novel alternative in ophthalmic dosage form

International Journal of Pharmaceutical Research Volume 2, Issue 1, 2010 ISSN 0975-2366 Review Article

A Novel Alternative to Ocular Drug Delivery System: Hydrogel

Divyesh H. Shastri*1, Lakshamanbhai D. Patel2

2Director & Professor, C.U. Shah College of Pharmacy & Research, Wadhwan-363030, Gujarat. 1Department of Pharmaceutics, K. B. Institute of Pharmaceutical Education & Research, Gandhinagar,

Gujarat, INDIA-382023. *Corresponding Author: Email Address: [email protected]

Received: 09.10.2009, Revised: 19.11.2009, Accepted: 22.02.2010 ABSTRACT Sustained and Prolonged drug delivery approaches are very common in today’s Pharmaceutical for-mulation design and research work is still going on in achieving better drug product. Ophthalmic use of viscosity-enhancing agents, penetration enhancers, cyclodextrins, prodrug approaches, ocular inserts and the ready existing drug carrier systems along with their application to ophthalmic drug delivery are very common to improve ocular bioavailability. Amongst these hydrogel (insitu gel forming) systems are of very important. They help to increase in precorneal residence time of drug to a sufficient extent that an ocularly delivered drug can exhibit its maximum biological action. The concept of this innovative oph-thalmic delivery approach is to decrease the systemic side effects and to create a more pronounced effect with lower doses of the drug. Many polymers are very useful with majority of hydrogels, which undergo reversible sol-gel phase transitions in the ocular cul-de-sac to form viscoelastic gels due to phase changes of polymers in response to the physiological environment (temperature, pH and presence of ions in organ-ism fluids. These insitu forming gels can be applied as solution and exhibit pseudo plastic behavior to minimize interference with blinking, increase precorneal residence of the delivery system and enhanced ocular bioavailability. Now a days insitu gels have been used as vehicles for the delivery of drugs for both local treatment and systemic effects. Different administration routes other than ocular have been explored, including for example, cutaneous and subcutaneous delivery, dental, buccal delivery and delivery to the esophagus, stomach, colon, rectum and vagina. Key Words: Ocular drug delivery, Environment sensitive, Preformed, Insitu, Hydrogel. INTRODUCTION One of the main problems encountered in ophthalmic drug delivery is the rapid and exten-sive elimination of conventional eye drops from the eye. [1-3] This process results in extensive drug loss (Figure 1). Consequently, only a small amount (1 - 6%) actually penetrates the cornea and reaches the intra ocular tissues. [4, 5] The reason for this inefficient drug delivery includes rapid tear turnover, lachrymal drainage and drug dilution by tears. [6] The higher drainage rate is due to tendency of the eye to maintain its residence volume at 7-10 μl permanently, whereas volumes of topically instilled range from 20-50μl. It has been demonstrated in vivo that 90% of the dose was cleared within 2 min. for an instilled volume of 50μl [8]. Consequently, the ocular resi-dence time of conventional solution is limited to few minutes, and the overall absorption of a topi-cally applied drug is limited to 1-10% [9]. Conse-

quently, most drugs get systemically absorbed via the nose or gut after draining from eye. This excessive systemic absorption not only reduces the ocular bioavailability but also may lead to unwanted side effects and toxicity. The following characteristics are required to optimize ocular drug delivery systems. [7]

A good corneal penetration. A prolonged contact time with corneal tissue. Simplicity of installation for the patient. A non-irritative and comfortable form (the

viscous solution should not provoke lachry-mation and reflex blinking).

Appropriate rheological properties and con-centration of viscolyzer.

Some common methods to prolong pre-corneal residence time include use of Hydrogels, Liposomes, Inserts, Micro and Nano-carrier sys-

January-March 2010 1

Shastri & Patel / International Journal of Pharmaceutical Research 2010 2(1) 1-13

tems. In comparison with traditional formulation, theses systems have the following advantages: -

Increase contact time Prolonged drug release Reduced systemic side effects Reduced number of applications Better patient compliance

Over the last three decades greater attention has been focused on development of controlled and sustained drug delivery systems. The goal in designing these systems is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, decreasing the dose required or providing uniform drug delivery. Polymers have historically been the keys to the great majority in drug delivery systems.

Figure 1: Drug elimination pathways from the precorneal area. Hydrogels The most common way to improve drug re-tention on the corneal surface is undoubtedly by using polymers to increase solution viscosity. Previous studies on rabbits by Robinson et al [10] established that the rate of drainage from the eye of an instilled solution is markedly reduced as the viscosity of the solution is increased. More re-cently, the approach to improve pre-corneal reten-tion is based on the use of mucoadhesive poly-mers that are able to interact with the mucin-coating layer present at the eye surface. [11] Hydrogels can be defined as polymers en-dowed with the ability to swell in water or aque-ous solvents and induce a sol-gel transition. However, in ophthalmology the limit between actual hydrogels and highly viscous solution is not clearly established. According to plazonnet et al, [12] aqueous gels are at the upper limit of viscous

preparations, and they are formed when high mo-lecular weight polymers or high polymer concen-trations are incorporated in the formulations. Currently, two groups of hydrogels are distin-guished (Figure 2), namely preformed and in situ forming gels. Preformed hydrogels can be defined as simple viscous solutions, which do not undergo any modifications after administration, while in situ forming gels are formulations, applied as a solution, which undergoes gelation after instilla-tion due to physico-chemical changes inherent to the eye.

Figure 2: Classification of hydrogels. The polymers chosen to prepare ophthalmic hydrogels should meet some specific rheological characteristics (Table 1). It is generally well ac-cepted that the instillation of a formulation should influence tear behavior as little as possible [13]. Because tears have a pseudoplastic behavior, pseudoplastic vehicles would be more suitable as compared to the Newtonian formulations, which have a constant viscosity independent of the shear rate. Pseudoplastic solutions exhibit decreased viscosity with increasing shear rate thereby offer-ing lowered viscosity during blinking and stability of the tear film during fixation. In-Situ Forming Gels The use of preformed hydrogels still has drawbacks that can limit their interest for oph-thalmic drug delivery. They do not allow accurate and reproducible administration of quantities of drug. They often produce blurred vision, crusting of eyelids and lachrymation upon administration. Distinguishing from preformed hydrogels, in situ forming gels are formulations, applied as a solution, which undergoes gelation after instilla-



tion due to physico-chemical changes inherent to the biological fluids. In this way, the polymers, which show sol-gel phase transition and thus trig-ger drug release in response to external stimuli, are the most investigated. In-situ hydrogels are providing such ‘sensor’ properties and can un-dergo reversible sol-gel phase transitions upon changes in the environmental condition. These “intelligent” or “smart” polymers play important role in drug delivery since they may dictate not only where a drug is delivered, but also when and with which interval it is released [14]. A new concept of producing a gel in-situ (in the cul-de-sac of the eye) was suggested. It is widely ac-cepted that increasing the viscosity of a drug for-mulation in the precorneal region will lead to in-creased bioavailability, due to slower drainage rate from the cornea. [15] Moreover, the efficacy of ophthalmic hydrogels is mostly based on an increase of ocular residence time via enhanced viscosity and mucoadhesive properties. Since re-sulted swollen hydrogel is aqueous based, it is very comfortable in the human eye. Among these polymers, in situ gels are preferred since they are conveniently dropped in the eye as a solution, where undergo transition into a gel. The first use of gels for medical applications was presented by Wichterle and Lim in 1960 [16] and involved the manufacturing of soft contact lenses and implant materials from hydroxyethyl methacrylate polymers. There are many mechanisms have been em-ployed to cause reversible sol-gel phase transition by different stimuli in physiological environ-mental conditions of human body: The stimuli that induce various responses of the hydrogel sys-tems include

1. Physical stimuli like: Change in temperature, electric fields, light, pressure, sound and magnetic fields.

2. Chemical stimuli like: Change in pH and ion-activation from biological fluid.

3. Biological/ biochemical (biomolecules) stimuli [17] like: Change in Glucose level.

One theory proposed that Gelation occurs via the cross linking of polymer chains, something that can be achieved by the following: either cova-lent bond formation (chemical cross-linking) or non-covalent bond formation (physical cross-linking) [19]

Three mechanisms have been employed to cause phase transition on the eye surface: can be triggered by as shown in (Table 3). [18] Thermoreversible hydrogels Gelling of solution is triggered by change in temperature, and sustained drug delivery can be achieved by the use of a polymer that changes from solution to gel at the temperature of the eye (37ºC) [28]. These hydrogels are liquid at room temperature (20ºC -25ºC) and undergo gelation when in contact with body fluids (35ºC -37ºC), due to an increase in temperature. For conven-ience, temperature-sensitive hydrogels are classi-fied into negatively thermo sensitive, positively thermo sensitive and thermally reversible gels [17, 29]. Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) and contract upon heating above the LCST i.e., Copolymers of (N-isopropylacrylamide) (NIAAm) show an on-off drug release [14] with on at a low temperature and off at high tempera-ture allowing pulsatile drug release. LCST sys-tems are mainly relevant for controlled release of drugs, and of proteins in particular [30]. Thermo-sensitive polymers may be fixed on liposome membranes; in that case liposomes exhibit control of their content release [31]. A positive tempera-ture-sensitive hydrogel has an upper critical solu-tion temperature (UCST), such hydrogel contracts upon cooling below the UCST. Polymer networks of poly (acrylic acid) (PAA) and polyacrylamide (PAAm) or poly (acryl amide-co-butyl methacry-late) have positive temperature dependence of swelling [17]. Poloxamers are thermo reversible gels that seem to fulfill the aforementioned conditions. Poloxamers are a broad group of compounds that were introduced in the early 1950s as food addi-tives and for pharmaceutical preparations. These water-soluble surfactants are triblock co-polymers [32] prepared from poly (ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide) com-mercially available as Pluronic® [17, 30] are the most commonly used thermosetting polymers and could be applicable for the development of effec-tive ophthalmic drug delivery [33]. Depending on the ratio and the distribution along the chain of the hydrophobic and hydro-philic subunits, several molecular weights are available, leading to different gelation properties.



Pluronic F127, which gives colorless and trans-parent gels, is the most commonly used in phar-maceutical technology. Poloxamers were em-ployed as solubilizers and proposed as artificial tears. Pluronic F 127 is no more damaging to the mouse or rabbit cornea than a physiological sa-line. [34] The Poloxamers are reported to be well tolerated and non-toxic even though large amounts (25-30%) of polymers are required to obtained a suitable gel. At concentrations of 20% w/v and higher aqueous solutions of Poloxamer-407 remain as a liquid at low temperatures [<15ºC] and yield a highly viscous semisolid gel upon instillation into the cul-de-sac. At low temperatures, the polox-amer forms micellar subunits in solution, and swelling gives rise to large micellar subunits and the creation of cross-linked networks. The result of this phenomenon is a sharp increase in viscos-ity upon heating. [35] Miller et al examined a temperature-sensitive solution of poloxamer used to deliver the miotic pilocarpine. [36] In order to reduce the concentration of polymer and/or to achieve a phase transition temperature higher than room temperature (25°C) and gelling at precorneal temperature (35°C), the combining Pluronic® analogs [33] or the addition of further polymer, e.g. PEG [37], PAA [38], methylcellulose (MC), HPMC, CMC [39] is often necessary. Some applications of thermo reversible hy-drogels in ophthalmology refer to the use of other polymers, the poloxamines, commercialized as Tetronic® [17, 30]. An alternative in situ gelling material of natural origin, xyloglucan, a polysac-charide derived from Tamarind seeds were evalu-ated for the sustained ocular delivery of pilo-carpine [40] and timolol [41]. When partially de-graded by Beta-galactosidase, this gelling material exhibits thermally reversible gelation in dilute aqueous solutions and varying sol-gel transition temperatures upon degree of galactose elimina-tion. Attwood et al has reported enhancement of the miotic response following sustained release of Pilocarpine from the 1% w/w xyloglucan gel. In order to develop a thermosetting gel with a suit-able phase transition temperature, Wei et al com-bined poloxamer (Pluronic F 127 and F 68) and sodium hyaluronan. Gamma scintigraphy demon-strated that the clearance of an optimized formula-tion containing 21% F127 and 10% F68 was sig-

nificantly delayed with respect to a phosphate buffer solution. A three-fold increase of the cor-neal residence time was achieved in the rabbits. [33] Three principal mechanisms have been pro-posed to explain the liquid-gel phase transition after an increase in temperature, including: -

1. Gradual desolvation of the polymer, 2. Increased micellar aggregation, and 3. The increased entanglement of the poly-

meric network. Despite all the promising results obtained with thermo reversible gels, there remains an im-portant drawback associated with their use; the risk of gelation before administration by increase in ambient temperature during packing or storage. pH-Sensitive Hydrogels Gelling of the solution is triggered by a change in the pH. Cellulose acetate phthalate (CAP) latex, cross linked acrylic, and derivatives such as Carbomer are used. [42] Cellulose acetate derivatives are the only polymer known to have a buffer capacity that is low enough to gel effec-tively in the cul-de-sac of the eye. The pH change of about 2.8 units after instillation of the native formulation (pH 4.4) into the tear film leads to an almost instantaneous transformation of the highly fluid latex into viscous gel. [43-45] The gamma scintigraphy technique was used to monitor the ocular residence time of an oph-thalmic preparation based on Cellulose acetate phthalate (CAP) dispersion. The gelled system constitutes a micro-reservoir of high viscosity [46, 47]. First preliminary investigations of pH-sensitive latexes for ophthalmic administration began in early 1980s and have been extensively studied by Boye [48]. He proposed the preparation of latexes containing Pilocarpine with Cellulose acetate phthalate (CAP). Cellulose acetate phthalate latex is a polymer with potentially useful properties for sustained drug delivery to the eye because latex is a free-running solution at a pH of 4.4, which undergoes coagulation when the pH is raised by the tear fluid to pH 7.4. The use of pH-sensitive latex nanopar-ticles has been described by Gurny. [49] But the low pH of the preparation can elicit discomfort in some patients. [50] The poly acrylic acid and its lightly cross-linked commercial forms (Polycar-bophil and Carbopol) exhibit the strongest muco-



adhesion. In the pioneering paper, Hui and Robin-son demonstrated that the use of acrylates for ocu-lar delivery of progesterone was based not only on viscosifying but also on bioadhesion properties. [51] Carbomer (Carbopol) a cross-linked acrylic acid polymer (PAA) also shows pH induced phase transition as the pH is raised above its pKa of about 5.5. [52] Different grades of Carbopol are available. The manufacturer states that Carbopol 934 gel has the lowest cross-linking density, while Carbopol 981 intermediate and Carbopol 940 have the highest. However, the amount of PAA required to form stiff gel upon instillation in the eye is not easily neutralized by the buffering action of tear fluid. Combination PAA with a suitable viscosity-enhancing polymer e.g. HPMC [53] or MC [54] allows a reduction in the PAA concentration without comprising the in situ gelling properties. The formulation containing Carbopol ® 940 and Methocel E50LV (HPMC) afforded sustained re-lease of ofloxacin over an 8-h period [53]. Polycarbophil-based in situ gelling systems were developed by Robinson and Miynek. [55] Polycarbophil is insoluble in water, but its high swelling capacity in a neutral medium per-mits the entanglement of the polymer chains with the mucus layer. The non-ionized carboxylic acid group binds to the mucin by means of hydrogen bonds. [55, 56] The proposed theory behind pH induced sol-gel phase transition: All the pH-sensitive polymers contain pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH [17]. The polymers with a large number of ionizable groups are known as polyelectrolytes. Swelling of hydrogel increases as the external pH increases in the case of weakly acidic (anionic) groups, but decreases if polymer contains weakly basic (cationic) groups. The most of anionic pH-sensitive polymers are based on PAA (Carbopol®, carbomer) or its derivatives [14]. Likewise poly-vinylacetaldiethylaminoacetate (AEA) solutions with a low viscosity at pH 4 form hydrogel at neu-tral pH condition [57]. Ion-sensitive hydrogels Ion-sensitive polymers belong to the mainly used in situ gelling materials for ocular drug de-

livery. Gelling of the instilled solution is also trig-gered by change in ionic strength. It is assumed that the rate at which electrolytes from the tear fluid is adsorbed by the polymer will depend on the osmotic gradient across the surface of the gel. It is therefore likely that the osmolality of the so-lution might have an influence on the rate of the sol-gel transition occurring in the eye. One exam-ple is Gelrite, an anionic extra cellular polysac-charide, low acetyl Gellan gum secreted by pseu-domonas elodea. Gelrite formulations in aqueous solutions form a clear gel in the presence of the mono or divalent cations typically found in the tear fluids. The electrolyte of the tear fluid and especially Na+, Ca++ and Mg++ cations are par-ticularly suited to initiate gelation of the polymer when instilled as a liquid solution in to the cul-de-sac. Gelrite has been the most widely studied and seems to be preferred compared to the pH sensi-tive or temperature setting systems. The poly-meric concentration is much lower compared to previously described systems. [58] Slightly viscous gellan gum solutions in low concentrations (<1%) show markedly increase in apparent viscosity, when introduced into presence of a physiological level of cations, without requir-ing more ions than 10–25% of those in tear fluid [59]. The precorneal contact times for drugs can thus be extended up to 20-h [60]. Gellan contain-ing formulations of pilocarpine HCl allowed re-duction of drug concentration from 2% to 0.5% obtaining the same bioavailability [61]. Rozier et al [62] found an improvement in the ocular absorption of timolol in albino rabbits when absorption of timolol in albino rabbits when administered in Gelrite when compared with an equiviscous solution of hydroxyl-ethyl cellulose. Sanzgiri et al [63] compared various systems of Methyl prednisolone (MP); esters of MP with Gelrite eye drops, Gellan-MP film, and Gellan film with dispersed MP. Gellan eye drops pro-vided better performance because they afforded the advantage of faster gelation over a high sur-face area in eye, whereas the results obtained with the Gellan-MP film seemed to indicate that the gelation at the surface of the film occurred very slowly, and the surface of release was not con-trolled. Mourice and srinivas [64] measured a two fold increase in the permeation of the fluorescein



in humans when using Gellan gum compared to isotonic buffer solution. The ability of gel formation at physiological Ca2+ levels was used in case of alginic acid as well. Presence of this polymer significantly ex-tended the duration of the pressure reducing effect of pilocarpine to 10-h [65] and carteolol to 8-h [66] allowing only once a day administration in case of carteolol. Cohen et al demonstrated that an aqueous so-lution of sodium alginate could gel in the eye, without addition of external calcium ions or other bivalent/polyvalent cations. The extent of alginate gelation and conse-quently the release of Pilocarpine were found to be dependent upon the percentage of Glucuronic Acid residues in the polymer backbone. Alginates with G content more than 65%, such as Manugel DMB [65], instantaneously formed gels upon their addition to STF. In vitro release studies indicated the slow release of Pilocarpine over a period of 24 hours Recently, some other natural polymers be-lieved to be able to form insitu gels by interacting with the lachrymal fluid have been evaluated as potential adjuvant in ophthalmic formulation. This includes carageenans, xyloglucans and some alginates that are rich in guluronic acid resi-dues. K-carrageenan forms rigid, brittle gels in reply of small amount of K+, I-carrageenan forms elastic gels mainly in the presence of Ca2+. Gela-tion of the low-methoxy pectins can be caused by divalent cations, especially Ca2+. Likewise, alginic acid undergoes gelation in presence of diva-lent/polyvalent cations e.g. Ca2+ due to the inter-action with guluronic acid blocks in alginate chains. Sodium alginate consists chiefly of the sodium salt of alginic acid, a linear glycuronan polymer consisting of a mixture of β- (1, 4)-D-mannosyluronic acid and α- (1, 4)-L-Gulosyluronic acid residues. Silver et al compared the commercial product Timoptic XE 0.5% with a timolol mealeate gel-forming solution with xanthan gum as the gelling polymer (Timolol GFS 0.5% Alcon Research). The xanthan gum preparation was developed for once-daily dosing. The reported data indicated equivalent efficacy in the reduction intraocular pressure (a maintained reduction during long term use) and consequently therapeutic equivalence. [67]

Keipert reported that the increase in therapeu-tic effects (i.e., miosis) in rabbits could be due to a permeation enhancing effect of gellan gum com-parable to EDTA. Apart from its in situ gelling property, Gellan gum diminishes drainage after instillation. The commercial product Timoptol XE prepa-ration containing Gelrite remains for a longer pe-riod at the eye surface when compared to conven-tional timolol maleate eye drops. This resulted in an enhanced drug transfer sufficient enough to obtain an intro ocular pressure reduction after a once-daily topical instillation. [68-70] Divalent ions were found superior to monova-lent in promoting the gelation of the polysaccha-rides. However, the conc. of sodium in tears (2.6 g/L) is quite sufficient to induce gelation. Because the presence of lachrymal fluid is necessary to induce gel formation, accidental gelation during storage does not occur as with thermo reversible gels. The characteristics of polymers used to pre-pare smart hydrogel for ocular drug delivery is shown in Table 1. The sol-gel transformation of the polymers at formulation and physiological conditions of the eye cavity is shown in Figure 3.

Figure 3: Sol-gel transformation of polymers at formulation and physiological conditions of the eye.



Table 1: Characteristics of polymers used to prepare preformed Hydrogels for Ophthalmic applica-tions.

Polymer Origin Characteristics

Sodium hyaluronate

Skin, Connective tissues, muscles, tendons, Aqueous humor, Vitreous

humor

Biocompatible, Mucoadhesive Pseudoplastic behavior

Cellulose derivatives Semi-synthetic Good tolerance, Optical clarity

Newtonian Behavior Poly vinyl

alcohol Synthetic Wetting agent, Newtonian behav-ior

Carbomer Synthetic Good tolerance, Bioadhesion Pseudoplastic behavior

Table 2: Environmentally sensitive polymers for drug delivery. [18]

Stimulus Hydrogel Mechanism

Light Gelatin hydrogel Photocrosslinkable/photo polymerization Chemical species Hydrogel containing elec-

tron-accepting groups Electron-donating compounds - formation of charge/transfer complex - change in swelling - release of drug

Enzyme-substrate Glucose-sensitive hydrogels containing immobilized en-zymes

Substrate present - enzymatic conversion - product changes swelling of gel- release of drug

Magnetic Magnetic particles dispersed in alginate microspheres

Applied magnetic field - change in pores in gel - change in swelling - release of drug

Electric signal Chondroitin 4-sulphate hy-drogels /Polyelectrolyte hydrogel

Applied electric field - membrane charging - electro-phoresis of charged drug - change in swelling - release of drug

Ultrasound irradia-tion

Ethylene-vinyl alcohol hy-drogel

Ultrasound irradiation - temperature increase - release of drug

Table 3: Three ways of Stimuli sensitive hydrogel with mechanism. [18]

Stimulus Hydrogel Mechanism

pH Acidic/basic

Cross-linked acrylic acid hydrogel

Change in pH - - swelling -

- release of drug

Ionic strength Na Alginate/ Gelrite Hydrogel

Change in ionic strength - change in concentration of ions inside gel - change in swelling - release of drug

Thermal Thermoreversible hydrogel poly(N-isopropyl acryl am-

ide)

Change in temperature - change in polymer-polymer and water-polymer interactions - change in swelling -

release of drug



Light-sensitive hydrogels Light-sensitive hydrogels can be used in the development of photo-responsive artificial muscle [17] or as the in situ forming gels for cartilage tissue engineering [20]. In the last study [20] gels that may undergo transdermal photo polymeriza-tion after subcutaneous injection were found to be applicable for drug release devices. T. Matsuda [21] developed novel tissue adhesive technology based on photocrosslinkable gelatin, which allows in situ drug-incorporated gelatinous gel formation on diseased tissue and sustained drug release. In situ photopolymerizable hydrogel systems for bar-riers and local drug delivery in the control of wound healing were also studied [22]. Electric signal-sensitive hydrogels Hydrogels sensitive to electric current are usually made of polyelectrolytes such as the pH-sensitive hydrogels [17]. Electro-sensitive hy-drogels undergo shrinking or swelling in the pres-ence of an applied electric field. Ramanathan and Block [23] evaluated and characterized the use of chitosan gels as matrices for electrically modu-lated drug delivery. In electrification studies, re-lease-time profiles for neutral (hydrocortisone), anionic (benzoic acid) and cationic (lidocaine hy-drochloride) drug molecules from hydrated chito-san gels were monitored in response to different milliamperages of current as a function of time. Likewise, chondroitin 4-sulphate hydrogels were examined by Jensen et al [24] as potential matri-ces for the electro-controlled delivery of peptides and proteins. Enzyme-substrate-sensitive hydrogels Intelligent stimuli-responsive delivery sys-tems using hydrogels that can release insulin have been investigated. Cationic pH-sensitive polymers containing immobilized insulin and glucoseoxi-dase can swell in response to blood glucose level releasing the entrapped insulin in a pulsatile fash-ion [25]. Another approach is based on competi-tive binding of insulin or insulin and glucose to a fixed number of binding sites in concanavalin A [26], where insulin is displaced in response to glucose stimuli, thus functioning as a self-regulating insulin delivery system. An alternative route through phenyl borate-poly (vinyl alcohol) polymers was discussed by I. Hisamitsu et al. [27]

OTHER POTENTIAL APPLICATIONS OF IN SITU HYDROGELS Parenteral delivery One of the most obvious ways to provide sus-tained-release medication is to place the drug in a delivery system and inject or implant the system into the body tissue. Thermoreversible gels mainly prepared from poloxamers are predomi-nantly used [71]. The suitability of poloxamer gel alone or with the addition of hydroxypropyl-methylcellulose (HPMC), sodium carboxymethyl-cellulose (CMC) or dextran was studied for epidu-ral administration of drugs in vitro [72]. The compact gel depot acted as the rate-limiting step and significantly prolonged the dural permeation of drugs in comparison with control solutions. J. M. Barichello et al. [73] evaluated Pluronic F127 gels, which contained either insulin or insulin-PLGA nanoparticles with conclusion, that these formulations could be useful for the preparation of a controlled delivery system. Like-wise, poloxamer gels were tested for intramuscu-lar and subcutaneous administration of human growth hormone [74] or with the aim to develop a long acting single dose injection of lidocaine [71]. J. R. DesNoyer and A. J. McHugh [75] in-vented a new class of injectable controlled release depots of protein which consisted of blends of Pluronics with poly (D, L-lactide)/1-methyl-2-pyrrolidone solutions. Some other thermosensitive hydrogels may also be used for parenteral admini-stration. ReGel ® (triblock copolymer PLGA-PEG-PLGA) was used as a drug delivery carrier for the continuous release of human insulin [76]. Steady amounts of insulin secretion from the Re-Gel ® formulations up to day 15 of the subcuta-neous injections were achieved. B. Jeong et al. [77] reported the synthesis of a biodegradable poly (ethylene oxide) and poly (L-lactic acid) hy-drogel, which exists in a form of sol at an elevated temperature (around 45°C) and forms a gel after subcutaneous injection and subsequent rapid cool-ing to body temperature. A. Chenite et al. [78] developed novel ther-mally sensitive combinations of chitosan/polyol salts, which turn into gel implants, when injected in vivo. The author presumes that formulations may be a prototype for a new family of thermoset-ting gels highly compatible with biological com-pounds.



Hydrogels formed by xyloglucan were also evaluated as a sustained release vehicle for the intraperitoneal administration of mitomycin [79]. PAA/polymethacrylic acid forms a pH-sensitive complex with PEG in situ, possessing the poten-tial to release drug substances subcutaneously over a period of a few days [80]. Alternatively, an aqueous solution containing MC in combination with polymethacrylate yields a reversible gel due to the change of temperature and pH shortly after parenteral administration. Peroral Drug Delivery The pH-sensitive hydrogels have a potential use in site-specific delivery of drugs to specific regions of the GI tract. Hydrogels made of vary-ing proportions of PAA derivatives and cross-linked PEG allowed preparing silicone micro-spheres, which released prednisolone in the gas-tric medium or showed gastroprotective property [81]. Cross-linked dextran hydrogels with a faster swelling under high pH conditions, likewise other polysaccharides such as amidaded pectins, guar gum and inulin were investigated in order to de-velop a potential colon-specific drug delivery sys-tem [29]. W. Kubo et al. [82] developed the for-mulations of gellan and sodium alginate both con-taining complexed calcium ions that undergo gela-tion by releasing of these ions in the acidic envi-ronment of the stomach. Oral delivery of paracetamol was studied. Rectal delivery The rectal route may be used to deliver many types of drugs that are formulated as liquid, semi-solid (ointments, creams and foams) and solid dosage forms (suppositories). Conventional sup-positories often cause discomfort during insertion. In addition, suppositories are unable to be suffi-ciently retained at a specific position in the rec-tum, sometimes they can migrate up-wards to the colon that makes them possible for drug to un-dergo the first-pass effect. Choi et al. [83] devel-oped novel in situ gelling liquid suppositories with gelation temperature at 30–36°C. Poloxamer 407 and/ or poloxamer 188 were used to confer the temperature-sensitive gelation property. Bioadhesive polymers were used to modulate the gel strength and the Bioadhesive force. Bioavail-ability of acetaminophen was studied. Charrueau et al. [84] proposed 18% poloxamer 407 solution as a vehicle for short-chain fatty acid enemas. Af-

ter gelation at 37°C it allows control release of short-chain fatty acids. Miyazaki et al. [85] inves-tigated the potential use of thermoreversible xy-loglucan can gels for rectal drug delivery. A more sustained release of Indomethacin was achieved in vitro in comparison with commercial supposito-ries. Vaginal delivery The vagina, in addition to being an important organ of reproductive tract, serves as a potential route for drug administration. Formulations based on a thermo-plastic graft copolymer that undergo in situ gelation have been developed to provide the prolonged release of active ingredients such as nonoxynol-9, progestins, estrogens, peptides and proteins [86]. Chang et al. [87] have recently re-ported a mucoadhesive thermo-sensitive gel (combination of poloxamers and polycar-bophil), which exhibited, increased and prolonged anti-fungal activity of clotrimazole in comparison with conventional PEG-based formulation. Dermal and transdermal delivery Thermally reversible gel of Pluronic F127 was evaluated as vehicle for the percutaneous ad-ministration of indomethacin [88]. In-vivo studies suggest that 20% w/w aqueous gel may be of practical use as a base for topical administration of the drug. Poloxamer 407 gel was found suitable for transdermal delivery of insulin [89] The com-bination of chemical enhancers and iontophoresis resulted in synergistic enhancement of insulin permeation. Nasal delivery Nasal formulations of AEA with chlor-pheniramine maleate and tetrahydrozoline hydro-chloride were investigated [88]. The findings sug-gest that liquid AEA formulations facilitate the instillation into the nose and the hydrogel formed on the mucous membrane pro-vide controlled drug release. CONCLUSIONS Drug delivery as it pertains to the eye is a ge-neric term, which is defined broadly as represent-ing an approach to controlling and ultimately op-timizing delivery of the drug to its target tissue in the eye thus it is easier to treat ocular diseases and complicated at the same time because the eye has



specific characteristics, which make the develop-ment of ocular drug delivery systems extremely difficult. The most widely developed drug deliv-ery system is represented by the polymeric hy-drogels. Hydrogels generally offer a moderate improvement of ocular drug bioavailability de-spite their favorable bioadhesive properties. One of the disadvantages is that hydrogel may result in blurred vision as well as foreign body sensation to patients. Insitu activated gel-forming systems seem to be preferred as they can be administered in drop form and create significantly less prob-lems with vision. Moreover, they provide good sustained release properties. Over the last decades, an impressive number of novel temperature, pH, and ion induced insitu forming solutions have been described in the literature. Each system has its own advantages and drawbacks. The choice of a particular hydrogel depends on its intrinsic properties and envisaged therapeutic use. Thus, the insitu gelling system seems promising because as with non-viscous eye drops, accurate and pre-cise sustained release properties with little or no eye irritation is possible. ACKNOWLEDGEMENT The Authors are highly thankful to Dr. M. C. Gohel, Principal, Department of Pharmaceutics, L.M. College Of Pharmacy, Ahmedabad and Dr. R. K. Parikh, Professor and head, Department of Pharmaceutics, L.M. College of Pharmacy, Ah-medabad, Gujarat, India for their kind Support and Valuable suggestions in this article. REFERENCES 1. Joshi A, Ding S, Himmelstein KJ. Reversible

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