrophilic substances.

Polymer used for matrix systems: guar gum, tragacanth (natural origin), Hpmc, cmc, xanthan gum (semisyntheic), polyacrylamides (Synthetic)¹³.

Graphs showing comparison between conventional and controlled release drug delivery system¹⁵:

Figure: Plasma concentration-time (Cp vs T) curve following oral administration of equal doses, D, of a drug every 4 hours

• a priming/loading dose: to attain therapeutic levels promptly;

• a maintenance/sustained dose to maintain therapeutic levels for a given period of time.

Figure : Plasma concentration-time curve following oral administration of a zero-order controlled release dosage form.

Polymer used for controlled release drug delivery system¹⁶:

Table Polymers commonly studied for fabrication of extended release monolithic matrices

Hydrophilic polymers:

Cellulosic

Methylcellulose

Hypromellose (Hydroxypropylmethylcellulose, HPMC)

Hydroxypropylcellulose (HPC)

Hydroxyethylcellulose (HEC)

Sodium carboxymethylcellulose (Na-CMC)

Noncellulosic: gums/polysaccharides

Sodium alginate

Xanthan gum

Carrageenan

Ceratonia (locust bean gum)

Chitosan

Guar gum

Pectin

Cross-linked high amylose starch

Noncellulosic: others

Polyethylene oxide

Homopolymers and copolymers of acrylic acid

Water-insoluble and hydrophobic polymers:

Ethyl cellulose

Hypromellose acetate succinate

Cellulose acetate

Cellulose acetate propionate

Methycrylic acid copolymers

Poly(vinyl acetate)

Fatty acids/alcohols/waxes:

Bees’ wax

Carnauba wax

Candelilla wax

Paraffin waxes

Cetyl alcohol

Stearyl alcohol

Glyceryl behenate

Glyceryl monooleate, monosterate, palmitostearate

Hydrogenated vegetable oil

Hydrogenated palm oil

Hydrogenated cottonseed oil

Hydrogenated castor oil

Hydrogenated soybean oil

Recent trends in pellets as controlled release drug delivery system:

1. Yue Cui, Yu Zhang, Xing Tang studied “in vitro and in vivo evaluation of ofloxacin sustained release pellets”. Being a sustained release dosage form, pellets allow ofloxacin to exhibit improved release and absorption profiles. In this paper, the centrifugal granulation method was employed to prepare ofloxacin pellets. Then the pellets were subjected to a coating process with methacrylic acid copolymers to produce sustained release characteristics. The pellets with different coatings were investigated by release tests in vitro Finally, pellets with the best coating suspension were subjected to a multiple doses pharmacokinetic study in beagle dogs¹⁷.

2. Srisagul Sungthongjeen et al.studied “Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique”. It is widely known that gastric residence time (GRT) is one of the important factors affecting the drug bioavailability of pharmaceutical dosage forms¹⁸. A multiple-unit floating drug delivery system based on gas formation technique was developed in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form¹⁹.

Fig. Design of multiple-unit FDDS.

CONCLUSION:

In conclusion, attempts to use pellets as controlled release drug delivery system offers certain advantages over the conventional drug delivery system, still pellets as controlled release drug delivery system requires certain consideration such as which controlled release system should be used, which polymer and excipients should be used ,which technique should be selected for pellet formulation. Hence, more work is needed to explore the potential of this formulation tool. In conclusion, pellet formulation can be of great value in developing new controlled formulations for a variety of drugs and their potential is not yet fully explored. This is an area with very high research and development value in near future.

REFERENCES:

1. Fatemeh Sadeghi et al. Comparative Study of Drug Release from Pellets Coated with HPMC or Surelease. Drug Development and Industrial Pharmacy.2000; 26(6): 651–660.

2. Vasant V. Ranade, Mannfred A. Hollinger. Oral drug delivery in drug delivery systems. CRC Press LLC, Florida.2004; 2nd ed: pp 1-56.

3. Giovanni Filippo Palmieri et al. Emulsion/Solvent Evaporation as an Alternative Technique in Pellet Preparation. Drug Development and Industrial Pharmacy.2000; 26(11): 1151–1158.

4. A. Dukic-Ott et.al. Production of pellets via extrusion–spheronisation without the incorporation of microcrystalline cellulose: A critical review. European journal of pharmaceutics and biopharmaceutics.2009; 71:38-46.

5. Issac Ghebre-Sellassie, Pharmaceutical Pelletization Technology, Marcel Dekker, Inc. /New York.basel.1989.

6. Isaac Ghebre-Sellassie, Axel Knoch. Pelletization Techniques in Encyclopedia of pharmaceutical technology volume 1, Edited by James Swarbrick, Informa Healthcare USA, Inc.,New York.2007;3 rd ed:pp 2651-2663.

7. Jamila Hamdani, Andre J. Moes, Karim Amighi Development and evaluation of prolonged release pellets obtained by the melt pelletization process. International journal of pharmaceutics.2002; 245:167-177.

8. Sreekhar Cheboyina, Christy M. Wyandt, Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique I.Formulation and process variables affecting pellet characteristics. International journal of pharmaceutics.2008; 359:158-166.

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12. S.P.Vyas, Roop k. Khar. Pharmacokinetic Basis of Controlled Drug Delivery In Controlled Drug Delivery concept and advances. Vallabh Prakashan, Delhi.2002; 1st ed: pp 54-97.

13. Brahmankar D.M., Jaiswal S.B. Controlled Release Medication in Biopharmaceutics and pharmacokinetics a treatise. Vallabh Prakashan, New Delhi. 1995; 1st ed: pp 335-375.

14. Anya M.Hillery, Advanced Drug Delivery and Targeting: An Introduction. In Edited by Anya M.Hillery, Andrew W.Lloyd, James Swarbrick. Advanced Drug Delivery and Targeting: An Introduction In Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists. Taylor & Francis, London and New York.2001: pp 55-71.

15. Anya M.Hillery, Drug Delivery: The Basic Concepts. In Edited by Anya M.Hillery Andrew W.Lloyd, James Swarbrick. Drug Delivery: The Basic Concepts In Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists. Taylor & Francis, London and New York.2001: pp 1-42.

16. Sandip B. Tiwari and Ali Rajabi-Siahboomi, Extended-Release Oral Drug Delivery Technologies: Monolithic Matrix Systems .In Edited by Kewal K.Jain, Methods in molecular biology 437 drug delivery systems. Humana press, 999 Riverview Drive, Suite 208, Totowa, NJ 07512 USA.2008; pp 217-245.

17. Yue Cui, Yu Zhang, Xing Tang, In vitro and in vivo evaluation of ofloxacin sustained release pellets. International Journal of pharmaceutics.2008; 360:47-52.

18. Desai, S., Bolton, S., A floating controlled-release drug delivery systems: in-vitro, in-vivo evaluation. Pharm. Res. 1993; 10:1321–1325.

19. Srisagul Sungthongjeen et al. Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique. International journal of pharmaceutics.2006; 324: 136–143.

Received on 17.09.2009

Accepted on 05.11.2009

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 179-183