Presentation on Osmotic drug delivery system 160 INDEX

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Presentation on Osmotic drug delivery system 1/60

INDEX 1) Introduction 2) Principle of osmosis 3) Classification of osmotic drug delivery system

INDEX 1) Introduction 2) Principle of osmosis 3) Classification of osmotic drug delivery system 4) Factors affecting release of medicament from osmotic DDS 5) Basic components of osmotic system 6) Evaluation 7) Advantages 8) Disadvantages 9) Marketed products 10) Patents 11) Current issues 12) References 2/60

1. Introduction • Osmotic drug delivery uses the osmotic pressure for controlled delivery of

1. Introduction • Osmotic drug delivery uses the osmotic pressure for controlled delivery of drugs by using osmogens • Osmosis : the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane • Osmotic pressure : the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semipermeable membrane • Osmotic pressure is a colligative property • These systems can be used for both route of administration i. e. oral and parenterals 3/60

2. Principle of Osmosis • The solvent membrane control delivery of agent from the

2. Principle of Osmosis • The solvent membrane control delivery of agent from the osmotic system across the semi permeable membrane, which in turn drive the agent out. Water influx of osmotic pump can be describe as, dv = A LP σ (ΔП – ΔP) dt h Where dv = water influx dt A = membrane area h = membrane thickness P = mechanical permeability ΔП = osmotic pressure ΔP = hydrostatic pressure difference between inside and outside the system σ = describes the lickages of solute through the membrane. 4/60

 • The general expression for the solute delivery rate, d. M / dt

• The general expression for the solute delivery rate, d. M / dt obtained by pumping through the orifice of the reservoir is given by, • d. M = d. V C dt dt Where C is concentration of solute if dispersed fluid 5/60

3. Classification of Osmotic drug delivery system 3. 1 Implantable Osmotic Drug Delivery System

3. Classification of Osmotic drug delivery system 3. 1 Implantable Osmotic Drug Delivery System 3. 2 Oral Osmotic Drug Delivery System 6/60

3. 1 Implantable Osmotic Drug Delivery System A. Rose nelson pump • • •

3. 1 Implantable Osmotic Drug Delivery System A. Rose nelson pump • • • the first osmotic pump developed in 1955 for the delivery of drugs to the sheep and cattle gut Composed of three chambers Water to be loaded prior to use was the drawbacks of Salt rose nelson osmotic pump Drug Water Chamber Rigid Semi permeable membrane Chamber Delivery orifice Elastic Diaphragm 7/60

B. Higuchi leeper osmotic pump • No water chamber • The activation of device

B. Higuchi leeper osmotic pump • No water chamber • The activation of device occurs after imbibition of the water from the surrounding environment • Employed for veterinary use • Either swallowed or implanted in body of animal for delivery of antibiotic or growth hormones to animals • Pulsatile delivery can be achieved 8/60

Higuchi leeper osmotic pump 9/60

Higuchi leeper osmotic pump 9/60

C. Higuchi Theeuwes Osmotic Pump • The release of the drug from the device

C. Higuchi Theeuwes Osmotic Pump • The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of outer membrane. • Diffusional loss of the drug from the device is minimized by making the delivery port in shape of a long thin tube. • Small osmotic pumps of this form are available under the trade name Alzet®. • Delivery of DNA by agarose hydrogel implant facilitate genetic immunization in cattle by using Alzet osmotic pumps 10/60

Higuchi Theeuwes Osmotic Pump 11/60

Higuchi Theeuwes Osmotic Pump 11/60

3. 2 Oral Osmotic Drug Delivery System A. Elementary osmotic pump B. Multichamber osmotic

3. 2 Oral Osmotic Drug Delivery System A. Elementary osmotic pump B. Multichamber osmotic pump - expandable - non expandable C. Modified osmotic pump D. Controlled porosity osmotic pump E. Multiparticulate delayed release system F. Monnolithic osmtic system 12/60

A. Elementary osmotic pump • Major method of achieving controlled drug release • The

A. Elementary osmotic pump • Major method of achieving controlled drug release • The EOP was developed by Alza undre the name OROS for controlled release oral drug delivery formulations Delivery Orifice Semi permeable membrane Core 13/60

MECHANISM OF EOP 14/60

MECHANISM OF EOP 14/60

 • Fabricated as tablet coated with semipermeable membrane usually cellulose acetate • Small

• Fabricated as tablet coated with semipermeable membrane usually cellulose acetate • Small orifice is drilled through the membrane coating • Eliminates separate salt chamber • Tablet working as a small pump withdrawing water from external environment • Ex. Swellable elementary osmotic pump (SEOP): An effective device for delivery of poorly water-soluble drug indomethacin - The results showed that concentration of wetting agent in the core formulation was a very important parameter in D 24 h and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60 mg) significantly increased D 24 h and improved zero order release pattern of indomethacin 15/60

B. Multichamber osmotic pump i. Ø • • • Expandable MCOP Expandable for solid

B. Multichamber osmotic pump i. Ø • • • Expandable MCOP Expandable for solid osmotic system PPOP ( push pull osmotic system ) They contain two or three compartment separated by elastic diaphragm Upper compartment contain drug with or without osmogen (drug compartment nearly 60 – 80 %) and lower compartment (Push compartment) contain Osmogen at 20 – 40 %. Example Procardia. XL for Nifedipine In vitro and in vivo evaluation of PPOP controlled release tablet of vinpocetine using numerical deconvolution technique. (Chemical Abstract, 63 - Pharmaceutical Vol. 164. , No. 6. , August 2010) 16/60

MECHANISM OF PPOP 17/60

MECHANISM OF PPOP 17/60

Ø Expandable for liquid osmotic system • A liquid formulation is use for delivering

Ø Expandable for liquid osmotic system • A liquid formulation is use for delivering insoluble drugs and macromolecules. • Such molecules require external liquid components to assist in solubilization, dispersion, protection from enzymatic degradation and promotion of gastrointestinal absorption. • Thus the L-OROS system was designed for continuous delivery of liquid drug. • 18/60

ii. Non expandable MCOP Depending on function of second chamber non–expandable osmotic pump are

ii. Non expandable MCOP Depending on function of second chamber non–expandable osmotic pump are divided into, Drug solution get diluted in second chamber before leaving device. Two separate EOP tablet formed in single tablet 19/60

Drug solution get diluted in second chamber before leaving device • Before the drug

Drug solution get diluted in second chamber before leaving device • Before the drug can exit from the device, it must pass through a second chamber • Water is also drawn Osmotically into this chamber due to osmotic pressure of the second chamber that bears watersoluble osmogen • Such is useful when saturated solution of drug irritate GIT • Reason behind the withdrawl of Osmosin (sodium indomethacin) 20/60

Two separate EOP tablet formed in single tablet Ø also known as sandwiched osmotic

Two separate EOP tablet formed in single tablet Ø also known as sandwiched osmotic tablet system 21/60

Ø A more sophisticated version of these devices consists of two rigid chambers :

Ø A more sophisticated version of these devices consists of two rigid chambers : one chamber contains osmogen and second chamber contain drug Osmogen SPM Drug Microporous membrane 22/60

C. Modified osmotic pump Ø particles of osmotic agent are coated with an elastic

C. Modified osmotic pump Ø particles of osmotic agent are coated with an elastic semipermeable film. These particles are then mixed with the insoluble drug and compressed in the form of a tablet 23/60

D. Controlled porosity osmotic pump • the delivery orifice is formed by incorporation of

D. Controlled porosity osmotic pump • the delivery orifice is formed by incorporation of a leachable water-soluble component in the coating material • Drug release from the whole surface of device rather than from a single hole which may reduce stomach irritation problem 24/60

 • The release rate from these types of systems has been reported to

• The release rate from these types of systems has been reported to be dependent on : • the coating thickness (20 -500 �� m) • level of soluble components in the coating solubility of the drug in the tablet core • osmotic pressure difference across the membrane (8 -500 atm) • independent of the p. H and agitation of the release media • EX. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: screening of formulation variables and in vitro investigation : microbially triggered colon-targeted osmotic pump (MTCT-OP) The gelable property at acid condition and colon-specific biodegradation of chitosan 25/60

E. Multiparticulate delayed release system • In the multiparticulate delayed-release system, pellets containing drug

E. Multiparticulate delayed release system • In the multiparticulate delayed-release system, pellets containing drug with or without osmotic agent are coated with an SPM-like cellulose acetate. • On contact with an aqueous environment, water penetrates into the core and forms a saturated solution of soluble components. • The osmotic pressure gradient induces a water influx, resulting in a rapid expansion of the membrane, leading to the formation of pores. • The osmotic ingredient and the drug are released through these pores according to zero order kinetics. 26/60

F. Monnolithic osmtic system • Dispersion of water soluble drug is made in a

F. Monnolithic osmtic system • Dispersion of water soluble drug is made in a polymeric matrix and compressed as tablet. • Tablet is then coated with semi permeable membrane or drilled on both side of tablet. • When MOS comes in contact with aqueous environment, the water penetrates in the core and forms a saturated solution of component which will generate osmotic pressure which results in the rupturing of membrane of polymeric matrix surrounding the agent. Thus liberating drug to move outside the environment. 27/60

 • MOS is simple to prepare but the system fails if more then

• MOS is simple to prepare but the system fails if more then 20 – 30 % volume of active agent is incorporated in device because above this level significant contribution is from leaching of substance • Ketoprofen Monolithic Osmotic Pump Control Release Tablet made up of PEG 6000, Na. Cl, CMC-Na and Polyvinyl pyrrolidone which releases drug at 93. 51 % for 24 hrs (Chemical Abstract, 63 - Pharmaceutical Vol. 147. , No. 6. , August 6. 2007. P=1912. , 215217 m) 28/60

4. Factors affecting release of medicament from Osmotic DDS A. B. C. D. Solubility

4. Factors affecting release of medicament from Osmotic DDS A. B. C. D. Solubility Osmotic pressure Delivery orifice Membrane type 29/60

4 A. solubility • Solubility of drug is one of the most important factors

4 A. solubility • Solubility of drug is one of the most important factors since kinetic of osmotic release is directly related to the drug solubility. • The fraction of a drug release with zero order kinetic is given by • F (z) = 1 – S P Where F (z): fraction release by zero order S: drug solubility in g / cm 3 P: density of core tablet. • Drug with density of unity and solubility less than 0. 05 g / cm 3 would release greater than or equals to 95 % by zero order kinetics • Drug with density > 0. 3 g / cm 3 solubility would demonstrate with higher release rate > 70 % by zero order. • Both highly soluble and poorly soluble drugs are not good candidates for osmotic drug delivery 30/60

Solubility modifying approaches i. Co-compression of drug with excipients Ø the modification in solubility

Solubility modifying approaches i. Co-compression of drug with excipients Ø the modification in solubility of CPOP of a highly watersoluble drug, diltiazem hydrochloride Ø Co-compression of drugs along with solubility modulating agents can also be utilized for pulsatile delivery of drugs Ex. Demonstrated by salbutamol, highly water soluble drug ii. Use of encapsulated excipients Ø Solubility modifier excipient used in form of mini-tablet coated with rate controlling membrane 31/60

iii. Use of swellable polymers Ø for drugs having poor aqueous solubility Ø Ex.

iii. Use of swellable polymers Ø for drugs having poor aqueous solubility Ø Ex. Carbamazapine, theophylline (US patent no. 4, 992, 278) vinylpyrrolidone /vinyl acetate copolymer and polyethylene oxide were used as swelling agent iv. Use of effervescent mixtures Ø Another approach to deliver poorly water-soluble drugs form osmotic drug delivery system Ø Citric acid and sodium bicarbonate were used as the effervescent couple for the delivery of acetyl salicylic acid (US Patent no. 4, 036, 228) 32/60

v. Use of cyclodextrin derivatives Ø CPOP of Testosterone : increase in solubility of

v. Use of cyclodextrin derivatives Ø CPOP of Testosterone : increase in solubility of drug from 0. 039 mg/ml to 76. 5 mg/ml through complexation with sulfobutyl ether-b-cyclodextrin sodium salt Ø Comparative study of CPOP of Testosterone with (SBE)- β -CD and HP- β –CD vi. Resin modulation approach Ø Release of a highly water-soluble drug, diltiazem hydrochloride from a CPOP was modulated effectively using positively charged anion-exchange resin poly (4 -vinyl pyridine) Ø Pentaerythritol was used as osmotic agent and citric and adipic acids were added to maintain a low core p. H to assure that both the drug and resin carry a positive charge. 33/60

vii. Use of alternative salt form Ø In case of metoprolol, use of fumarate

vii. Use of alternative salt form Ø In case of metoprolol, use of fumarate salt instead of tartarate salt achieves optimum solubility and provided extended release up to 24 hr. viii. Use of crystal habit modifiers Ø a slightly soluble drug, carbamazepine along with crystal modifying agents (combination of hydroxymethyl cellulose and hydroxyethyl cellulose) and other excipients was formulated. (US patent no. 5, 284, 662) 34/60

ix. Use of lyotropic crystals Ø swell in presence of water Ø Ex. phosphatidyl

ix. Use of lyotropic crystals Ø swell in presence of water Ø Ex. phosphatidyl choline (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol Ø for osmotic delivery of prazosin lecithin and mixture of soybean phospholipids was utilized (US patent no. 5, 108, 756) x. Use of wicking agents Ø an approach for poorly water-soluble drugs Ø Ex. of wicking agent : colloidal silicon dioxide, PVP, sodium lauryl sulfate 35/60

4 B Osmotic pressure • The next release-controlling factor that must be optimized is

4 B Osmotic pressure • The next release-controlling factor that must be optimized is the osmotic pressure gradient between inside the compartment and the external environment • The simplest and most predictable way to achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment • The release rate of a drug from an osmotic system is directly proportional to the osmotic pressure of the core formulation 36/60

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4 C. Delivery orifice • To achieve an optimal zero order delivery profile, the

4 C. Delivery orifice • To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice • Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system • The typical orifice size in osmotic pumps ranges from 600µ to 1 mm. 38/60

Methods to create a delivery orifice in the osmotic tablet coating • • Mechanical

Methods to create a delivery orifice in the osmotic tablet coating • • Mechanical drill Laser drilling : CO 2 laser beam Use of modified punches Use of pore formers : used in controlled porosity osmotic pump Ex. of pore formers: dimethyl sulfone, nicotinamide, saccharides, amino acids, sorbitol, pentaerythritol, mannitol, organic aliphatic, and aromatic acids, including diols and polyols 39/60

4 D. Membrane type Ø Type and nature of polymer • polymer that is

4 D. Membrane type Ø Type and nature of polymer • polymer that is permeable to water but impermeable to solute can be selected • Ex. cellulose esters such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate Ø Membrane thickness • release rate from osmotic systems is inversely proportional to membrane thickness Ø Type and amount of plasticizer • Chlorpromazine release from CPOP was found to increase with decreasing amounts of TEC (triethyl citrate) 40/60

5. Basic components of osmotic system Ø Drug : itself may act as osmogen

5. Basic components of osmotic system Ø Drug : itself may act as osmogen otherwise osmogenic salt can be added in formulation Ø Semipermeable membrane: criteria: • Sufficient wet strength and water permeability • Should be biocompatible, rigid and non swelling • Should be sufficient thick to withstand the pressure within the device • Any polymer that is permeable to water but impermeable to solute can be used as a coating material in osmotic devices • Ex. Cellulose esters like Cellulose Acetate, Cellulose Acetate Butyrate, Cellulose Triacetate and Ethyl Cellulose And Eudragits 41/60

Ø Hydrophilic and hydrophobic polymers ( CMC, HEC, HPMC ) Ø Wicking agent :

Ø Hydrophilic and hydrophobic polymers ( CMC, HEC, HPMC ) Ø Wicking agent : the material with ability to draw water into the porous network of a delivery device ( SLS, PVP, bentonite ) Ø Solubilizing agent (PVP, CD, PEG ) Ø Osmogens Ø Surfactants : act by regulating the surface energy of materials to imrove their blending into the composite Ø Coating solvent : ( methanol, IPA, acetone, cyclohexane ) Ø Plasticizer : ( phalates, alkyl adipates, TEC ) Ø Flux regulator : ( poly propylene, poly butylene ) Ø Pore forming agent 42/60

6. Evaluation • • Pore diameter Coating thickness Hardness Friability Weight variation In vitro

6. Evaluation • • Pore diameter Coating thickness Hardness Friability Weight variation In vitro evaluation In vivo evaluation 43/60

IN VITRO DELIVERY RATE MEASUREMENTS 1. Method used by theeuwes and co workers •

IN VITRO DELIVERY RATE MEASUREMENTS 1. Method used by theeuwes and co workers • osmotic pumps are placed in loosely woven mesh bags of nylon or polyethylene, and the bags are attached to a rod, which in turn is attached to a horizontal transfer arm connected to a vertically reciprocating shaker. The arms containing several systems are then positioned over test tubes/containers containing a known amount of release media • The release rate (mg/hr) is determined by dividing the amount of drug in each container by the time (in hours) of the test interval 44/60

2. Conventional USP dissolution apparatus 1 and 2 3. flow-through apparatus 4. In vitro

2. Conventional USP dissolution apparatus 1 and 2 3. flow-through apparatus 4. In vitro release of phenylpropanolaminehydrochloride (PPA) from the oral osmotic pump system and a marketed long-acting product (spansules) was compared using a calibrated Ghannam-Chien diffusion system as the dissolution apparatus 45/60

IN VIVO DELIVERY RATE MEASUREMENT • Carrid out mainly in dogs • Theeuwes et

IN VIVO DELIVERY RATE MEASUREMENT • Carrid out mainly in dogs • Theeuwes et al. studied the in vivo release of indomethacin from OROS pumps in mongrel dogs • Gastrointestinal transit of an osmotic tablet was measured by radiolabeling an intact osmotic tablet (placebo osmosin tablets) and monitoring the movement of the unit in the GI tract of young and old healthy volunteers using gamma scintiography (47). The units were observed to move through the GI tract at about the same rate as the released contents, arriving at the cecum about 7 hr after dosing 46/60

7. Advanteges • • Zero order release Delivery may be delayed or pulsed High

7. Advanteges • • Zero order release Delivery may be delayed or pulsed High release rate For oral osmotic system, drug release is independent of gastric p. H, agitation, presence of food, GI motility • The release rate is predictable • high degree of IVIVC • Production scale up is easy 47/60

8. Disadvantages • Expensive • Chance of toxicity due to dose dumping • Rapid

8. Disadvantages • Expensive • Chance of toxicity due to dose dumping • Rapid development of tolerance • Hypersensitivity reaction may occur • Integrity and consistency are difficult • Release of drug depends on : - size of hall - surface area - thickness and composition of membrane 48/60

9. Marketed products ELEMENTARY OSMOTIC PUMP BRAND NAME API Efidac 24® Chlorpheniramine Acutrim ®

9. Marketed products ELEMENTARY OSMOTIC PUMP BRAND NAME API Efidac 24® Chlorpheniramine Acutrim ® Phenylpropanolamine Sudafed 24®, Efidac 24® Pseudoephedrine Volmax ® Albuterol Minipress XL® Prazosin IMPLANTABLE OSMOTIC SYSTEMS Viadur® Leuprolide acetate Chronogesic™ Sufentanil 49/60

PUSH-PULL OSMOTIC SYSTEMS Ditropan XL ® Oxybutynin chloride Procardia XL® Nifedipine Glucotrol ® Glipizide

PUSH-PULL OSMOTIC SYSTEMS Ditropan XL ® Oxybutynin chloride Procardia XL® Nifedipine Glucotrol ® Glipizide Covera HS ® Verapamil HCl Dyna. Circ CR® Isradipine Invega® Paliperidone Alpress LP® Prazosin Cardura XL® Doxazosin 50/60

10. Patents PATENTS OF ELEMENTARY OSMOTIC PUMP YEAR US PATENT NO. DRUG 1981 4,

10. Patents PATENTS OF ELEMENTARY OSMOTIC PUMP YEAR US PATENT NO. DRUG 1981 4, 265, 874 Indomethacin formulation 1981 4, 305, 927 Acetazolamide formulation 1984 4, 439, 195 Theophylline formulation 1986 4, 610, 686 Haloperidol 1987 4, 662, 880 Pseudoephedrine and bromopheniramine 1988 4, 751, 071 Salbutamol formulation 1991 4, 986, 987 Dimenhydrinate 51/60

1993 5, 200, 194 Mucosal delivery of antiplaque agents and nicotine 1998 5, 776,

1993 5, 200, 194 Mucosal delivery of antiplaque agents and nicotine 1998 5, 776, 493 Mucosal delivery of nystatin 1999 5, 869, 096 Covers mucosal osmotic device of levodopa 2002 6, 352, 721 Combined diffusion/osmotic pumping drug delivery system 2003 6, 534, 090 Oral osmotic controlled drug delivery system for a sparingly soluble durg (carbamazepine) 2006 7, 008, 641 Osmotic device containing venlafaxine and an anti psychotic agent 52/60

Patents of multichamber Osmotic Pumps 1986 4, 612, 008 Diclofenac sodium formulation 1988 4,

Patents of multichamber Osmotic Pumps 1986 4, 612, 008 Diclofenac sodium formulation 1988 4, 765, 989 Nifedipine and a blockers 1989 4, 837, 111 Doxazosin formulation 1989 4, 859, 470 Diltiazem formulation 1990 4, 904, 474 Beclomethasone (colonic) 1991 5, 024, 843 Glipizide formulation 1992 5, 160, 744 Verapamil dosage form 1993 5, 185, 158 Tandospirone 1993 5, 248, 310 Beclomethasone (oral) 1997 5, 591, 454 Glipizide formulation 53/60

2000 6, 113, 938 Implant capsule 2000 6, 284, 276 Soluble form osmotic dose

2000 6, 113, 938 Implant capsule 2000 6, 284, 276 Soluble form osmotic dose delivery system 2006 CN-1872031 Hydroxy camptothecin osmotic tablet 2008 7, 338, 663 Expandable osmotic composition and coating suspension 2009 CN 101422442 levetiracetam 2010 CN 101829069 Pitavastatin calcium 54/60

11. CURRENT ISSUES 1. Microporous bilayer osmotic tablet for colon-specific delivery (Eur J Pharm

11. CURRENT ISSUES 1. Microporous bilayer osmotic tablet for colon-specific delivery (Eur J Pharm Biopharm. 2011 Jan 19) ü Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting ü The colon-specific biodegradation of pectin could form in situ delivery pores for drug release ü The effect of formulation variables like inclusion of osmogen, amount of HPMC and Na. CMC in core, amount of pore former in semipermeable membrane was studied 55/60

2. Push-pull osmotic pump for zero order delivery of lithium carbonate: Development and in

2. Push-pull osmotic pump for zero order delivery of lithium carbonate: Development and in vitro characterization 3. Development and evaluation of push-pull based osmotic delivery system for pramipexole Ø offer significant patient benefits by providing enhanced efficacy and reduced side effects and may also reduce the number of daily doses compared to conventional therapies 4. A controlled porosity osmotic pump system with biphasic release of theophylline Ø The developed system was composed of a tablet-in-tablet (TNT) core and a controlled porosity coating membrane Ø osmotic agent: sodium phosphate, sodium chloride Ø coating solution: cellulose acetate-polyethylene glycol 400 - diethyl phthalate (54. 5 -36. 4 -9. 1%, w/w) Ø micro-environmental osmotic pressure and microenvironmental p. H 56/60

5. Release mechanisms of sparingly water-soluble drug from controlled porosity-osmotic pump pellets using Sulfobutyl

5. Release mechanisms of sparingly water-soluble drug from controlled porosity-osmotic pump pellets using Sulfobutyl ether-β-Cyclodextrin as both solubilizing & osmotic agent. (JPS, VOL-98, NO. -6, JUNE-2009, Page NO. -1992) 57/60

12. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. A Review Article on

12. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. A Review Article on Osmotic Drug Delivery System. Authors: Gohel M. C , Parikh R. K. , Shah N. Y. , from L. M. College Of Pharmacy, Ahmedabad. (www. pharmainfo. net) L. F. Prescott. The need for improved drug delivery in clinical practice, In: Novel Drug Delivery and Its Therapeutic application, John Wiley and Sons, West Susset, U. K. , 1 -11; 1989. Dr. P. P. Bhatt. Osmotic drug delivery systems for poorly water soluble drugs, Pharmaventures Ltd. , Oxford, UK, 26 -29; 2004. R. K. Verma, D. M. Krishna and S. Garg. Review article on Formulation aspects in the development of Osmotically controlled oral drug delivery systems, J. Control. Release, 79, 7 -27; 2002. Chemical Abstract, 63 - Pharmaceutical Vol. 147. , No. 6. , August 6. 2007. P=1912. , 215217 m Chemical Abstract, 63 - Pharmaceutical Vol. 164. , No. 6. , August 2010 Microporous bilayer osmotic tablet for colon-specific delivery, Chaudhary A, Tiwari N, Jain V, Singh R. , School of Pharmaceutical Sciences, Shobhit University, Meerut, UP, India. , Eur J Pharm Biopharm. 2011 Jan 19 J. Pharm. Res. Vol. 5. No. 2. April 2006. P=34. 9. Ind. J. Pharm. Sci. May – June 2006, P= 295 -300. 10. J. Pharm. Sci. Vol. 96. No. 5. May 2007. P= 1008. 58/60

12 F. Theeuwes and S. I. Yum. Principles of the design and operation of

12 F. Theeuwes and S. I. Yum. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid formulations, Ann. Biomed. Eng. , 4, 343 -53; 1976. 13 G. M. Zentner, K. J. Himmelstein and G. S. Rork. Multiparticulate controlled porosity osmotic. US Patent 4851228; 1989. 14 R. W. Baker. Controlled release delivery system by an osmotic bursting mechanism. US Patent 3952741; 1976 59/60

THANK YOU 60/60

THANK YOU 60/60