ISSN 0974-3618

INTRODUCTION:

The oral route of drug delivery is typically considered the preferred and most patient-convenient means of administration. Modified-release formulation technologies offer an effective means to optimize the bioavailability of drug usage. There are many ways to modulate the drug release from dosage forms on oral administration e.g. via film coated pellets and tablets, multi-layered tablets or capsules to more sophisticated and complicated delivery systems. Such as osmotically driven system and applications of three dimensional printing technology. ^{1, 2, 3}

Modulation of drug release from polymeric matrices is not only a science but also an art. Controlled release tablets encompassing oral dosage forms from which the active drug is released over an extended period of time with the aim of decreasing dosing frequency and reducing unwanted peak plasma concentrations; result in to improved patient compliance of therapy.

Generally, because of low manufacturing cost and ease of application, tablets continue to be a preferred dosage form for controlled release applications. However, according to Ficks first law of diffusion the release of drugs from monolithic matrix systems are incapable of attaining zero-order release due to inherent limitations i.e. generally area of diffusing surface decreases and diffusion path-length increases as time progresses.^{4, 5}

In the past few decades significant advances in controlled release technology have been accomplished. Their applications in the development of dosages forms showing sustained release, extended release, constant release or zero-order release rate are known to offer a drug release generally desirable in prolonged therapies. Numerous methodologies, devices and innovations have been investigated and utilized in order to achieve zero-order kinetics over a prolonged period of time. Incorporation of hydrophilic and swellable polymers in to tablet matrix has been demonstrated to alter the release kinetic from square root of time to non-fickian. Basically drug release from hydrophilic polymer matrices follows first order release kinetics. Also such tablets as a single unit dosage form may have several therapeutic disadvantages; due to their considerable variation of residence time in gastrointestinal tract of such dosage forms and significant variations in the absorption of active drugs. ^6,7,8 Most of the highly water soluble drugs, if not formulated properly may readily release the drug at a faster rate, and likely to produces toxic concentration of drug on oral administration.⁹ In order to improve the versatility in release kinetic, system designed as a triple-layered matrix tablet composed of individual matrix layers following probably different release mechanisms viz. swellable, erodable and disintegrating.^10,11 Many authors earlier reported that a number of variables are responsible for release pattern of drugs from matrix devices like physico-chemical properties of the actives ingredients and excipients viz. solubility, viscosity, as well as the type of dosage form and manufacturing variables.^12,13,14 Although these factors are responsible for drug dissolution, generally release pattern follows the diffusion of dissolved drug from polymeric matrices.^15,16 The diffusion pattern may be maintained by introduction of layering in tablets to achieve predetermined drug release pattern. Triple layered design is an example of commercially successful hydrophilic system which is based on symmetrical three-layered tablet geometry.

In recent literature study new matrix systems are noted, claiming to provide zero-order controlled release exemplified by triple-layered matrix tablets which are prepared with the middle layer containing the active compound embedded in water insoluble material and barrier top and bottom layers containing water-soluble and/or water-insoluble material and other excipients. Such proposed system is claimed to be a unique drug delivery device which overcomes the major disadvantage of non-linear release associated with diffusion controlled matrix devices. The system also has the advantage of employment for conventional manufacturing methods. General mechanism involved in modulation of drug release from multi-layered tablet compared with plane matrix tablet as shown in fig. 1

It is apparent that as far as controlling of release of highly soluble drugs is concerned, simple and practical formulations for molecules of different physicochemical characteristics are in demand and remains a challenge for pharmaceutical scientist.^17,18 Some of the serious problems facing in formulation of single unit matrix formulation with highly soluble drugs were highlighted as below. However such problems could be overcome by using multi-layered matrix tableting technology.

1. Burst effect: Resulting in to tissue toxicity and probably tachyphylaxis on repeated dosing.

2. First order release kinetics: unable to achieve study state plasma concentration.

3. Increase in metabolic rate: Matrix system fails to achieve steady release rate resulting in to increase in metabolic rate.

Increase in dosing frequency:increase in dosing frequency due to rapid release of drug from dosage form.

Multi-layered matrix tablet - a solution. Multilayered tablets have some obvious advantages over conventional matrix tablets to overcome the problems encountered with highly soluble drugs. The multi-layered matrix tablet represents a viable alternative to existing single unit oral controlled release dosage forms. They are commonly used to avoid incompatibilities of formulation components by physical separation. Attempts are being made to improve the cost-efficiency of the system by developing a limited number of “standard cover layers” with different erosion time that may be used as “off-the-shelf items” in the development of such formulations. The system is quite versatile and its unique design offers some new and exciting therapeutic options. Most importantly, it is possible to combine two matrix layers that contain different active drugs and design the release profile of each drug to maximize its therapeutic effect.^{19, 20}Barrier layers plays a key role to overcome some of the obvious problems encountered with highly soluble drugs. Press coated layers on both faces of tablet acts as a mechanical barrier between dissolution medium and core tablet which helps to release drug through matrix diffusion controlled by swelling and erosion mechanism. Following steps involved in the manufacturing of triple layered tablets.

Diagram

Material taken for layer 1(Bottom layer)	→	Pre-compression (Uniform spreading of Granules within die)	→	Material taken for layer 2 (Middle/Core layer)
				↓
Final compression with calculated force	←	Material taken for third layer (Top layer)	←	Pre-compression (uniform spreading of Granules within die)

Techniques involved in designing of Multi-layered matrix tablets

Different techniques used to design multilayered matrix tablets to overcome the problems encountered with plane matrix tablet of highly soluble drugs.

Triple – Layered tablets

Triple-layered system having matrix core with two barrier layers (Type1)

Three-layered matrix tablets were prepared with the middle layer containing the active compound sandwiched in water insoluble (e.g. waxes, polymers) materials. Two press coated barrier layers contains water-soluble (polymers) and/or water-insoluble (e.g. hydrogenated oils, waxes, and polymers) materials and other excipients. The proposed system is unique drug delivery device which overcomes the disadvantage of non-linear release associated with diffusion controlled matrix devices.

The designs of three hydrophobic matrix type systems are schematically defined as follow. The matrix or middle layer is denoted by M, hydrophilic barrier layer is denoted by H, hydrophobic or liphophilic barrier layer is denoted by L.

1. Layered matrix HMH: - A hydrophobic non-Swellabe matrix tablet (M) containing

the drug is coated with hydrophilic barriers (H) on both faces by compression.

2. Layered matrix HML: - A hydrophobic non-swellable matrix tablet (M)containing the drug is coated with a hydrophilic barrier (H) on one face and a hydrophobic barrier (L) on the other face by compression.

3. Layered matrix LML: - A hydrophobic non swellable matrix tablet (M) containing the drug is coated with hydrophobic barriers on both faces by compression.

The Smartrix system (“smart matrix”) is a novel erosion-controlled delivery system based on the above principles that the design of drug containing core in combination with slowly eroding cover layers provides qusi-lineare release of the drug. When the core itself not covered by the eroding layers, shows a release profile typical for inert porous plastic matrix including polyvinyl chloride.^21,22,23 vinyl acetate, vinyl chloride copolymer and ethyl cellulose. However, when core covered with erodable layers, controlled erosion of these outer layers causes a steady increase of surface area that available for the release of drugs and provides a linear release of drug.^24,25,26Multi-layered tablets that consist of individually shaped layers, where as shape of the cover layers is determines the shape of the core layer. To obtain desired linearity of release profiles, rate of erosion of cover layers has to be adjusted to match the intended release. A strong bond between core matrix and cover layers is essential to ensure desired release profile over intended application period. A critical factor affecting on bonding strength is surface structure of core. The swelling of the drug-containing layer causes an increase in surface area and therefore an increase in amount of drug released per unit time.^{27,
28, 29}

Triple-layer system having matrix core coated with asymmetric barrier layers (Type 2)

The asymmetric configuration drug delivery system based on disproportional swellable and erodable triple layered tablet technology provides constant drug release over long period of time. The swellable and erodable polymer used as, poly (ethylene oxide) and water soluble resin over wide range of molecular weights.^30,31 It shows that drug release from such a system exhibited zero-order kinetics and independent of variation in the dissolution medium pH and compression force.^32.33,34 It consists of three layers of particulate system directly compressed together. The middle layer representing drug containing core coated by external layers on both sides. The two external layers have dissimilar thickness and composition designed to delay initial hydration rate of the middle layer which restrict the early drug release by diffusion, only through cylindrical side surfaces of the tablet. ^{35, 36}

The external layers disappear gradually at disproportionate rates and reduction of diffusing surface area due to the erosion as well as the increase in diffusion path-length resulting from continuous system swelling.^{37, 38}It is possible that during the time period between system swelling and erosion, complete erosion of the third layer, a certain amount of drug diffused through the barrier layers in addition to the amount released from the lateral side. This system provides significant flexibility in modulation of release kinetics for drugs of different solubility. It also accommodates variable drug loadings and polymers of different characteristics. This review also demonstrated that zero-order release kinetics are easily achievable as long as the surface area of the system is carefully modulated^{, 39, 40, 41.}

Triple-layer matrix system with different layer position (Type 3)

This system focuses on control of the overall release kinetics is primarily determined by the composition of each layer. When there are more than two layers effects on the release rate is expressed by relative position of the individual layers.^{42, 43, 44}Each individual layer of the matrix exhibited a different release mechanism viz. Swellable, erodable, and disintegrating. The three-layers assembled in the monolithic matrix in different relative positions. It is found that in this monolithic three-layer interact with each other producing in vitro release profile depending on their relative position.^45,46,47Just by changing the position of the swellable, erodible and disintegrating layers, three different monoliths were produced and coded as SDE, DSE, and SED respectively. The relative position of the layers show different release profiles. When the disintegrating layer located in one of two possible external positions (DSE and SED), disintegrating layer quickly exposed to dissolution medium than swellable or erodible layers in the middle position. As a consequence, equivalent two-layer monoliths were generated in both cases and non-significantly different release kinetics. When the disintegrating layer compressed between the swellable and erodible layers, as in SDE monolith, release curves were significantly different than previous two configurations. In this case more linear and lower release rate were seen because of different area exposed to dissolution medium by each layer depends on its position in the monolith. ^{48, 49, 50}

An unexpected release with the SDE monolith, duo to disintegration of middle layer split monolith in to two pieces i.e. the swellable and the erodable. Swellings of overlaid layer provide quite a coating on the middle layer slowing down its disintegration and delay the splitting of the monolith in two halves. Depending on the sequence of these layers and their relative position, combination of these release mechanism in the monolith occurred. The monolith DSE and SDE, despite the same composition delivers the two drugs with different kinetics. They could be used alternatively for e.g. in Parkinson treatment for satisfying the need of a fast or slow delivery. The DSE monolith gives rise in a levodopa plasma profile significantly different from the SDE monolith.

Table No. I Different type of multilayer designs with release kinetics

Type of design	No. of barrier layers	Symmetry of barrier layer	Position of barrier layer	Release kinetics
Type 1	Three	Constant	Unchanged	Zero-order
Type 2	Three	Constant	Unchanged	Zero-order
Type 3	Three	Vary	Changed	Zero-order
Type 4	Two	Constant	NA	Zero-order

NA: Not Applicable

In terms of the rate of absorption, DSE monolith having the disintegrating layer externally levodopa peak followed by prolonged drug plasma level. While from the SDE monolith disintegrating layer in the middle and peak of levodopa delayed, giving rise to a plateau of drug plasma concentration.^51,52 For therapeutic use DSE layer having swellable layer at middle position useful for the reduction of morning on-off fluctuation because of the early levodopa plasma peak concentration. The SDE monolith showing prolonged release, useful for afternoon administration in order to avoid end-off dose deterioration. They can be combined in a product having a morning and afternoon administration schedule in order to tailor better Parkinson therapy to individual patient requirements.

Two Layered tablets (Type 4)

In the application of a drug free barrier layer on active core reduces the surface area available for drug release. The result is an extended release that is drawn close to a linear release profile. The device is mainly intended for soluble drugs, while excessive reduction of the release rate may be obtained with drugs of low solubility. In this technology a new time dependent polymeric barrier proposed to control the release of highly soluble drugs. Two different barrier compositions one swellable and one erodable applied on

active core containing drugs of different solubility. During dissolution the swellable barrier swells and gels but does not erode, thus acting as a release modulating membrane during the release process. The erodable barrier instead progressively removed by the dissolution medium, exposing the planer surface of the core to interact with dissolution medium and drug release. Both types of coatings are able to control drug release from the devices. The swellable barrier shows stronger modulation efficiency and more suitable to modify the delivery pattern of highly soluble drugs. The erodable barrier shows a time dependent coating effect that provides better control of the dissolution profile of sparingly soluble drugs.^{53,
54, 55}

The application of the swellable barrier on active cores containing highly soluble drug leads to extended release with steady state plasma concentration clearly approaches constant rate release kinetics. Although it is able to reduce the initial burst release of the drug, three layer systems would have to give some obvious advantages with respect to release as compare to that of the two layer devices. Swellable barrier on active cores containing the less soluble drugs produces a dramatic decrease in release rate but using the erodable barriers an excellent linearization of the dissolution profile and at the same time more suitable release rate. This difference in behaviors because of the presence of active ingredient particularly of soluble or insoluble, influences water penetration to the matrix and the consequent polymer hydration/swelling process.^{56, 57}

The soluble drug enhances water uptake and the molecule can easily mobilize and becomes available for diffusion through the gel layer. On the other hand, less soluble drugs tend to depress or delay the hydration/swelling process of the matrix and consequently the mobilization of molecules for diffusion is significantly hindered. All the core formulations prevailing diffusion-dependent rather than erosion-dependent release mechanism, even if erosion process completely over the core does not actually dissolved but recovered from the vessel as gelled spheres (smooth cylinders). In such dissolution mechanism drugs characterized by low solubility surface area available for active interaction with the dissolution medium becomes an extremely critical parameter for the overall release process. The dissolution profile obtained from the devices coated by compression on the whole surface confirms that the erodible barrier perform only a time dependent control. Once the coating is removed, release processes can not be influenced any further and excluding the time lag is comparable with the dissolution curve of the core. While the swellable barrier shows a double effect: a. at the beginning (as long as portion remains in a glassy state) it acts as an impermeable coating until it is sufficiently gelled. This process takes longer time than the erodible coating. 2. Then the gellable barrier, when completely gelled (but not eroded) behaves as modulating membrane and acts as a mechanical protection against core erosion and still controls the core hydration and release process^58,59

CONCLUSION:

The present literature illustrate that design of multi-layered matrix tableting technology is one of the excellent skill in the development of new drug delivery devices. Beginning of such design provides significant flexibility in modulation of release kinetics for drugs of high solubility. Also system overcomes the major disadvantage of non-linear release associated with diffusion controlled matrix devices by providing additional drug release with time.

Future prospectus for the design of such delivery devices by insertion of naturally occurring materials like hydrophobic waxes and hydrophilic gums provides an excellent platform in drug delivery system.

REFERENCES:

1. Chein Y W, Fundamentals of controlled release of drug administration in: j. Swarbrick (Ed.), Novel Drug Delivery System, Marcel Deckker, New York:1982, 465-574.

2. Rathbone J, Hadgraft J, Roberts S, Modified-Release Drug Delivery technology, oral Modified-Release Delivery Systems, (Ed) J.Swarbrick Marcel Deckker Inc, New York and Basel, 1982, 14, 1-10.

3. KrishnaiahYSR., Al Saidan SM, Satyanarayan V, Bhaskar P, Kartikeyan RS; Pharmacokinetic evaluation of guar-gum based three-layer Matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate as a model drug, Eur. J. Pharm and Biopharm, 2004, 58, 697-703.

4. E Nelson. Pharmaceuticals for prolonged action Clin pharmacol Ther. 1963, 4, 283, 1963.

5. Munzel K, Der Einfluss der Formgebung guf die Wirkung lines Arzneimittus (The effect of the shape of Dosage form on its efficacy). Based: Birkhauser Verlag, 1966, 290.

6. Bechgard H. Critical factors influencing gastrointestinal absorption – what is the role of pellets? Acta Pharm Technol. 1982, 28, 149.

7. Davis SS, The design and evaluation of controlled release system for the gastrointestinal tract. J. control Rel. 1985, 12, 27-32.

8. Al-Saidan SM, Krishnaiah YSR, Styanarayana V, Bhaskar P, Karthikeyan RS, pharmacokinetic evaluation of guar gum- based three-layer matrix tablets for oral controlled delivery of highly soluble metoprolol tartarate as a model drug, Eur J. Pharm and Biopharm. 2004, 58, 697-703.

9. Conte U, Maggi L, Colombo P, and La Manna A, Multi-layered hydrophilic matrices as constant release devices (Geomatrix^TM system), 1993, 26, 39-47.

10. Lee L, Diffusion-controlled Matrix Systems, in: A. Kedonieus (Ed), Treatise on Controlled Drug Delivery, Marcel Deckker Inc., New York, 1992, 155-198.

11. Qiu Y, Chidambaram N, Kolettee Flood, design and evaluation of layered diffusional matrices for zero-order sustained release, J.control. Release, 1998, 51, 123-130.

12. Lipper RA, Higuchi WI, Analysis of theoretical behavior of proposed zero-order drug delivery system , J. Pharm sci. 1977, 66, 163-164.

13. Colombo P, Conte U, Gazzania A et al. Drug release modulation by physical restriction of matrix swelling. Int. J. Pharm 1990, 42, 43-48.

14. Colombo P, Catellani PL, Peppas NA Maggi L, Conte U. Swelling characteristic of hydrophilic matrices for controlled release. New dimensionless number to describe the swelling and release behavior. Int J. Pharm 1992, 43, 99-109.

15. Conte U., Colombo P, Maggi L, La Manna A, Compressed barrier layers for constant drug release in Swellable matrix tablets. STP Pharma Sci 1994, 4, 107-113.

16. Conte U., Maggi L, Torre ML, Giunchedi P, La Manna A. Press coated tablets for time programmed release of drugs Biomatarial 1993, 14, 1017-1023.

17. Mitchel K, Ford JL, Armstrong DJ, Elliot PN, Hogan JE, Rostron C. The influence of drugs on properties of gels and swelling characteristics of matrices containing methylcellulose or hydroxypropylmethylcellulose.Int J Pharm 1993, 100, 165-173.

18. Skoug JW, Mikelsons MV, Vigneron CN, Stemm NL. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release. J. Control Rel. 1993, 27, 227-245.

19. Wan LSC Heng PWS, Wong LF. The effect of hydroxyl propyl methyl cellulose on water penetration in to a matrix system. Int J. Pharm. 1991, 73, 111-116.

20. Alderman DA. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int J Pharm prod. Manufact 1984, 5, 1-9.

21. Yang LB., Fassihi R., Modulation of diclofenac release from a totally soluble controlled release drug delivery system. J. control Release 1997, 44, 135-140.

22. Colombo, P., La Manna, A., Contt.U., System for the controlled release of active substances. US Patent 4,839,1989.

23. Harland, R.S., Gazzaniga, A., Sangalli, M. E., Colombo, P., Peppas, N. A., Drug Polymer Matrix Swelling and dissolution. Pharm. Res. 1998, 5, 488-494.

24. Lee, P.I., Diffusional release of a solute from a polymeric matrices approximate analytical solutions. J. Membrane Sci. 1980, 7, 255-275.

25. Alderman, D. A., A review of cellulose esters in hydrophilic matrices for controlled release dosage forms. J. Pharm.Technol.Prod. Mfr. 1984, 5, 1-9.

26. Apicella, A., Cappello, B., Del M. A., La Rontonda, M. I., Mensitieri, G., Nicolais, L., Poly (ethylene oxide) and different molecular weight PEO blend monolithic devices for drug release. Biomaterials 1993, 14, 83-91.

27. Kim, C, j., Drug release from compressed hydrophilic POLYOX-WSR tablets. J. Pharm. Sci. 1995, 84, 303-306.

28. Kim, H., Fassihi, R., Application of the Binary polymer system in drug release rate modulation. 1. Characterization of release mechanism. J. Pharm. Sci. 1997, 86, 316-322.

29. Higuchi T., Mechanism of sustained action, Theoretical analysis of solid drugs dispersed in solid matrices. J. Pharm.Sci. 1963, 52, 1145-1149.

30. Windle, AH., Case-II sorption. In: comyn, J. (ED), Polymer permeability. Elsevier Applied Science, London, 1995, 75-118.

31. Sangali, M.E., Conte, U., GAzzaniga , A., La Manna A., Inert monolithic device with central hole for constant Release Proceed Inert. Symp. Control. Rel. Bioact Mater 1993, 20, 316-317.

32. Zhang, G.H., vadino WA. Chaudry I., Drug release from erodible tablets. Proceed. Intern. Symp Control. Rel Bioact. Mater. 1990, 17, 333-333

33. Kim C. J., Kinetics of drug release from erodible polymer matrices. Pharm Res. 1996, 13, 290.

34. Kim C.J., Compressed donut- shaped tablets with zero-order release kinetics Pharm. Res. 1995, 12, 1045-1048.

35. Nangia A., Molloy T., Fahie, B.J., Chopra, S.K., Novel regulated release system based on geometric configuration. Proceed Intern.Symp. Control. Rel. Bioact. Mater. 1995, 22, 294-295.

36. Bayomi, M A., Geometric approach for zero-order release of drugs dispersed in an inert matrix. Pharm Res. 1994, 11, 914-916.

37. Pokharkar, V B., Sivaram, S., Permeability studies across polt (alkane carbonate) membranes. J. Control. Rel. 1996, 41, 157-162.

38. Maurin, MB., Rowe, SM., Kowal, CA., Hussan, M A., Solublization of nicardipinehydrochlorid via complexation and salt formation J.Pharm. Sci. 1994, 83, 1418-1420.

39. Fassihi RA, Ritschel WA, Multiple-layer, direct-compression, controlled-release system: in vitro and in vivo evaluation, J. Pharm. Sci.1992, 82,750-754.

40. Colombo P, Catellani PL, Peppas NA, Maggi L, Contte U, Swelling Characteristics of hydrophilic matrices for controlled release: new dimensionless number to describe the swelling and release behavior, Int. J. Pharm. 1992, 88, 99-109.

41. Bettini R, Colombo P, Massimo G, Cattilani PL, Vitali T, Swelling and drug release in hydrigel matrices: polymer viscosity and matrix porosity effects, E. J. Pharm. Sci. 1994, 2, 213-219.

42. Bettini R, Acerbi D, caponetti G, Mussa R, Maggi N, Colombo P, Cocconi D, Santi P, Catellani PL, Ventura P, influence of layer position on in vitro and in vivo release of levodopa methyl ester and carbidopa from three-layer matrix tablets. Eur. J. Pharm and Biophar. 2002, 53, 227-232.

43. Marrel C, Boss G, van de Watterbemb H, Cooper D, Jener P, Marsden CD, Testa B, L-DOPA esters as potential prodrugs, Eur. J. Med. Chem-chim. Ther. 1985, 20, 459-465.

44. Kao HD, Trabouisi A, Itoh S, Ditter L, Hussain A, Enhancement of the systemic and CNS specific delivery of L-DOPA by the nasal administration of its water soluble prodrugs, pharm Res.2000, 17 (8) , 978-984.

45. Moes AJ, Gastroretensive dosage forms, Crit. Rev. Ther. Drug Carrier Syst.1993, 10, 143 195.

46. Rondelli I, Acerbi D, Mariotti F, Ventura P Simultaneous determination of levodopa methyl ester, levodopa, 3-O- methyldopa and dopamine in plasma by high performance liquid chromatography with electrochemical detection, J. chromatogr. 1994, B 653, 17-23.

47. Vora MS, Zimmer AJ, maney VP, Sustained release aspirin tablets using an insoluble matrix. J Pharm Sci.1964, 53, 481-487.

48. Rowe RC, Sustained Release plastic matrix tablets Manu. Chem. Aerosol News. 1975, 3, 23-56.

49. Cremer K, Asmussen B. Novel Controlled release tablet with erodible layers. Proc Int Symp Control Rel Bioact Mater.1995, 22, 732-733.

50. Cremer K Verfahren zur Kontrollierten fristzung von wirkstoffen. German patent DE 44 16 926 1995.

51. Cremer K. Vorrichtung zur kontrollierten freisetzung von Workstoffen sowie ihre verwendung. German patent DE 43 41 442, 1998.

52. Higuchi.T, Mechanism of sustained action medication: theoretical analysis of rate of release of solid drug dispersed in solid matrices. J Pharm sci.1963, 52, 1145-1149.

53. Conte U, Maggi L, modulation of dissolution profils from Geomatrix multilayered tablets containing drug of different solubility, Biomaterials.1996, 17, 889-896.

54. Davis SS., The design and evaluation of controlled release system for the gastrointestinal tract. J. control Rel. 1985, 12, 27-32.

55. Qiu Y, Chidambaram N, K flood. Design and evaluation of layered diffusion matrices for zero-order sustained Release. J Control Rel. 1998, 51, 123-130.

56. Yang L, fassihi R, Examination of drug solubility, polymer types, hydrodynamics and loading dose on release behavior from triple-layer asymmetric configuration delivery devices. Int. J. pharm.1997, 155, 219-229.

57. Abrum M A, Shirwaikar A, formulation of Multi-layered sustained release tablets using insoluble matrix system. Indian J. Pharm Sci. 1997, 59, 312-315.

58. Chidambaram N, porter W, K flood, Qiu. Y, Formulation and characterization of new layered diffusional matrices for zero-order sustained release J Control. Rel .1997, 52, 149-158.

59. Korsch W, schmett M, Presse Zur Herstellung ummantelter tabletten. German patent DE 4 025 484, 1990.

Received on 26.07.2009 Modified on 23.10.2009

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 664-669439