IJPRD, 2011; Vol 3(5): July 2011 (53 - 59)

International Standard Serial Number 0974 9446

---------------------------------------------------------------------------------------------------------------------------------------------------------------A REVIEW ON NOVEL IN SITU POLYMERIC DRUG DELIVERY SYSTEM

Vyas Jigar1*, Ghedia Tejas1, Gajjar Vishal1, Christian Vishal1, Upadhyay Umesh1
1

Department of Pharmaceutics, Sigma Institute of Pharmacy, India

ABSTRACT The in situ gel forming polymeric formulations offer several advantages like sustained and prolonged action in comparison to conventional drug delivery systems. In situ forming polymeric formulations are drug delivery systems that are in sol form before administration in the body, but once administered, undergo gelation in situ, to form a gel. The formation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, electrical sensitivity, enzyme sensitive from which the drug gets released in a sustained and controlled manner. Hydrogels are presently under investigation as a delivery system for bioactive molecules, because of their similar physical properties as that of living tissue, which is due to their high water content, soft and rubbery consistency, and low interfacial tension with water or biological fluids. The article presents a detailed review of these types of polymeric systems, their evaluation, advancements and their commercial formulations. From a manufacturing point of view, the production of such devices is less complex and thus lowers the investment and manufacturing cost. Different methods of preparation of hydrogels, novel methods of crosslinking used in the preparation of hydrogels, the mechanism of water transport through the ionic hydrogels, and the release mechanism of the solute from the hydrogels, are discussed in the present article. It is concluded that the advantages of using biodegradable polymers in clinical applications are apparent. Various natural and synthetic polymers are used for formulation development of in situ forming drug delivery systems. The primary requirement of a successful controlled release product focuses on increasing patient compliance, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable. Use of biodegradable and water soluble polymers for the in situ gel formulations can make them more acceptable and excellent drug delivery systems. Available online on www.ijprd.com

Correspondence to Author

Dr. Jigar R. Vyas

HOD, Pharmaceutics Department, Sigma Institute of Pharmacy, Baroda, Gujarat, India. Email drjrvyas@yahoo.co.in Key Words In Situ Gel, Polymeric Gel, Biodegradable, Cross Linking, Drug Delivery systems

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International Journal of Pharmaceutical Research & Development 1. INTRODUCTION Extensive research has been carried in development of polymeric drug delivery systems. The development of in situ gel systems has received considerable attention over the one decade[1]. This interest has been evolved by the advantages shown by in situ forming polymeric delivery systems such as ease of administration and reduced frequency of administration, improved patient compliance and comfort, sustained and controlled delivery systems[2]. In the past few years, increasing number of in situ gel forming systems have been investigated and many patents have been filed. In Smart polymeric systems represent promising means of delivering the drugs; these polymers undergo sol-gel transition, once administered[3]. In situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation, solvent exchange, presence of ions, electrical stimuli etc. In this review, different types of smart polymers, their mechanisms of gel formation from the sol forms, various route of administration, evaluation and characterization of in situ polymeric formulations are discussed. From the early 1970's natural and synthetic polymers began to be investigated for controlled release formulations. The advantages of using biodegradable polymers in clinical applications are apparent. Various natural and synthetic polymers are used for formulation development of in situ forming drug delivery systems. 1. 1 Classification In situ gel forming systems have been classified in two categories as below: Based on Mechanism of Gelation Based on Route of Administration

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e) Presence of Ions 1.1.2 Based on Route of Administration a) In situ forming polymeric systems for oral administration b) In situ forming polymeric systems for ocular delivery c) In situ forming polymeric systems for rectal and vaginal delivery d) In situ forming injectable drug delivery systems e) In situ forming nasal drug delivery systems 2. METHOD OF PREPARATION Several techniques have been reported for the synthesis of hydrogels. The first approach involves Copolymerization/crosslinking of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. The polymerization reaction is initiated by chemical initiator. The polymerization reaction can be carried out in bulk, in solution, or in suspension. The second method involves crosslinking of linear polymers by irradiation, or by chemical compounds [4]. The monomers used in the preparation of the ionic polymer network contain an ionizable group, a group that can be ionized, or a group that can undergo a substitution reaction after the polymerization is completed. As a result, hydrogels synthesized contain weakly acidic groups like carboxylic acids, or a weakly basic group like substituted amines, or a strong acidic and basic group like sulfonic acids, and quaternary ammonium compounds. Some of the commonly used crosslinking agents include N, N - methylenebisacrylamide, divinyl benzene, and ethylene glycol dimethacrylate. 2.1 Solution Polymerization/Crosslinking In solution, co-polymerization/crosslinking reactions, and ionic or neutral monomers are mixed with the multifunctional crosslinking agent. The polymerization is initiated thermally, by UV-light, or by redox initiator system. The presence of solvent serves as heat sink, and minimizes temperature control problems. The prepared hydrogels need to be washed with distilled water to remove the unreacted monomers, crosslinking agent, and the initiator. The best example is preparation of poly (2- hydroxyethyl methacrylate) [5] hydrogels from

1.1.1 Based on Mechanism of Gelation a) PH Sensitive Gel b) Gel Sensitive to electrical current c) Thermosensitive Gel d) Enzyme Sensitive

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International Journal of Pharmaceutical Research & Development hydroxyethyl methacrylate, using ethylene glycol dimethacrylate as crosslinking agent. Using the above method, a great variety of hydrogels have been synthesized [6].The hydrogels can be made pH- sensitive or temperature- sensitive, by incorporating methacrylic acid [7], or N- isopropylacrylamide [8] as monomers. 2.2 Suspension Polymerization This method is employed to prepare spherical hydrogel microparticles with size range of 1 m to 1mm. In suspension polymerization, the monomer solution is dispersed in the non-solvent forming fine droplets, which are stabilized by the addition of stabilizer. The polymerization is initiated by thermal decomposition of free radicals. The prepared microparticles then washed to remove unreacted monomers, crosslinking agent, and initiator. Hydrogel microparticles of poly(vinyl alcohol) and poly(hydroxy ethyl methacrylate) have been prepared by this method. 2.3 Polymerization By Irradiation High energy radiation like gamma and electron beam, have been used to prepare the hydrogels of unsaturated compounds. The irradiation of aqueous polymer solution results in the formation of radicals on the polymer chains. Also, radiolysis of water molecules results in the formation hydroxyl radicals, which also attack the polymer chains, resulting in the formation of macroradicals. Recombination of the macroradicals on different chains results in the formation of covalent bonds, and finally a crosslinked structure is formed [9]. During radiation, polymerization macroradicals can interact with oxygen, and as a result, radiation is performed in an inert atmosphere using nitrogen or argon gas. Examples of polymers crosslinked by radiation method include poly(vinyl alcohol) [10], poly (ethylene glycol) [11, 12], poly(acrylic acid) [13]. The major advantage over chemical initiation is the production of relatively pure, residue-free hydrogels. 2.4 Chemically Crosslinked Hydrogels Polymers containing functional groups like OH, COOH, NH 2, are soluble in water. The presence of these functional groups on the polymer chain can be used to

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prepare hydrogels by forming covalent linkages between the polymer chains and complementary reactivity, such as amine-carboxylic acid, isocyanateOH/NH2 or by Schiff base formation [14]. Gluteraldehyde can be used as a crosslinking agent to prepare hydrogels of polymers containing OH groups like poly(vinyl alcohol) [15]. Also, polymers containing amine groups (albumin, gelatin, polysaccharides) [16, 17], can be crosslinked using gluteraldehyde. Polymers that are water soluble, can be converted to hydrogels, using bis or higher functional crosslinking agents like divinylsulfone [18], and 1,6-hexanedibromide [19] . The crosslinking agents react with the functional groups present on the polymer, via addition reaction. These crosslinking agents are highly toxic, and hence unreacted agents have to be extracted. Moreover the reaction has to be carried out in organic solvent, as water can react with the crosslinking agent. The drugs have to be loaded after the hydrogels are formed, as a result the release will be typically first order. Crosslinking between polymers through hydrogen bond formation occur as in the case of poly(methacrylic acid) and poly(ethylene glycol). The hydrogen bond formation takes place between the oxygen of poly(ethylene glycol) and carboxylic acid group of poly(methacrylic acid)51. Carriers consisting of networks of poly (methacrylic acidg- ethylene glycol) showed pH dependent swelling due to the reversible formation of interpolymer complex, stabilized by hydrogen bonding between the etheric groups of the grafted poly(ethylene glycol), and the carboxylic acid protons of the poly(methacrylic acid) [20]. 2.5 Physically Crosslinked Hydrogels Most of the covalent crosslinking agents are known to be toxic, even in small traces. A method to overcome this problem and to avoid a purification step, is to prepare hydrogels by reversible ionic crosslinking. Chitosan, a polycationic polymer can react with positively charged components, either ions or molecules, forming a network through ionic bridges between the polymeric chains. Among anionic molecules, phosphate bearing groups, particularly sodium tripolyphosphate is widely studied [21, 22]. Ionic

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International Journal of Pharmaceutical Research & Development crosslinking is a simple and mild procedure. In contrast to covalent crosslinking, no auxiliary molecules such as catalysts are required [23]. Chitosan is also known to form polyelectrolyte complex with poly (acrylic acid). The polyelectrolyte complex undergoes slow erosion, which gives a more biodegradable material than covalently crosslinked hydrogels [24, 25] 3. DYNAMICS OF SWELLING OF IONIC HYDROGELS Water diffusion in glassy polymers often deviates from the predictions of Ficks law, leading to anomalous or non-Fickian diffusional behavior. The deviation from Fickian behavior has been associated with the finite rate at which the polymer structure rearranges, to accommodate water molecules, and has been observed for many hydrophilic polymer systems. Depending upon the dynamics of polymer swelling and the relative mobilities of drug and water, Fickian or non-Fickian drug transport may be observed. The relative importance of water diffusion and polymer relaxation can be described by the Deborah number (De), defined as the ratio of a characteristic relaxation time () to a characteristic diffusion time (). De=/, =L2/Dwp where L is the characteristic length of the controlled release device, and Dwp is the water diffusion coefficient. When De<<1, relaxation is much faster than diffusion, and Fickian transport is observed. When De~1, relaxation and diffusion are coupled leading to a complex transport behavior, known as anomalous or non-Fickian transport [4] . In Fickian diffusion, the rate of water absorption shows a linear increase as a function of the square root of time. Fickian diffusion is observed when the time scale of the macromolecular relaxation is either effectively infinite or zero, compared to the time required to establish a concentration profile in the polymer sample. In non- Fickian or anomalous transport,both diffusion as well as macromolecular relaxation time scales are similar, and both control the overall rate of penetrant absorption. Case II transport is the limit, when relaxation predominates. Zero- order, time-independent Case II kinetics is characterized by a linear mass uptake with time.

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The amount of drug released from a thin slab at time t (Mt) with respect to the total amount of drug released (M), can be expressed in terms of an exponential expression as follows: Mt/M=ktn, for 0<Mt/M<0.6, where n is diffusional exponent. The value of n determines the dependence of the release rate on time [26] . Usually there is accumulation of drug on the surface of the hydrogel when the drug is loaded to preformed hydrogel, which leads to burst effect. This makes the release profile to have an intercept. To correct for this, the equation can also be written as Mt/M=+ktn for 0< Mt/M<0.6, where takes into account the burst release observed. The constant is estimated as the intercept at time zero [27]. Gumusderelioglu and kesgin [28] studied the release behaviour of bovine serum albumin from the copolymer of ethylene glycol vinyl ether, butyl vinyl ether, and acrylic acid, in the presence of crosslinking agent, diethylene glycol divinyl ether. Calculated n-values were ranging between 0.46 and 0.84, which indicated that the release deviates from the Fickian mode. It was concluded that the existence of some molecular relaxation process in addition to diffusion, was responsible for the observed non-Fickian behavior. Garca et al.[29] studied the Timolol maleate release from pH-sensitive poly(2-hydroxyethyl methacrylate-comethacrylic acid) hydrogels. The n value was close to 0.50, which indicated a Fickian behavior.The diffusion coefficient calculated was in the range of 3.2110-6 cm2/sec to 11.5210-6 cm2/sec for pH7.4, also the diffusion coefficient depended on the methacrylic acid content in the hydrogel. 4. EVALUATION AND CHARACTERIZATION OF IN SITU GELS SYSTEMS 4.1 In Vitro Drug Release Studies For the in situ gel formulations to be administered by oral, ocular or rectal routes, the drug release studies are carried out by using the plastic dialysis cell [30]. The cell is made up of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane. The sol form of the formulation is placed in the donor compartment. The assembled cell is then shaken

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International Journal of Pharmaceutical Research & Development horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media. This receptor solution is analyzed for the drug release using analytical technique. For injectable in situ gels [31], the formulation is placed into vials containing receptor media and placed on a shaker water bath at required temperature and oscillations rate. Samples are withdrawn periodically and analyzed. 4.2 Sol-gel transition temperature and gelling time For in situ gel forming systems incorporating thermoreversible polymers, the sol-gel transition temperature may be defined as that temperature at which the phase transition of sol meniscus is first noted when kept in a sample tube at a specific temperature and then heated at a specified rate [32]. Gel formation is indicated by a lack of movement of meniscus on tilting the tube. Gelling time is the time for first detection of gelation as defined above [32]. 4.3 Gel Strength This parameter can be evaluated using a rheometer. Depending on the mechanism of the gelling of gelling agent used, a specified amount of gel is prepared in a beaker, from the sol form [32]. This gel containing beaker is raised at a certain rate, so pushing a probe slowly through the gel. The changes in the load on the probe can be measured as a function of depth of immersion of the probe below the gel surface. 4.4 Fourier Transform Infra-Red Spectroscopy And Thermal Analysis During gelation process, the nature of interacting forces can be evaluated using this technique by employing potassium bromide pellet method. Thermo-gravimetric analysis can be conducted for in situ forming polymeric systems to quantitate the percentage of water in hydrogel. Differential scanning calorimetry is used to observe if there are any changes in thermograms as compared with the pure ingredients used thus indicating the interactions [33]. 4.5 Clarity Clarity can be determine by visual examination

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4.6 Viscosity And Rheology This is an important parameter for the in situ gels, to be evaluated. Viscosity and rheological properties of in situ forming drug delivery systems may be assesses using Brookfield rheometer or some other type of viscometers such as Ostwald's viscometer. The viscosity of these formulations should be such that no difficulties are envisaged during their administration by the patient, especially during parenteral and ocular administration [33] . 4.7 Texture Analysis The firmness, consistency and cohesiveness of hydrogels are assessed using texture analyzer which mainly indicates the syringeability of sol so the formulation can be easily administered in vivo. Higher values of adhesiveness of gels are needed to maintain an intimate contact with surfaces like tissues [33].

5.COMMERCIAL FORMULATIONS OF IN SITU POLYMERIC SYSTEMS 5.1 Regel Depot Technology Regel is one of the Macromed's proprietary drug delivery system and based on triblock copolymer, composed of poly (lactide-co-glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide). It is a family of thermally reversible gelling polymers developed for parenteral delivery that offers a range of gelation temperature, degradation rates and release characteristics as a function of molecular weight, degree of hydrophobicity and polymer concentration. Following injection, the physical properties of polymer undergo a reversible phase change resulting in formation of a water insoluble, biodegradable gel depot. Oncogel is a frozen formulation of paclitaxel in Regel. It is a free flowing liquid below room temperature which upon injection forms a gel in situ in response to body temperature. hGHD-1 is a novel injectable depot formulation of human growth hormone (hGH) utilizing Macromed's Regel drug delivery system for treatment of patients with hGH deficiency [34]. 5.2 Cytoryn

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International Journal of Pharmaceutical Research & Development This is one of the Macromed's products, which is a novel, peritumoral, injectable depot formulation of interleukin-2 (IL-2) for cancer immunotherapy using Regel drug delivery system. It is a free flowing liquid below room temperature that instantly forms a gel depot upon injection from which the drug is released in a controlled manner. Cytoryn enhances the immunological response by safely delivering four times the maximum tolerated dose allowed by conventional IL-2 therapy. Cytoryn also activates the systemic antitumor immunity. Regel system stabilizes and releases IL-2 in its bioactive form. The release of drugs is controlled by the rate of diffusion from and degradation of the depot [35,36]. 5.3 Timoptic-Xe It is a timolol maleate ophthalmic gel formulation of Merck and Co. Inc., supplied as a sterile, isotonic, buffered, aqueous gel forming solution of timolol maleate. This formulation is available in two dosage strengths 0.25% and 0.5% in market. The pH of the solution is approximately 7.0, and the osmolarity is 260330 mOsm. Each ml of Timoptic-XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Inactive ingredients include gellan gum, tromethamine, mannitol, and water for injection and the preservative used is benzododecinium bromide 0.012%. Timoptic-XE, when applied topically on the eye, reduces the elevated, as well as normal intraocular pressure, whether or not accompanied by glaucoma [37]. 6. CONCLUSION Recent developments in the field of polymer science and technology has led to the development of various stimuli sensitive hydrogels like pH, temperature sensitive, which are used for the targeted delivery of proteins to colon, and chemotherapeutic agents to tumors. Exploitation of polymeric in situ gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable. Use of biodegradable and water soluble polymers for the in situ gel formulations

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can make them more acceptable and excellent drug delivery systems. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. New synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range of drugs, peptides, and protein delivery applications. Random copolymers with balanced hydrophobicity/hydrophilicity, can offer desirable release rates and dissolution profiles, for the development of oral controlled drug delivery. 7. REFERENCES 1. Peppas NA, Langer R. New challenges in biomaterials. Science, 1994; 263:1715-20. 2. Zhidong L, Jaiwei L, Shufang N, Hui L, Pingtian D, Weisan P. Study of an alginate/HPMC based in situ gelling ophthalmic delivery system for gatifloxacin. Int J Pharm, 2006; 315:12-17. 3. Al-Tahami K, Singh J. Smart polymer based delivery systems for peptides and proteins, Recent Pat Drug Delivery Formul, 2007; 1:66-71. 4. Peppas NA and Khare AR. Adv. Drug Del. Rev., 1993; 11:1. 5. Wichterle O and Lim D, Nature, 1960; 185:117. 6. Langer RS and Peppas NA, Biomaterials, 1981; 2: 201. 7. Morishita M, Lowman AM, Takayama K, Nagai T and Peppas N. J. Control. Release, 2002; 81: 25. 8. Zhang K and Wu XY, J. Control. Release, 2002; 80: 169. 9. Peppas NA and Mikos AG, In: Peppas NA, Eds. Preparation method and Staracture of Hydrogels, Hyrogels in Medicine and pharmacy, Vol I, CRC Press, Boca Rton, FI., 986: 1. 10. Peppas NA and Merrill EW, J. Appl. Polym. Sci., 1977; 21. 11. Kofinas P, Athanasssiou V and Merrill EW, Biomaterials, 1996, 17, 1547. 12. Stringer JL and Peppas NA, J. Control. Release, 1996; 42: 195. 13. Jabbari E and Nozari S, Eur. Polym. J., 2000; 36: 2685.

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International Journal of Pharmaceutical Research & Development 14. Hennink WE and Nostrum CF, Adv. Drug Deliv. Rev., 2002; 54: 13. 15. Dai WS and Barbari TA, J. Membr. Science, 1999; 156: 67. 16. Tabata A and Ikada Y, Pharm. Res., 1989; 6: 422. 17. Lopes MA and Felisberti MI, Biomaterials, 2003; 24: 1279. 18. Gehrke SH, Uhden LH and McBride JF, J. Control. Release, 1998; 55: 21. 19. Coviello T, Grassi M, Rambone G, Santucci E, Carafa M, Murtas E, Riccieri F. and Alhaique F, J. Control. Release, 1999; 60: 367. 20. Lowman AM and Peppas NA, Macromolecules, 1997; 30: 4659. 21. Shu XZ and Zhu KJ, Int. J. Pharm., 2002; 233: 217. 22. Ko JA, Park HJ, Hwang SJ, Park JB and Lee JS, Int. J. Pharm., 2002; 249; 165. 23. Berger J, Reist M, Mayer JM, Felt O, Peppas NA and Gurny R, Eur. J. Pharm. Biopharm., 2004; 57: 1. 24. Torre PM, Enobakhare Y, Torrado G and Torrado S. Biomaterials, 2003; 24: 1499. 25. Noble L, Gray AI, Sadiq L and Uchegbu IF, Int, J. Pharm. 1999; 192: 173. 26. Koresmeyer RW, Gurny R, Doelker E, Buri P and Peppas NA, Int. J. Pharm., 1983; 15: 25. 27. Lugo MT and Peppas NA, Macromolecules, 1999; 32: 6646. 28. Gmdereliolu M and Kesgin D, Int. J. Pharm., 2005; 288: 273. 29. Garca DM, Escobar JL, Noa Y, Bada N, Hernez E and Katime I, Eur. Polym. J., 2004; 40: 1683. 30. Suisha F, Kawasaki N, Miyazaki S, Shirakawa M, Yamotoya K, Sasaki M, et al. Xyloglucan gels as sustained release vehicles for intraperitoneal administration of mitomycin C. Int J Pharm. 1998;172:2732. *****

ISSN: 0974 9446 31. Chandrashekhar G, Udupa N. Biodegradable injectable implant system Indian Journal of Pharmaceutical Sciences for long term drug delivery using poly (lactic-co-glycolic) acid copolymers. J Pharm Pharmacol 1998; 48:669-74. 32. Miyazaki S, Suisha F, Kawasaki N. Thermally reversible xyloglucan gels as vehicles for rectal drug delivery. J Control Rel. 1998; 56:7583. 33. Kashyap N, Viswanad B, Sharma G, Bhardwaj V, Ramarao P, Kumar MNV. Design and evaluation of biodegradable, biosensitive in situ gelling systems for pulsatile delivery of insulin. Biomaterials 2007; 28:2051-60. 34. Ramesh CR, Zentner GM, Jeong B. Macro med, Inc. Biodegradable low molecular weight triblock poly (lactide-coglycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US patent 2001; 6201072. 35. Rathi R, Zentner C, Gaylen M, Jeong B. Macro med, Inc. Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US patent 2000; 6117949 36. Rathi R, Zentner C, Gaylen M. Macro med, Inc. Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US patent 1999; 6004573. 37. Sterile ophthalmic gel forming solution, TimopticXE, 0.25% and 0.5%, (Timolol maleate ophthalmic gel forming solution) Whitehouse Station, USA: Merck and Company Inc.; NJ 08889.

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