INTRODUCTION:

Extensive research has been carried in designing of polymeric drug delivery systems. The development of in situ gel systems has received considerable attention over the past few years¹. This interest has been sparked 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 comfort².

In the past few years, increasing number of in situ gel forming systems have been investigated and many patents for their use in various biomedical applications including drug delivery have been reported. Smart polymeric systems represent promising means of delivering the drugs; these polymers undergo sol-gel transition, once administered³. In situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and solvent exchange. In this review, different types of smart polymers, their mechanisms of gel formation from the sol forms, evaluation and characterization of in situ polymeric formulations are discussed.

Various natural and synthetic polymers are used for formulation development of in situ forming drug delivery systems. Depending on the route of administration, these in situ polymeric systems may be classified as.

§ In Situ Forming Polymeric Systems for Oral Delivery

§ In Situ Forming Polymeric Systems for Ocular Delivery

§ In Situ Forming Polymeric Systems for Rectal And Vaginal Delivery

§ In Situ Forming Injectable Drug Delivery Systems

§ In Situ Forming Nasal Drug Delivery Systems

Gel (jelly-like) formulations for oral drug administration have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and taking oral dosage forms. These gel preparations are preferred by the elderly, because of their ease of handling and swallowing compared to more conventional oral dosage forms such as tablets and powders and have been prepared with various materials, including agar^4,5 gelatin^6,7,carrageenan⁸,carrageenan and gelatin mixtures⁹,sodium caseinate^10,11, glycerogelatin¹², and silk fibroin^13–15.KazepitanTM jelly (150 mg/30 g) is commercially available

These preparations are not, however, primarily intended as vehicles for sustained release of drugs and are frequently designed to melt at body temperature for easy swallowing rather than to retain their integrity in the gastrointestinal tract. There have been only limited pharmacokinetic evaluations of these gel formulations.

Polymers:

Xyloglucan:

Xyloglucan (Fig. 1), a polysaccharide derived from tamarind seed, forms thermoresponsive gels in water, under certain conditions. Xyloglucan is composed of a (1-4)-b-D-glucan backbone chain (GLU) which presents (1-6)-a-D-xylose branches (XYL) partially substituted by (1-2)-b-D-galactoxylose (GAL). Tamarind seed xyloglucan is composed of three units of xyloglucan oligomers with heptasaccharide, octosaccharide and nanosaccharide, which differ in the number of galactose side chains. When xyloglucan is partially degraded by b-galactosidase, the resultant product exhibits thermally reversible gelation in dilute aqueous solutions. Such behavior does not occur with native xyloglucan. Gelation is only possible when the galactose removal ratio exceeds, 35%¹⁶. The transition temperature is inversely related to polymer concentration¹⁷ and the galactose removal ratio¹⁶. For example, the sol–gel transition of xyloglucan was shown to decrease from 40⁰ to 58⁰C when the galactose removal ratio increased from 35 to 58%.

Fig 1: The unit structures of oligosaccharides from tamarind xyloglucan showing (a) heptasaccharide, (b) and (c) octasaccharides, and (d) nonasaccharide.

Xyloglucan gels have been evaluated for the rectal delivery of indomethacin in rabbits¹⁷.They provided a broader absorption peak and longer residence time than commercial suppositories. Moreover, morphological studies of rectal mucosa after a single administration showed no evidence of tissue damage. Intraperitoneal administration of mitomycin C in a 1.5-wt% xyloglucan gel to rats resulted in a broad concentration–time profile, as opposed to a narrow peak and rapid disappearance from the peritoneal fluid and plasma when the drug was given as a solution¹⁸. In two other studies, the gels were investigated as vehicles for the oral delivery of indomethacin¹⁹ and theophylline²⁰. The bioavailability of indomethacin from xyloglucan gels was increased approximately three-fold compared to the control suspension. Likewise, theophylline bioavailability was 1.7–2.5 times higher than that of the commercially available oral, sustained-release liquid dosage form. Xyloglucan formulations were also assessed for ocular delivery of pilocarpine, using poloxamer 407 as a positive thermosensitive control²¹. The 1.5 wt% xyloglucan formulation enhanced the miotic response to a degree similar to that of a 25 wt% poloxamer 407 gel. More recently, xyloglucan gels were evaluated for the percutaneous administration of nonsteroidal anti-inflammatory drugs²². After topical application, the xyloglucan formulations performed better than poloxamer 407 gels in improving the bioavailabilities of ibuprofen and ketoprofen. As for cellulose derivatives, xyloglucan solutions gel at low concentrations (1–2 wt %), and this may be advantageous from a toxicological viewpoint as the amount of administered polymer is low. In addition, xyloglucan is approved for use as a food additive. However, its relatively low transition temperature (22–27 ⁰C) makes handling at room temperature problematic.

Fig 2: Rheological properties of xyloglucan gels of concentrations (a) 1.5% (b) 1.0% and (c) 0.5% w/w in simulated gastric fluid, pH 1.2, at 37°C.

Pectin:

Pectin are a family of polysaccharides, in which the polymer backbone mainly comprises α-(1-4)-D-galacturonic acid residues²³. Low methoxypectin (degree of esterification <50%) readily form gels in aqueous solution in the presence of free calcium ions, which crosslink the galacturonic acid chains in a manner described by egg-box model²⁴. Although the gelation of pectin will occur in the presence of H⁺ ions, a source of divalent ions, generally calcium ions is required to produce the gels that are suitable as vehicles for drug delivery. The potential of an orally administered in situ gelling pectin formulation for the sustained delivery of paracetamol has been reported²³. The main advantage of using pectin for these formulations is that it is water soluble, so organic solvents are not necessary in the formulation. Divalent cations present in the stomach, carry out the transition of pectin to gel state when it is administered orally²⁵.Calcium ions in the complexed form may be included in the formulation for the induction of pectin gelation.

Sodium citrate may be added to the pectin solution to form a complex with most of calcium ions added in the formulation. By this means, the formulation may be maintained in a fluid state (sol), until the breakdown of the complex in the acidic environment of the stomach, where release of calcium ions causes gelation to occur. The quantities of calcium and citrate ions may be optimized to maintain the fluidity of the formulation before administration and resulting in gelation, when the formulation is administered in the stomach. Gels suitable as sustained release vehicles were formed in situ at low pH. However, very weak gels were formed at pH 3.0 resulting in poor sustained release characteristics compared with those at pH 1.2; no significant in vitro gelation was observed at pH 3.5.

After ingestion of a meal the gastric-acidity can vary over a wide range depending on the composition of the meal but is typically in the range pH 3–7. There is a decrease of acid secretion with age which may result in very low gastric hydrogen ion concentrations in the elderly. Other influences on gastric pH include several pathophysiological conditions and also proton pump inhibitors. A decrease in the degree of methylation increases the hydrophilicity of the pectin and also its susceptibility to cross-linking by divalent cations. Consequently, low methoxy pectin may have potential for gelation over a wider pH range than observed with the pectin sample examined previously. In the present study, we have investigated the possibility of using pectin of very much lower degree of esterification (average DE = 9%) in the formulation of in situ gelling formulations and have examined the sustained release characteristics using ambroxol as a model drug.

Fig. 3: Photographs showing the appearance of gels formed at pH 1.5, 2.5, 3.5 and 4.5 from 1.5% (w/v) pectin DE9 formulations in the presence of added 1.6mM Ca++.

Gellan gum:

Gellan gum (commercially available as Gelrite^TMor Kelcogel^TM )is an anionic deacetylated exocellular polysaccharide secreted by Pseudomonas elodea with a tetrasaccharide repeating unit of one α-L-rhamnose, one β-D-glucuronic acid and two β-D-glucuronic acid residues²⁶. It has the tendency of gelation which is temperature dependent or cations induced²⁷. This gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water^28-30. In situ gelling gellan formulation as vehicle for oral delivery of theophylline is reported²⁶. The formulation consisted of gellan solution with calcium chloride and sodium citrate complex. When administered orally, the calcium ions are released in acidic environment of stomach leading to gelation of gellan thus forming a gel in situ. An increased bioavailability with sustained drug release profile of theophylline in rats and rabbits was observed from gellan formulations as compared to the commercial sustained release liquid dosage form.

Sodium Alginate:

Alginic acid is a linear block copolymer polysaccharide consisting of β-D-mannuronic acid and α-L-glucuronic acid residues joined by 1,4-glycosidic linkages^31,32 . The proportion of each block and the arrangement of blocks along the molecule vary depending on the algal source. Dilute aqueous solutions of alginates form firm gels on addition of di- and trivalent metal ions by a cooperative process involving consecutive glucuronic residues in the α-L-glucuronic acid blocks of the alginate chain. A property of aqueous solutions of alginates which has been widely exploited for the fabrication of vehicles for the sustained delivery of bioactive molecules is their ability to form firm gels on the addition of di- and tri-valent metal ions by a co-operative process involving consecutive guluronic residues in the G blocks of the alginate chain^33-36.There have been many investigations of the use of alginate gels for the sustained release of drugs. Nakano and Ogata³⁷investigated tablets containing sodium alginate for the sustained release of theophylline. Matrices containing sodium alginate and sodium calcium alginate have been investigated for their sustained release effect³⁸. In vitro release from capsules containing sodium alginate and sustained calcium phosphate³⁹ and from solid beads consisting of a calcium alginate gel matrix has been reported^40-42. There have been very few reports on the use of alginates in liquid sustained release preparations for oral administration. Zatz and Woodford⁴³developed a suspension formulation of theophylline which contained sodium alginate and which formed a gel when in contact with simulated gastric fluid. A liquid sustained release formulation containing so- dium alginate intended for the eradication of Helicobacter pylori has recently been reported⁴⁴.The formulation depends for its action on in situ gelling induced by the separate oral administration of a solution of a calcium salt immediately following that of the sodium alginate solution. In the work reported here we apply a similar strategy to that reported previously for the in situ gelation of gellan⁴⁵ in which gelation of a solution of sodium alginate containing Ca⁺⁺ions is delayed until the preparation reaches the acid environment of the, stomach through complexation of the Ca⁺⁺ ions with sodium citrate.

Physical parameters:

The formulated in situ gel solution was tested for clarity, pH, gelling capacity, and drug content estimation.

Gelling Capacity:

The gelling capacity of the prepared formulation was determined by placing a drop of the formulation in a vial containing 2ml of freshly prepared hydrochloric acid buffer of pH1.2 and visually observed. The time taken for its gelling was noted^48,49.

Gel Strength:

A comparison of the gel strengths of different polymers was carried out at 20 ◦C using a rheometer (CR-200D, Sun Scientific Co., Tokyo). A cylindrical gel of different concentrations were prepared by placing 20 ml of the sol into Visking tubing (Viskase Sales Co., size 36/32), immersing the tube in 100 ml of pH 1.2 simulated gastric fluid (as specified for the JP XIV disintegration test) and equilibrating for 24 h. The cylindrical gels (15mm diameter and 15mm height), formed as a result of the release of complexed calcium ions in the acidic environment, were placed in the rheometer and raised at a rate of 60mmmin⁻¹ so pushing a probe slowly through the gel. The changes in the load on the probe were measured as a function of the depth of immersion of the probe below the gel surface.

Comparison of gel strengths (kN/m2).

Concentration (%)	Gellan	Pectin	Xyloglucan
0.5	1.02	_	_
1.0	2.93	2.50	1.05
1.5	8.96	3.64	3.90
2.0	31.40	3.65	5.25

Rheological Studies:

The viscosity measurements were done using Brookfield viscometer DV-2 model. The in situ gel formulations were placed in the sampler tube. From the literature it was evident that, the formulation before gelling should have a viscosity of 5 to 1000 m Pa s and after gelling, will have a viscosity of from about 50-50,000 m Pa s. The samples were analyzed both at room temperature at 25°C and thermostated at 37°C ± 0.5°C by a circulating bath connected to the viscometer adaptor prior to each measurement.^50-53The angular velocity of the spindle was increased 20, 30, 50, 60, 100, 200 and the viscosity of the formulation was measured. All the formulations exhibited Newtonian and pseudoplastic flow characteristics before and after gelling respectively.

In Vitro Drug Release Studies:

In vitro release study of in situ gel solution was carried out by using Franz diffusion cell. The formulation containing 5 mg/ml concentration of formulation was placed in donor compartment and freshly prepared simulated tear fluid in receptor compartment. Between donor and receptor compartment dialysis membrane is placed (0.22μm pore size). The whole assembly was placed on the thermostatically controlled magnetic stirrer. The temperature of the medium was maintained at 37°C ± 0.5°C. 1ml of sample was withdrawn at predetermined time interval of 1hr for 6 hrs and same volume of fresh medium was replaced^46-48.The withdrawn samples were diluted to 10ml and analyzed by UV spectrophotometer using reagent blank. The drug content was calculated using the equation generated from standard calibration curve (y= mx + c). The % cumulative drug release (%CDR) was calculated. The data obtained was further subjected to PCP DISSO software for curve fitting for drug release data⁵⁴.

Accelerated Stability Studies:

Formulation were placed in ambient colored vials and sealed with aluminium foil for a short term accelerated stability study at 40 ± 2 °C and 75 ± 5% RH as per International Conference on Harmonization states Guidelines^55,56. Samples were analyzed every month for clarity, pH, gelling capacity, drug content, rheological evaluation, and in vitro dissolution.

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Received on 19.01.2010 Modified on 30.01.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 682-687