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Osmotic Controlled Drug Delivery System

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During the past three decades significant advances have been made in the area of novel drug delivery. This was in part due to the evolving discipline of biopharmaceutics, pharmacokinetics and pharmacodynamics.

In a typical therapeutic regimen the drug dose and dosing interval are optimized to maintain drug concentration with in the therapeutic window, thus ensuring efficacy while minimizing toxic effects. Survey indicated that dosing more than one or twice daily, greatly reduces patient compliance. So in recent year considerable attention has been focused on the development of novel drug delivery system and the main reason for this paradigm shift is relatively low development cost and time required for introducing a novel drug delivery system as compared to a new chemical entity. In the form of novel drug delivery system, an existing drug molecule can get a new life there by increasing its market value competitiveness and patent life among the various novel drug delivery system available in the market, per oral controlled release system hold the major market share because of their obvious advantages of ease of administration and better patient compliance. These products provide significant benefits over immediate release formulation, including greater effectiveness in the treatment of chronic conditions, reduced side effects, and greater patient convenience due to simplified dosing schedule1.

A number of design options are available to control or modulate the drug release from a dosage form. Majority of per oral dosage form fall in the category of matrix, reservoir or osmotic system. In matrix system, the drug is embedded in polymer matrix and the release takes place by partitioning of drug into the polymer matrix and the release medium. In contrast, reservoir systems have a drug core surrounded\coated by the rate controlling membrane. However factor like pH, presence of food and other physiological factor may affect drug release from conventional controlled release systems. Osmotic systems utilize the principle of osmotic pressure for the delivery of drugs. Drug release from these systems is independent of pH and other physiological parameter to a large extent and it is possible to modulate the release characteristic by optimizing the properties of drug and system2.

The oral osmotic pumps have certainly came a long way and the available products on this technology and number of patent granted in the last few years makes it presence felt in the market3. They are also known as gastro intestinal therapeutic system. Alza corporation of the USA was first to develop an oral osmotic pump and today also they are the leaders in this field with a technology named OROS4.Osmotic drug delivery has come long way since Australian pharmacologist Rose and Nelson developed an implantable osmotic pump in 1955.Next quantum leap in osmotic dosage form came in1972 when Theuwes invented elementary osmotic pump. After that many of have been invented which enable controlled delivery of almost all drugs.5

Osmotic Drug Delivery Devices6,7

They fall in two categories

1. Implantable

I.The Rose and Nelson Pump

II.Higuchi Leeper Pump

III. Higuchi Theuwes pump

IV.Implantable Miniosmotic pump

2. Oral osmotic Pump

Single chamber osmotic pump

Elementary osmotic pump

Multi chamber osmotic pump

Push pull osmotic pump

Osmotic pump with non expanding second chamber

Specific types

Controlled porosity osmotic pump

Osmotic bursting osmotic pump

Liquid OROS

Delayed Delivery Osmotic device

·Telescopic capsule

·Oros ct (colon targeting)

Sandwiched oral therapeutic system

Osmotic pump for insoluble drugs

Monolithic osmotic systems

OSMAT

Advantage8,9

Osmotic drug delivery system for oral and parenteral use offer distinct and practical advantage over other means of delivery. The following advantages contributed to the popularity of osmotic drug delivery system.

1. They   typically give a zero order release profile after an initial lag.

2. Deliveries may be delayed or pulsed if desired.

3. Drug release is independent of gastric pH and hydrodynamic condition.

4.They are well characterized and understood.

5. The release mechanisms are not dependent on drug.

6. A high degree of in-vitro and in vivo correlation  

7. The rationale for this approach is that the presence of water in g.i.t. is relatively constant, at least in terms of the amount required for activation and controlling osmotically base technologies.

Disadvantage

1 Costly

2. If the coating process is not well controlled there is a risk of film defects, which    results in dose dumping 

3. Size hole is critical

Osmosis

Osmosis refers to the process of movement of solvent molecules from lower concentration to higher concentration across a semi permeable membrane. Osmosis is the phenomenon that makes controlled drug delivery a reality. Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic device. Rate of drug delivery from osmotic pump is directly proportional to the osmotic pressure developed due to imbibitions of fluids by osmogen. Osmotic pressure is a colligative property of a solution in which the magnitude of osmotic pressure of the solution is independent on the number of discrete entities of solute present in the solution. Hence the release rate of drugs from osmotic dispensing devices is dependent on the solubility and molecular weight and activity coefficient of the solute (osmogent).

Principles Of Osmosis11, 12

The first report of an osmotic effect dates to Abbenollet {1748}. But Pfeffer obtained the first quantitative measurement in 1877. In Pfeffer experiment a membrane permeable to water but impermeable to sugar is used to separate a sugar solution from pure water. A flow of water then takes place into the sugar solution that cannot be halted until a pressure π is applied to the sugar solution. Pfeffer showed that this pressure, the osmotic pressure π of the sugar solution is directly proportional to the solution concentration and the absolute temperature. With in few years, Vant Hoff had shown the analogy between these results and ideal gas laws by the expression

π  = Ф c r t   

Where Ф is the osmotic coefficient of the solution, c is the molar concentration of sugar in the solution, r is the gas constant and t is the absolute temperature.

Osmotic pressure for concentrated solution of   soluble solutes commonly used in controlled release formulation are extremely high ranging from 30 atm for sodium phosphate up to 500 atm for a lactose-fructose mixture, as their osmotic pressure can produce high water flow across semi permeable membrane. The osmotic water flow through a membrane is given by the equation

dv\dt   = A Q Δ π\ L

Where dv\dt is water flow across the membrane of area A, thickness L, and the permeability Q in cm2 and Δ π is the osmotic pressure difference between the two solutions on either side of the membrane. This equation is strictly for completely perm selective membrane that is membrane permeable to water but completely impermeable to osmotic agent.

Basic Component Of Osmotic Pumps

1. Drug

2. Osmotic agent

3. Semi permeable membrane

Drugs

·Short biological half-life {2-6h}

·Highly potent drug

·Required for prolonged treatment

 e.g. nifedipine, glipizide, virapamil.

Osmotic agents

Osmogents used for fabrication of osmotic dispensing device are inorganic or organic in nature a water soluble drug by it self can serve the purpose of an osmogent

Inorganic water-soluble osmogents

                    Magnesium sulphate

                    Sodium chloride

                    Sodium sulphate

                    Potassium chloride

                    Sodium bicarbonate

Organic polymer osmogents

                     Sodium carboxymethyl cellulose

                     Hydroxypropylmethyl cellulose

                     Hydroxyethylmethylcellulose

                     Methylcellulose

                     Polyethylene oxide      

                     Polyvinyl pyrollidine

Semi Permeable Membrane

The semi permeable membrane should be a stable both to the outer inner environment of the device. The membrane must be sufficiently rigid so as to retain its dimensional integrity during the operational lifetime of the device. The membrane should also be relatively impermeable to the contents of dispenser so that osmogent is not lost by diffusion across the membrane finally, the membrane must be biocompatible

Ideal Property of Semi Permeable Membrane

The Semi Permeable Membrane must meet some performance criteria

1. The material must posses sufficient wet strength (-105) and wet modulus so as to retain its dimensional integrity during the operational lifetime of the device.

2. The membrane exhibit sufficient water permeability so as to retain water flux rate in the desired range. The water vapor transmission rates can be used to estimate water flux rates

3. The reflection coefficient and leakiness of the osmotic agent should approach the limiting value of unity. Unfortunately, polymer membranes that are more permeable to water are also, in general more permeable to the osmotic agent.

4. The membrane should also be biocompatible

Elementary Osmotic Pump13-15

The elementary osmotic pump is a new delivery system for drugs. It delivers the agent by an osmotic process at a controlled rate. Control resides in the :

A) Water permeation characteristics of a semi permeable membrane surrounding the formulating agent

b) Osmotic properties of the formulation

In its simplest embodiment the system is constructed by coating an osmotically active agent with the rate controlling semipermeable membrane. This membrane contains an orifice of critical size through which agent is delivered. The dosage form after coming into contact with aqueous fluids, imbibes water at a rate determined by the fluid permeability of the membrane and osmotic pressure of the core formulation. This osmotic imbibitions of water result in formation of a saturated solution of drug with in the core, which is dispensed at controlled rate from the delivery orifice in the membrane. Though 60 -80 percent of drug is released at a constant rate from the EOP, a lag time of 30-60 minute is observed in most of the cases as the system hydrates before zero order delivery from the system begins.

These system are suitable or delivery of drugs having moderate water solubility.

image

Push Pull Osmotic Pump16,17

Push pull osmotic pump is a modified EOP. through, which it is possible to deliver both poorly water-soluble and highly water soluble drugs at a constant rate. This system resembles a standard bilayer coated tablet. One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients. This polymeric osmotic agent has the ability to form a suspension of drug in situ. When this tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and tablet excipients. These layer are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with semipermeable membrane. After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet. When the system is placed in aqueous environment water is attracted into the tablet by an osmotic agent in both the layers. The osmotic attraction in the drug layer pulls water into the compartment to form in situ a suspension of drug. The osmotic agent in the non-drug layer simultaneously attract water into that compartment, causing it to expand volumetrically and the expansion of non drug layer pushes the drug suspension out of the delivery orifice.

Osmotic Pump Wih Non Expanding Second Chamber18

The second category of multi-chamber devices comprises system containing a non-expanding second chamber. This group can be divided into two sub groups, depending on the function of second chamber.

In one category of these devices, the second chamber is used to dilute the drug solution leaving the devices. This is useful because in some cases if the drug leaves the oral osmotic devices a saturated solution, irritation of GI tract is a risk.

Example: - the problem that lead to withdrawal of osmosin, the device consist of a normal drug containing porous tablet from which drug is released as a saturated solution. However before the drug can escape from the device it must pass through a second chamber. Water is also drawn osmotically into this chamber either because of osmotic pressure of drug solution or because the second chamber contain, water soluble diluents such as NaCl. This type of devices consist of two rigid chamber, the first chamber contains a biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride, the second chamber contains the drug. In use water is drawn into both the chamber through the surrounding semi permeable membrane. The solution of osmotic agent formed in the first chamber then passes through the connecting hole to the drug chamber where it mixes with the drug solution before exiting through the micro porous membrane that form a part of wall surrounding the chamber. The device could be used to deliver relatively insoluble drugs

Osmotic Brusting Osmotic Pump19

This system is similar to an EOP expect delivery orifice is absent and size may be smaller. When it is placed in an aqueous environment, water is imbibed and hydraulic pressure is built up inside until the wall rupture and the content are released to the environment. Varying the thickness as well as the area the semipermeable membrane can control release of drug. This system is useful to provide pulsated release

Liquid Oral Osmotic System20, 21

Liquid OROS are designed to deliver drugs as liquid formulations and combine the benefits of extended release with high bioavailability. They are of three types: -

L OROS hard cap,

L OROS soft cap

Delayed liquid bolus delivery system

Each of these systems includes a liquid drug layer, an osmotic engine or push layer and a semipermeable membrane coating. When the system is in contact with the aqueous environment water permeates across the rate controlling membrane and activate the osmotic layer. The expansion of the osmotic layer result in the development of hydrostatic pressure inside the system, there by forcing the liquid formulation to be delivered from the delivery orifice. Where as L OROS hardcap or softcap system are designed to provide continuous drug delivery, the L OROS delayed liquid bolus drug delivery system is designed to deliver a pulse of liquid drug. The delayed liquid bolus delivery system comprises three layers: a placebo delay layer, a liquid drug layer and an osmotic engine, all surrounded by rate controlling semi permeable membrane. The delivery orifice is drilled on the placebo layer end of the capsule shaped device. When the osmotic engine is expands, the placebo is released first, delaying release of the drug layer. Drug release can be delayed from I to 10 hour, depending on the permeability of the rate controlling membrane and thickness of the placebo  layer

image

Delayed Delivery Osmotic Device22, 23

Because of their semi permeable walls, an osmotic device inherently show lag time before drug delivery begins. Although this characteristic is usually cited as a disadvantage, it can be used advantageously. The delayed release of certain drug (drugs for early morning asthma or arthritis) may be beneficial. The following text describe other means to further delay drug release

Telescopic Capsule For Delayed Release

This device consists of two chambers, the first contains the drug and an exit port, and the second contains an osmotic engine. a layer of wax like material separates the two section. To assemble the delivery device, the desired active agent is placed into one of the sections by manual or automated fill mechanism. The bilayer tablet with the osmotic engine is placed into a completed cap part of the capsule with the convex osmotic layer pointed in to the closed end of the cap and the barrier into the closed end of the cap and the barrier layer exposed towards the cap opening. The open end of the filled vessel is fitted inside the open end of the cap, and the two pieces are compressed together until the cap, osmotic bilayer tablet and vessel fit together tightly. As fluid is imbibed the housing of the dispensing device, the osmotic engine expand and exerts pressure on the slidable connected first and second wall sections. During the delay period the volume of reservoir containing the active agent is kept constant, therefore a negligible pressure gradient exists between the environment of use and interior of the reservoir. As a result, the net flow of environmental fluid driven by the pressure enter the reservoir is minimal and consequently no agent is delivered for the period

OROS-CT

OROS-CT is used as a once or twice a day formulation for targeted delivery of drugs to the colon. The OROS-CT can be a single osmotic agent or it can be comprise of as many as five to six push pull osmotic unit filled in a hard gelatin capsule.

image

After coming in contact with the gastric fluids, gelatin capsule dissolved and the enteric coating prevents entry of fluids from stomach to the system as the system enters into the small intestine the   enteric coating dissolves and water is imbibed into the core thereby causing the push compartment to swell. At the same time flowable gel is formed in the drug compartment, which is pushed out of the orifice at a rate, which is precisely controlled, by the rate of water transport across the semi permeable membrane.

Sandwiched Osmotic Tablets (SOTS) 24

It is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices. When placed in the aqueous environment the middle push layer containing the swelling agents swells and the drug is released from the two orifices situated on opposite sides of the tablet and thus SOTS can be suitable for drugs prone to cause local irritation of the gastric mucosa

image

Monolithic Osmotic System25

It constitutes a simple dispersion of water-soluble agent in polymer matrix. When the system comes in contact in with the aqueous environment.  Water imbibtion by the active agents takes place rupturing   the polymer matrix capsule surrounding the drug., thus liberating it to the outside environment. Initially this process occurs at the outer environment of the polymeric matrix, but gradually proceeds towards the interior of then matrix in a serial fashion. However this system fails if more then 20 –30 volume per liter of the active agents is incorporated in to the device as above this level, significant contribution from the simple leaching of the substance take place.

Osmat26

It is a novel osmotically driven matrix system, which utilizes the hydrophilic polymers to swell, and gel in aqueous medium forming a semipermiable membrane in-situ releases from such a matrix system containing an osmogen could, therefore be modulated by the osmotic phenomenon. Osmat thus judiciously combines both matrix osmotic characteristics resulting in a quantum improvement in drug delivery from swellable matrix system.

Osmat produces controlled drug release with adequate delivery rates in an agitation in dependent manner. Thus osmat represents simple, versatile, and easy to fabricate osmotically driven controlled drug delivery system based upon low cot technology.

Controlled Porosity Osmotic Pump27, 28

The pump can be made with single or multicompartment dosage form, in either form, the delivery system comprises a core with the drug surrounded by a membrane which has an asymmetric structure, i.e. comprises a thin dense skin layer supported by a porous substructure. The membrane is formed by phase inversion process controlled by the evaporation of a mixed solvent system. Membrane is permeable to water but impermeable to solute and insensitive pore forming additive dispersed through out the wall.

When exposed to water, low levels of water-soluble additive are leached from polymer materials that were permeable to water yet remained insoluble. Then resulting sponge like structure formed the controlled porosity walls of interest and was substantially permeable to both water and dissolved drug agents. Rate of drug delivery depends upon the factors are water permeability of the semi permeable membrane and the osmotic pressure of the core formulation, thickness and total surface area of coating. All of these variable are under the control of the designer and do not vary under physiological condition, leading to the robust performance allued to above. The rate of flow dv/dt of water into the device can be represented as

dv / dt = Ak / h (Dp-DR)

Where   k  =  Membrane permeability

        A   = Area of the membrane

       Dp  = Osmotic pressure difference

       DR =  Hydrostatic pressure difference

image

SPM             PORE

Theory Of Osmotic Delivery From Asymmetric Membrane Dosage Forms 29-30.

Drug delivery from asymmetric membrane dosage forms is primarily controlled by the differ­ence in osmotic pressure between the external fluid and drug-containing core of the dosage form. The mechanism of drug release from an AM tablet consists of imbibitions of water through the membrane into the tablet core, dissolution of soluble compo­nents (including drug) in the core, and pumping of the solution out of pores in the membrane. The imbibitions of water through the membrane are driven by its thermodynamic activity gradi­ent between the external medium, e.g., receptor solution or gastric / intestinal fluids, and the os­motic agent(s) in the core. Dissolution of the soluble components within the core produces the activity gradient and establishes the osmotic pressure difference between the core and external environment. The approximately constant dosage form volume means that the volume of drug solution delivered will be roughly equal to the volume of water imbibed within a given time in­terval. As water diffuses into the core, the volume of the imbibed water creates a hydrostatic pressure difference across the membrane, which forces the solution out through the pores in the coating. Therefore, the rate of drug delivery will be constant as long as a constant osmotic pres­sure gradient is maintained across the membrane, the membrane permeability remains constant, and, the concentration of drug in the expelled solution is constant. Sustained zero-order drug re­lease can be achieved using AM devices while the concentration of dissolved drug within the fluid portion of the core remains constant. When the drug concentration in the core fluid falls below saturation, the release rate declines.

A comprehensive model describing drug release from an AM dosage form consists of os­motic and diffusional contributions. The diffusional contribution is derived from the fact that the asymmetric membrane is not perfectly semipermeable, and therefore a portion of drug is released by diffusion, primarily through pores in the coating. The total mass of drug delivered per unit time, (dm / dt)t is modeled by:

(dm/dt)t = (dm/dt) + (dm/dt)d

where (dm/dt)t is the mass released by osmotic pumping and (dm/dt)d is the mass released due to diffusion. The osmotic drug release component is described by Eq 2.

(dm/dt)d = (AC/h)pw∆∏

Here A is the surface area of the device, h the membrane thickness, C the dissolved drug con­centration in the core fluid, Pw the water permeability of the semipermeable membrane, and ∆∏ the osmotic pressure difference across the membrane. The diffusional release component is de­pendent on the dissolved drug permeability in the membrane, Pd, the device surface area, A, the drug concentration in the core, C, and the membrane thickness, h, as described in Eq. 3.

(dm/dt)d = (PdAC)/h................................................................3

The total drug release is described by equation 4.

(dm/dt)t = (AC/h)pw∆∏ + (PdAC)/h....................................... ....................4

The combination of both osmotic and diffusional release mechanisms has been addressed previously by Theeuwes for the simple osmotic pump and by Zenter et al for the controlled porosity osmotic pump.

Features of Asymmetric Membrane Osmotic Systems 30.

Asymmetric membrane (AM) film-coated delivery systems are a unique embodiment of osmotic devices in the use of phase inversion technology to create the semipermeable asymmet­ric membrane. As with other osmotic pumps, the AM drug delivery system releases the active ingredient by an osmotically controlled mechanism which, when properly constructed, delivers the active agent independently of pH or external agitation. The critical differentiating features that distinguish AM dosage forms from other osmotic devices are the high water permeability and controlled porosity resulting from the spray-coating process.

An elegantly simple appearing osmotic drug delivery technology developed jointly by Pfizer and Bend Research features an asymmetric membrane to control release. As the same indicates, the membrane structure is asymmetrical in nature and comprises a thin dense skin layer supported by a porous substructure as depicted in the following Fig.  

image

The membrane is formed by a phase inversion process controlled by the evaporation of a mixed solvent system.

There are several important advantages of the AM dosage form over previous osmotic technologies. The first benefit is that higher water flux and permeability of symmetric mem­branes allows greater flexibility in designing faster release rates or incorporating lower solubil­ity drug substances into the dosage form (8). Second, the skin layer porosity is easily controlled with selection of pore former type and concentration. Another advantage is the ability to fabri­cate AM dosage forms in conventional pharmaceutical process equipment without additional manufacturing complexities. Finally, the physical design of an AM dosage form is flexible it is possible to adapt the technology to fabricate coatings on tablets or on small particles, or to fabricate osmotic capsules directly from the asymmetric polymer membrane.

Marketed Products

Product Name

Active

Design

Dose

Acutrim

Phenylpropanolamine

Elementary pump

75 mg

Alpress LP

Prazosin

Push -Pull

2.5 - 5 mg

Cardura XL

Doxazosin

Push -Pull

4, 8 mg

Covera HS

Verapamil

Push -Pull with time delay

180, 240 mg

Ditropan XL

Oxybutinin chloride

Push -Pull

5, 10 mg

Dynacirc CR

Isradipine

Push -Pull

5, 10 mg

Efidac 24

Pseudoephiderine

Elementary Pump

60 mg IR, 180 mg CR

Efidac 24

Chlorpheniramine meleate

Elementary Pump

4 mg IR, 12 mg CR

Glucotrol XL

Glipizide

Push - Pull

5, 10 mg

Process for manufacturing asymmetric membrane capsules:

The asymmetric membrane capsule was made by a phase inversion process in which the membrane structure was precipitated on a stainless sted mold pin by dipping the mold pin a coating solution followed by quenching in an aqueous solution. as shown in Fig.

image

The coating solution was a multi component polymer-solvent-non-solvent system containing a film forming polymer, cellulose acetate. The solvent non-solvent mixtures were formulated with acetone, water and glycerol. The ratio of solvents / non-solvents in the coating solution was selected so that on evaporation, phase inversion was immediately initiated. This assured the formation of an asymmetric as opposed to a dense membrane structure.

Physical evaluation of asymmetric membrane capsule

Colour                                                         Any imperfection

Texture and membrane size                        Size Height and radius

Scanning electron microscopy                    Drug content

Dissolution behavior                                  Stability studies

References

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2. Theuwes,F., Swanson, D. R., Guitttard , G., Ayer, A., Br. J.Clin. Pharmacology, (1985),19, 69-76.

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4. Verma,R.K., Garg,  S., J. Control. Release, 2002, 79, 7-27.

5. Verma, R. K., Mishra, B., Drug Dev. Ind .Pharm.,2001,22.

6. Parmar, N.S., and VyasS.K., {Ed} N. K. Jain. In: Advanced in controlled and novel drugdelivery., CBS publisher, 22-31

7. Kaushal, Aditya.and Garg Sanjay, Pharma. Technol. 2003, 27,32-37.

8. Rastogi, S.K. ,Vaya,N.,Mishra,B.,Eastern pharmacist, 38,79-82.

9. Fix,J.,in; Encyclopedia of controlled drug delivery,Edmathiowitz,vol-2, John Wiley and sons,Inc,700.

10.  Martin,A..,In;phyical pharmacy,4th edition,Lippincott Williams and Wilkins,,1994,116-117.

11.  Santus, G., Baker, R.W., J.Control.Release , 1995,  35, 2.

12.  Pfefer,W.E.P.Osmotishe Umtersuchen, Leipzig,1877

13.  Theeuwes, F., J.Pharm.sci., 1975,64,1987-1991.

14.  Theeuwes, F,U.S.Patent no-3760,984,1973.

15.  Jerzewski, R.L., Chien,Y.W., In :A Kydonieus (ed), treatise on controlled drug delivery : fundamentals, optimization application, marcel dekker , new york ,1992, 225-253.

16. Parmar, N.S., and Vyas S.K., (ed) N.K.jain, In: Advanced in controlled and novel drug delivery., CBS publisher, 28-29.

17.Swanson ,, D.R. , Barclay,B.L., Wong,P.S.L., Theuwes, F., American.J.Med., 1987,83,3-9.

18.  Srenivasa, B., Kumar, N. R., Murthy, K. V. R., Eastern Pharmacist,2001,22

19.Parmar, N.S., and Vyas S.K.,{Ed }N.K.jain. In: Advanced in controlled and novel drug delivery., CBS publisher, 22-

20. Verma,R.K., Garg, S., J.Control.Release, 2002,79,11.

21. Dong,L., shafi,K., Wan, J., Wong,  P.,– In: proceeding of the international symposium on controlled release of bioactive material, paris (july) 200.

22. Kaushal, Aditya.and Garg Sanjay, pharma. Technol. 2003, 27,39.

23.     Theuwes, F., Wong, P.S.L..Burkoth, T.L., Fox, D.A., P.R.Bicek (ed), In: colonic drug absorption and metabolism, Marcel Decker , new york , 1993,137-158.

24.  LiuL., J. Ku,. Khana, G., Lee, B., Rhee, J.M., Lee, H.B., J. Cont. Release, 68(2000) 145-156.

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About Authors

Shailesh Sharma

Shailesh Sharma is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India.He had completed his graduation from B . R. Nahata College of pharmacy, Mandsaur, (MP) and  post graduation from B.N.College of pharmacy, Udaipur, Raj. He has very good academic and extra circular record.

Mr.Sukhjinder Pal Singh

Mr.Sukhjinder Pal Singh is a B.Pharm. final year student of ASBASJSM College of Pharmacy, Bela, Ropar, India.

Sudhir Bhardwaj

Sudhir Bhardwaj is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India . Mr. Bhardwaj  has author of number of books and published several Research Paper / Abstract in National and International conferences. He is a Memership Coordinator for INPHARM Association,  active member of FIP, International Society of Agriculture and Applied Science, and APTI

Mr.Kumar Gaurave

Mr.Kumar Gaurave, is working as a Reader in Guru Govind Singh College of Pharmacy, Yamunanagar, Haryana, India .

Dr.G.D.Gupta

Dr. G. D. Gupta is working as a professor and principal in ASBASJSM College of Pharmacy, Bela, Ropar, India . Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.

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