INTRODUCTION:

In recent years, pulsatile release systems have gained increasing interest. Pulsatile drug delivery systems are the system in which the rapid and transient release of an active molecule within a short time period is produced immediately after a predetermined off release period Alternative terms used to describe pulsatile release are delayed or sigmoidal release. The pulsatile effect i.e. the release of drug as a “pulse” after a lag time has to be designed in such a way that complete and rapid drug release should follow the lag time. Such systems are also called time-controlled as the drug release is independent of the environment. Besides one-pulse systems; multipulse systems release the drug in subsequent pulses. Two different methods have been investigated to induce the pulsatile release of therapeutic agents. One method is the elaboration of pre programmed delivery systems in which the drug is released at a predetermined time or in pulses of known sequence. A second method is the production of system that respond to specific stimuli. The application of pulsatile release systems can be advantageous to adapt a drug therapy to chronopharmacological needs or to target a drug to a specific site in the gastrointestinal tract (GIT), e.g., to the colon^{1, 2}.

Such a novel drug delivery has been attempted for the following:

1. Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology.

2. Avoiding degradation in upper gastrointestinal tract, e.g., proteins and peptides.

3. For time-programmed administration of hormones and many drugs such as isosorbide dinitrate, respectively, to avoid suppression of hormones in the body that can be hampered by constant release of hormone from administered dosage form and development of resistance.

4. For drugs which develop biological tolerance, for the drug with extensive first pass metabolism, for drug targeted to specific site in the intestinal tract, e.g., colon.

CHRONOPHARMACOLOGY OF DRUG EFFECTS

The dependence of several diseases and body function on circadian rhythms is well known. A genetic control of a ‘‘master clock’’ located in the nucleus suprachiasmaticus was recently proposed . A number of hormones, such as renin, aldosterone,or cortisol, show distinct daily fluctuations. Circadian rhythms in the onset and extent of disease symptomswere observed, including diseases such as bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer disease, and hypertension.

Chronopharmacology can affect the drug therapy in two ways, either in daily variations in pharmacodynamics effects or in pharmacokinetics. Many drugs were studied with respect to their pharmacokinetics and chronopharmacology, including analgesics, anticancer drugs, antibiotics, psychoactive drugs, local anesthetics, antiasthmatics, anticonvulsants, and beta blockers. Beta-receptor blocking agents reduced ischemic events mainly during the morning hours. All body functions involved in absorption, distribution, and elimination of drugs can be dependent on circadian rhythms. For example, the gastric emptying time of solids is faster in the morning than in the afternoon. Blood perfusion of the gastrointestinal tract was also found to be higher during early morning hours, which could affect the absorption via passive diffusion.Especially for lipophilic drugs, the time of maximum plasma concentration, tmax, may decrease and maximum plasma concentration, Cmax, may increase when applied in the morning hours. These findings lead to the requirement of a time programmed therapeutic scheme, whereby the drug is at the site of action at the right time in the required amount. This can be realized with pulsatile drug delivery systems ².

CHRONOPHARMACO THERAPY: ³

Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome in selected chronic conditions.^73.

"Chronopharmaceutics" consist of two words chronobiology and pharmaceutics. Chronobiology is the study of biological rhythms and their mechanisms. There are three types of mechanical rhythms in our body. They are:

1. Circadian

2. Ultradian

3. Infradian

Circadian

This word comes from Latin word "circa" means about and "dies" means day

Ultrdian

Oscillation of shorter duration are termed as ultradian (more than one cycle per 24 h)

Infradian
Oscillations that are longer than 24 h (less than one cycle per day)

DISEASES WITH ESTABLISHED OSCILLATORY RHYTHM IN THEIR PATHOGENESIS ³

The diseases currently targeted for chronopharmaceutical formulations are those for which there are enough scientific background to justify chronopharmaceutical drug delivery system, compared to conventional drug administration approach. These include asthma, arthritis, duodenal ulcer, cancer, cardiovascular diseases (e.g., hypertension and acute myocardial infarction), hypercholesterolemia, and ulcer.

Asthma
The circadian rhythm of asthma has been extensively studied. Airway resistanc

increases progressively at night in asthmatic patient.

Arthritis
There is circadian rhythm in the plasma concentration of C- reactive protein and interleukin-6 of patient with rheumatoid arthritis. Patients with osteoarthritis tend to have less pain in the morning and more at night. While patients with rheumatoid arthritis have pain that usually peaks in the morning and decreases throughout day.

Fig no.1 Drug release profile (A) Pulsatile (B) Conventional (C) Extended Release

Duodenal ulcer

Gastric acid secretion is highest during nights in peptic ulcer patients.

Cancer
The blood flow to tumors and tumor growth rate are up to threefold greater during each daily activity phase of the circadian cycle.

Cardiovascular diseases

Capillary resistance and vascular reactivity are higher in the morning and decreases latter in the day. Platelet agreeability is increased and fibrinolytic activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood.

Hypercholesterolemia
Cholesterol synthesis is generally higher during the night time than during day light. The maximal production occurs early in the morning, i.e., 12 h after last meal. Studies with 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors have suggested that evening dosing was more effective than morning dosing .

i. 1:00 am - Post surgical death

ii. 2:00 am - Peptic ulcer

iii. 3:00 am - Blood pressure

iv. 4:00 am - Asthma

CLASSIFICATION:

Method of pulsatile system:-

v Method I :-

This system can be classified into single and multiple unit systems.

· Single unit systems :-

These are sub-classified as:-

Ø Capsule based systems

Ø Osmotic systems

Ø Delivery systems with soluble or erodible membranes

Ø Delivery systems with rupturable coating.

Fig. no.2 Pulsincap^R system

· Multiple unit pulsatile systems :-

These are sub –classified as

Ø System based upon change in membrane permeability.

Ø System based upon rupturable coating.

v Method II

This system can be classified as:

Ø Magnetically stimulated systems.

Ø Ultrasonically stimulated systems.

Ø Electrically stimulated systems.

Ø Photo stimulated systems.

Ø Temperature stimulated system

Ø Mechanical force stimulated system

METHOD – I:

CAPSULE BASED SYSTEM:

Several single unit pulsatile dosage forms with a capsular design have been developed. Most of them consist of an insoluble capsule body, which contains the drug, and a plug, which prevents drug release during the lag phase. Mechanisms of plug removal include dissolution, erosion, or induced pushing-out of the plug by swelling or osmotic pressure. The Pulsincap_ system consisted of a water-insoluble body (hard gelatin capsule coated with polyvinyl chloride), filled with the drug formulation⁴.The capsule half was closed at the open end with a swellable hydrogel plug. Upon contact with dissolution media or gastrointestinal fluids, the plug swelled and pushed itself out of the capsule after a lag time, followed by a rapid release of the capsule content (Fig. 2). The lag time prior to the drug release was controlled by the dimension and the position of the plug. Plug degradation could also be achieved by enzymes being directly incorporated into the plug.In an example, plugs containing pectin, a natural polysaccharide, were degraded by pectinolytic enzymes, whereby the lag time of the system was controlled by the ratio of pectin to enzymes.

Fig no.3 Three layer pulsatile system

Fig. no.4 Chronotopic^R system

OSMOTIC SYSTEM:

Increasing the osmotic pressure within a device may be used as driving force to activate pulsatile release . The principle of an osmotically bursting delivery system is shown in (Fig no.3). Antigen was included in a compressed core of Explotab^® which was coated with Eudragit^® S film plasticized with dibutyl phthalate and Eudragit^® NE with 3% hydroxypropylmethylcellulose (HPMC) as pore former formed an outer coat. When this system came in contact with an aqueous environment, HPMC in the outer coat dissolved to create pores through which water could access Eudragit S film and then enter the implant core. The compressed core would then swell until Eudragit S film ruptured and antigen was released in a single shot. In vitro release profile showed a delay of between 14 and 26 days before release of model antigen. Pulsatile antigen administration was achieved by co-administration of coated and uncoated tablets and produced elevated antibody titers for at least 3 months. Osmotic pressure is used to achieve pulsatile release of tetanus toxoid².

DELIVERY SYSTEM WITH SOLUBLE OR ERODIBLE MEMBRANE:

Most pulsatile delivery systems are reservoir devices coated with a barrier layer. The barrier dissolves or erodes after a specified lag time, after which the drug is released rapidly from the reservoir core. In general, the lag time prior to drug release can be controlled by the thickness of the coating layer. The Chronotopic_ system (Fig.no.4) consisted of a core tablet containing the drug and a HPMC layer, optionally coated with an outer enteric coating. Lag time prior to drug release was controlled by the thickness and the viscosity grade of the HPMC layer. After erosion or dissolution of the rubbery HPMC layer, a distinct pulse was observed. To avoid retarding effects in the drug release phase, the thickness as well as the viscosity grade of the HPMC layer should be limited.

The system probably works best for poorly water-soluble drugs².

DELIVERY SYSTEM WITH RUPTURABLE COATING:

The other class of reservoir-type pulsatile systems is based on rupturable coatings in contrast to the swellable/ erodible layers of the previous section. The drug is released from a core (tablet or capsule) after rupturing of a surrounding polymer layer, caused by a pressure build-up within the system. The pressure necessary to rupture the coating can be achieved with gas-producing effervescent excipients, an increased inner osmotic pressure or swelling agents, such as cellulose ethers, polysaccharides, or superdisintegrants.

Drug-containing tablets with an effervescent mixture of citric acid and sodium bicarbonate coated with ethyl cellulose resulted in a pulsatile release after rupturing of the coating, which was caused by the carbon dioxide development after water penetration into the Core^5.

SYSTEM BASED UPON CHANGE IN MEMBRANE PERMIABILITY:

The permeability and water uptake of Eudragit_ RS or RL [chemical name, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride)], can be influenced by the presence of different counterions in the release medium⁶.It was found that theophylline was released faster from Eudragit_ RS-coated pellets, when succinic, acetic, glutaric, tartaric, malic, or citric acid are present in the release medium⁷.Increased permeability was explained by the higher hydration of the film, also expressed as the ‘‘free volume.’’ Several delivery systems with sigmoidal or pulsatile release patterns were derived on this ion exchange. The sigmoidal release system (SRS) consisted of pellet cores, containing drug and succinic acid, coated with Eudragit_ RS ⁸.The lag time was controlled by the rate of water influx through the coating. The water then dissolved succinic acid and the drug inside the core, and the acid solution increased the drug permeability of the hydrated polymer film by interacting with the quaternary ammonium groups. In a similar system, theophylline and sodium acetate, acting as the permeability modifying salt, were layered on sugar pellets, followed by coating with Eudragit_ RS30D⁹.The lag time increased with increasing thickness of the outer membrane. The slope of the drug release phase was independent of the thickness but was influenced by the amount of the salt in the system. The release profile of systems based on permeability changes appeared to depend strongly on the physicochemical properties of the drug and its interaction with the membrane. A pulsatile release profile may be obtained for some particular drug molecules in a specific formulation but cannot be generally applied to all drugs.

SYSTEM BASED UPON RUPTURABLE COATING:

The time-controlled explosion system (TES) was a multiparticulate system, whereby the drug was layered on an inner core, followed by a swellable layer (e.g. hydroxypropyl cellulose) of optimal thickness (at least180 mm) and an insoluble polymeric top layer (e.g., ethylcellulose^{) 10,11}. Upon water ingress, the swellable layer expanded resulting in film rupturing with subsequent rapid drug release. The release was described to be independent of the environmental pH and drug solubility. The lag time increased with increasing coating level and higher amounts of talc or lipophilic plasticizer in the coating, and the release rate increased with increasing concentration of the osmotically active agents. In vivo studies of the time-controlled explosion system, which had an in vitro lag time of 3 hr, showed first drug blood levels after 3 hr and maximal blood levels after 5 hr¹².

METHOD II:

MAGNETICALLY STIMULATED SYSTEM:

Use of an oscillating magnetic field to modulate the rates of drug delivery from a polymer matrix was one of the first methodologies investigated to achieve an externally controlled drug delivery system . Magnetic carriers can receive their magnetic response to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt and steel. Magnetic steel beads were embedded in an ethylene and vinyl acetate (EVAc) copolymer matrix that was loaded with bovine serum albumin as a model drug. it demonstrated that increased rates of drug release in the presence of an oscillating magnetic field . During exposure to the magnetic field, the beads oscillate within the matrix, alternatively creating compressive and tensile forces. This in turn acts as a pump to push an increased amount of the drug molecule out of the matrix. Co-polymers with a higher Young's modulus were more resistant to the induced motion of steel beads, and consequently the magnetic field has less effect on the rate of drug release from these materials. Different formulations developed for in vitro magnetically triggered delivery of insulin based on alginate spheres. In an experiment, ferrite microparticles (1 mm) and insulin powder were dispersed in sodium alginate aqueous solution. The ferrite-insulin alginate suspension was later dropped in aqueous calcium chloride solution which causes the formation of cross linked alginate spheres, which were further cross linked with aqueous solution of poly(L-lysine) or poly(ethylene imine). They described that the magnetic field characteristics due to the ferrite microparticles and the mechanical properties of the polymer matrices could play role in controlling the release rates of insulin from the system.

US Patent 2006997863 provides a treatment method that involves the administration of a magnetic material composition, which contains single-domain magnetic particles attached to a target-specific ligand, to a patient and the application of an alternating magnetic field to inductively heat the magnetic material composition, which cause the triggered release of therapeutic agents at the target tumor or cancer cells¹.

ULTRASONICALLY STIMULATED SYSTEM:

Ultrasound is mostly used as an enhancer for the improvement of drug permeation through biological barriers, such as skin, lungs, intestinal wall and blood vessels. There are several reports describing the effect of ultrasound on controlled drug delivery. In an ultrasound-enhanced polymer degradation system, during polymer degradation incorporated drug molecules were released by repeated ultrasonic exposure. As degradation of biodegradable matrix was enhanced by ultrasonic exposure, the rate of drug release also increased. Thus, pulsed drug delivery was achieved by the on-off application of ultrasound^. Macromolecular drug release from biodegradable poly (lactic acid) microspheres was also reported. Drug release from porous poly (lactic acid) microspheres showed an initial burst followed by a sustained release for over several months. When ultrasound was applied to this release system, pulsatile and reversible drug release was observed. It speculated that ultrasonic exposure resulted in the enhancement of water permeation within microspheres of the polymer matrix, inducing drug dissolution into the releasing media. Ultrasound used to achieve up to a 27-fold increase in the release of 5-fluorouracil from an ethylene and vinyl acetate (EVAc) matrix^.Increasing the strength of the ultrasound resulted in a proportional increase in the amount of 5-fluorouracil released. Increase in the rate of p-nitroaniline delivery from a polyanhydride matrix during ultrasonic irradiation is reported^.It noted that the increase in drug delivery was greater than the increase in matrix erosion when the ultrasound triggering was active. Thus, it was hypothesized that acoustic cavitation by ultrasonic irradiation was responsible for the modulated delivery of p-nitroaniline¹.

ELECTRICALLY STIMULATED SYSTEM:

An electric field as an external stimulus has advantages such as availability of equipment, which allows precise control with regards to the magnitude of the current, duration of electric pulses, interval between pulses etc. Electrically responsive delivery systems are prepared from polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus pH-responsive as well as electro responsive. Under the influence of electric field, electro responsive hydrogels generally deswell, swell or erode. The mechanisms of drug release include ejection of drug from the gel as the fluid phase synereses out, drug diffusion along a concentration gradient, and electrophoresis of charged drug towards an oppositely charged electrode and liberation of the entrapped drug as the gel complex erodes¹³. Synthetic as well as naturally occurring polymers, separately or in combinations, have been used for this purpose. Examples of naturally occurring polymers include hyaluronic acid, chondrotin sulphate, agarose, carbomer, xanthan gum and calcium alginate. The synthetic polymers are generally acrylate and methacrylate derivatives such as partially hydrolysed polyacrylamide, polydimethyl aminopropyl acrylamide.

Poly (2-acrlamide-2-methylpropanesulfonic acid-co-butyl methacrylate) (P(AMPS-co-BMA) hydrogels were used for electric stimuli-induced drug delivery system. Positively charged edrophonium chloride was incorporated as drug molecule within negatively charged P(AMPS-co-BMA) hydrogels. By applying an electric field, ion exchange between edrophonium ions and protons commenced at cathode, resulting in rapid drug release from hydrogels. This rapid drug release was attributed to the electrostatic force, squeezing effect, and electro-osmosis of the gel. Complete on-off drug release was achieved, as no drug release was apparent without the application of electric current. Complex multi-component gels or interpenetrating networks have been prepared in order to enhance the gel's electro responsiveness. Calcium alginate/ poly (acrylic acid) composites were prepared, where the polyacrylic acid (PAA) chains were expected to be entangled through the calcium alginate matrix. PAA, which contains a large number of free carboxylic groups, was included to increase the gel's sensitivity to pH and electrical stimuli. The increased proportion of PAA in the composites led to a greater pH and electro-response¹⁴.

PHOTO STIMLATED SYSTEM:

The interaction between light and material can be used to modulate drug delivery. This can be accomplished by combining a material that absorbs light at a desired wavelength and a material that uses energy from the absorbed light to modulate drug delivery. Gold nanoshells are a new class of optically active nanoparticles that consist of a thin layer of gold surrounding a core. The optical properties of the nanoshells can be tuned over the visible and near IR spectrum. Embedding the nanoshells in a NIPAAm-co-AAM hydrogel formed the required composite material. When exposed to near-infrared light, nanoshells absorb the light and convert it to heat, raising the temperature of composite hydrogel above its LCST. The hydrogel collapses and these results in an increased rate of release of soluble drug held with in the matrix¹⁵.

TEMPERATURE STIMULATED SYSTEM:

Temperature is the most widely utilized triggering signal for a variety of triggered or pulsatile drug delivery systems. The use of temperature as a signal has been justified by the fact that the body temperature often deviates from the physiological temperature (37º) in the presence of pathogens or pyrogens. This deviation sometimes can be a useful stimulus that activates the release of therapeutic agents from various temperature-responsive drug delivery systems for disease accompanying fever. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery devices such as hydrogels and micelles. Special attention has been given to the thermally responsive poly (N-isopropylacrylamide) and its derivative hydrogels. Poly (N-isopropyl acryl amide) (PIPAAm) cross-linked gels have shown thermo responsive, discontinuous swelling/deswelling phases: swelling for example, at temperatures below 32°, while shrinking above this temperature. A sudden temperature increase above the transition temperature of these gels resulted in formation of a dense, shrunken layer on the gel surface (skin layer), which hindered water permeation from inside the gel into the environment. Drug release from the PIPAAm hydrogels at temperature below 32° was governed by diffusion, while above this temperature drug release was stopped completely, due to the 'skin layer' formation on the gel surface (on-off drug release regulation)¹⁶^-19 . Thermo-responsive polymeric micelle systems constitute polymeric micelles whose properties and biological interests make them a most noteworthy candidate as drug carrier for the treatment of cancer . The polymeric micelle is composed of amphiphilic block copolymers exhibiting a hydrophobic core with a hydrophilic corona. Due to these unique characteristics, polymer micelles exhibit stealth characteristics and are not detected by the body defense system (reticuloendothelial system). Thus passive targeting could be achieved through enhanced permeation retention (EPR) effect of tumor sites¹ .

MECHANICAL FORCE STIMULATED SYSTEM:

Drug delivery can also be initiated by mechanical stimulation of an implant. Alginate hydrogels that release vascular endothelial growth factor in response to compressive forces of varying strain amplitudes were developed. Free drug that is held with in the polymer matrix is released during compression; once the strain is removed hydrogel returns to its original volume. This concept is essentially similar to squeezing the drug out of a sponge²⁰.

MERITS:

1. As time specific, PDDS reduces hepatic degradation of drug, increases bioavailability and reduces dose of drug.

2. As site specific, damage to tissue other than the targeted is reduced.

3. Maintain nearly constant drug levels at the site of action and therefore minimization of peak-trough-fluctuations, reduced frequency of administration.

4. The system like, Port® system, avoided second time dosing which was beneficial for school children during day time.

DEMERITS:

1. Skilled person is required.

2. Dose dumping may be problem.

3. High cost of production.

COMMERCIALPRODUCTS:

Advancis Pharmaceutical Corp., German town, Maryland, USA has developed once-a-day pulsatile delivery system called Pulsys®, which enables the delivery of antibiotic amoxicillin in regular concomitant pulses. Advancis is developing Pulsysβ versions of three of the top five most prescribed antibiotics in the United States. Asthmatic patients suffer from lung discomfort more in early morning due to circadian changes. Therefore, it is desirable to get maximum bronchodilating effect in the morning hours. One such example is of a bronchodilator "Uniphyl" (theophylline) which was developed by Purdue Pharmaceuticals Products L. P., Stamford, USA, and approved by FDA in 1989. It's a once-a-day formulation. When taken in the evening, it reaches to peak blood levels in the morning hours, resulting in improved lung functioning and relief to the patient.
There are examples where varying plasma levels are required during the day time. Elan applied this technology to a product of Novartis, Ritalinβ, containing methylphenidate to get a pulsatile once-daily dosage form that replaces the twice-a-day regimen¹.

CURRENT AND FUTURE DEVLOPMENT:

Pulsatile-release formulations have many advantages over immediate-release formulations. With these formulations, less-frequent drug administration is possible, and patient compliance can correspondingly be improved. In the field of drug delivery, increased attention has recently been focused on the potential of systems that are able to release drugs after a programmable lag phase commencing at administration time, i.e., in a pulsatile mode. During the last two decades, technologies to ensure time-controlled pulsatile release of bioactive compounds have been developed. Significant progress has been made towards achieving pulsatile drug delivery systems that can effectively treat diseases with non-constant dosing therapies, such as diabetes. However, there is much work that needs to be carefully demonstrated for the pulsatile delivery of bioactive compounds, especially hormones³.

CONCLUSION:

As the pulsatile drug delivery system is site specific or time controlled, it has great advantage over the controle drug delivery system. As the external regulated system, it provides the drug when we need. it is conclude that Pulsatile drug delivery is one such system that, by delivering drug at the right time, right place, and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension, etc.

REFERENCE:

1. Arora S, Ali J, Ahuja A, Baboota S, Qureshi J. Pulsatile drug delivery systems: An approach for controlled drug delivery. Indian J Pharm Sci 2006;68:295-300

2. James swarbrick, encyclopedia of pharmaceutical technology ,3 edn.,2007, 2, 1287

3. Belgamwar VS, Gaikwad MV, Patil GB, Surana S. Pulsatile drug delivery system. Asian J Pharm 2008;2:141-5

4. Wilding, I.R.; Davis, S.S.; Bakhshaee, M.; Stevens, H.N.E.; Sparrow, R.A.; Brennan, J. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharm. Res. 1992, 9, 654–657.

5. Kro¨ gel, I.; Bodmeier, R. Floating or pulsatile drug delivery systems based on coated effervescent cores. Int. J. Pharm. 1999, 187, 175–184.

6. Bodmeier, R.; Guo, X.; Sarabia, R.E.; Skultety, P. The influence of buffer species and strength on diltiazemhcl release from beads coated with aqueous cationic polymeric dispersions, Eudragit RS, RL30D. Pharm. Res. 1996, 13 (1), 52–56.

7. Narisawa, S.; Nagata, M.; Danyoshi, C.; Yoshino, H.; Murata, K.; Hirakawa, Y.; Noda, K. An organic acidinduced sigmoidal release system for oral controlled-release preparations. Pharm. Res. 1994, 11 (1), 111–116.

8. Narisawa, S.; Nagata, M.; Hirakawa, Y.; Kobayashi, M.; Yoshino, H. An organic acid-induced sigmoidal release system for oral controlled-release preparations: 2. Permeability enhancement of Eudragit RS coating led by the physicochemical interactions with organic acid. J. Pharm. Sci. 1996, 85 (2), 184–188.

9. Beckert, T.E.; Pogarell, K.; Hack, I.; Petereit, H.-U. Pulsed drug release with film coatings of Eudragit RS30D. Proceed. Int. Symp. Control. Rel. Bioact. Mater., Boston, MA, 1999; Controlled Release Society: Minneapolis, MN, 1999; 5219.

10. Ueda, Y.; Hata, T.; Yamaguchi, H.; Ueda, S.; Kotani, M. Time Controlled Explosion System and Process for Preparation the Same. US Patent 4,871,549, October 3, 1989.

11. Ueda, S.; Yamaguchi, H.; Kotani, M.; Kimura, S.; Tokunaga, Y.; Kagayama, A.; Hata, T. Development of a novel drug release system, time-controlled explosion system (TES): II. Design of multiparticulate TES and in vitro drug release properties. Chem. Pharm. Bull. 1994, 42 (2), 359–363.

12. Hata, T.; Shimazaki, Y.; Kagayama, A.; Tamura, S.; Ueda, S. Development of a novel drug delivery system (TES): V. Animal pharmacodynamic study and human bioavailability study. Int. J. Pharm. 1994, 110, 1–7.

13. Murdan, S., J. Control. Release, 2003, 92, 1.

14. Kim, S.Y. and Lee, Y.M., J. Appl. Polym. Sci., 1999, 74, 1752

15. Averitt, R.D., Westcott, S.L. and Halas, N.J., J. Opt. Soc. Amer. B., 1999, 16, 1824.

16. Bae, Y.H., Okano, T. and Kim, S.W., Pharm. Res., 1991, 8, 531.

17. Bae, Y.H., Okano, T. and Kim, S.W., Pharm. Res., 1991, 8, 624.

18. Dong, L.C. and Hoffman, A.S., J. Control. Release, 1990, 13, 21.

19. Okano, T., Bae, Y. H., Jacobs, H. and Kim, S.W., J. Control. Release,1990, 11, 255.

20. Lee, K.Y., Peters, M.C., Anderson, K.W. and Mooney, D.J., Nature, 408, 998.

Received on 19.08.2009 Modified on 23.10.2009

Research J. Pharm. and Tech. 3(1): Jan. - Mar. 2010; Page 32-38