AN INSIGHT TO IN-SITU GEL FORMING STOMACH SPECIFIC DRUG DELIVERY SYSTEM

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ABOUT AUTHORS:
Deepak Kumar*, Palak Kapoor
Shoolini University,
Solan, Himachal Pradesh
deepakkaushik354@gmail.com

ABSTRACT:
The oral delivery of drugs having narrow absorption window in the gastro-intestinal tract is limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the time of absorption. To provide controlled delivery of drugs novel drug delivery systems have been developed. Different systems have been developed to increase the gastric residence time viz. floating system, mucoadhesive, high density, expandable. Among all oral dosage forms, liquid orals are more prone to low bioavailability due to fast transit time from stomach to duodenum. Sustained/Controlled delivery can be achieved by decrease in the transit time of the dosage form. This can be augmented by an approach of liquid in-situ gelling system. These in-situ formulations are the drug delivery systems that are in sol form before administration in the body, but when administered, undergo gelation, in-situ, to form a gel. Formation of gel depends on various factors viz. temperature modulation, pH change, presence of ions, ultra-violet irradiation, from which drug releases in a sustained and controlled fashion. Different polymers which can be used for formation of in-situ gel include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly-caprolactone, poly-lactic acid, poly-lactic-co-glycolide. This article presents a detailed review of introduction, approaches to achieve in situ gelling system, polymers used, evaluation parameters, advantages of in situ gelling system.

REFERENCE ID: PHARMATUTOR-ART-2110

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 2

Received On: 11/01/2014; Accepted On: 19/01/2014; Published On: 10/02/2014

How to cite this article: D Kumar, P Kapoor, An Insight to In-Situ Gel Forming Stomach Specific Drug Delivery System, PharmaTutor, 2014, 2(2), 25-32

1. INTRODUCTION:
Controlled and sustained release drug delivery systems received considerable attention of all pharmacists/ scientists from the last 30 years. Among them extensive research has been carried out in designing of polymeric drug delivery system. In-situ gel forming systems has been widely investigated as vehicle for the sustained delivery of drug. Also, the development of in-situ gel forming systems has drawn attention over the past few years1. The advantages shown by in-situ forming polymeric delivery systems such as ease of administration and reduced frequency of administration, which increases patient compliance and comfort, has drawn considerable interest in their development2.

Formation of in situ gel occurs by one or by the combination of different stimuli like pH change, temperature modulation, and solvent exchange3. In-situ gel forming system via different route such as orla, nasal, opthalmic etc. can be formulated. The system basically utilizes polymers that undergo transformation from sol to gel like consistency, due to the change in physicochemical properties. The formulation development of in situ forming drug delivery system can be done using various natural and synthetic polymers viz. gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly-lactic acid, poly-lactic-co-glycolide and poly-caprolactone4. In situ gelling system increases the bioavailability of drug as compared to conventional liquid dosage form. The gel formed in situ being lighter than gastric fluids, floats over the stomach contents or adhere to gastric mucosa due to bioadhesive nature of polymer and produce gastric retention of dosage form and increases the gastric residence time which results in the prolonged drug delivery in gastrointestinal tract5.

2. APPROACHES OF IN SITU GELLING SYSTEM:
There are different approaches used for triggering the in situ gel formation viz. physical changes in biomaterial (diffusion of solvent and swelling), chemical reactions (enzymatic, chemical and photo-initaited polymerization), and physiological stimuli (temperature and pH). These are explained below:

2.1 In situ gel formation based on physical mechanism:

2.1.1   Swelling and Diffusion:
Polymer swells by the absorption of water. This swelling of polymer causes formation of gel6. The example of the polymer which undergoes swelling is myverol 18-99 (glycerol mono-oleate)7.

Solution of the polymer such as N-methylpyrrolidone (NMP) uses diffusion mechanism which involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix8.

2.2 In situ gelling based on chemical stimuli:

2.2.1   Ionic crosslinking:
Certain ion sensitive polysaccharides like carrageenan, gellan gum, pectin, sodium alginate undergo phase transitions in presence of various such as K+, Ca2+, Mg2+, Na+ 9. In instance, alginic acid undergoes gelation in presence of divalent/polyvalent cations (Ca2+) due to interaction with glucoronic acid10.

2.2.2   Enzymatic crosslinking:
Certain natural enzymes operate under physiologic conditions without need for potentially harmful chemicals such as monomers, and initiators provide a convenient mechanism for controlling rate of gel formation, which facilitates the mixtures to be injected before gel formation in situ11.

2.2.3   Photo-polymerisation:
A solution of the monomers such as acrylate or other polymerizable functional groups and initiator viz. 2, 2-dimethoxy-2-phenyl acetophenone, camphorquinone and ethyl eosin can be injected into a tissue site and the application of electromagnetic radiation used to form gel12. Ultraviolet and visible wavelengths are used for polymerization. Sawhney reported the controlled release carrier form a photopolymerizable-biodegradable hydrogel as tissue contacting material13.

2.3 In situ gel formation based on physiological stimuli:

2.3.1   Temperature dependent in situ gelling:
These transform from solution form to gel after administration. These hydrogels remain liquid at room temperature (20-250C) and undergo gelation when comes in contact with body fluids (35-370C). This approach exploits temperature-induced phase transition. Some of the polymers undergo abrupt changes in solubility with the increase in environmental temperature (lower critical solution temperature, LCST)14, 15. Polymer solution is a free flowing liquid at ambient temperature and gels at body temperature16. A positive temperature sensitive hydrogel has an upper critical solution temperature (UCST). Such hydrogel contracts upon cooling below the UCST.

2.3.2   pH dependent gelling:
Another approach for formation of in situ gel is based on change in pH. Polymers which shows change from sol to gel with change of pH are Carbolpol or its derivatives17, polyvinylacetaldiethylaminoacetate18, mixtures of poly (methacrylic acid) and poly (ethylene glycol)19. Swelling of hydrogel increases as the external pH increases in case of weakly acidic groups, and decreases in case of weakly basic groups.

3. POLYMERS USED FOR IN SITU GELLING SYSTEM:

3.1 Pectin:
Pectins are the class of polysaccharides which are anionic in nature, in which the polymer backbone is mainly comprise of α-(1-4)-D-galacturonic acid residues. Low methoxypectins readily form gels in aqueous solution in presence of Ca2+ ions, which crosslink galactouronic acid chain. Although gelation of pectin will occur in the presence of hydrogen ions, but calcium ions are required to produce the gels that are suitable as a vehicle for the delivery of drug20. The main advantage of using pectin is that it is water soluble, so organic solvents can be excluded. Also, the divalent cations present in the stomach carryout the phase transition of pectin when administered orally. Calcium ions may be included in the formulation in complexed form for the induction of gelation of pectin21. Sodium citrate can be added to which form a complex with calcium ions, due to which the formulation may be maintained in a sol state, until the complex breaks in acidic environment of the stomach. This breakdown of complex releases the calcium ions causing gelation to occur. The quantities of the calcium and citrate ions may be optimized to maintain the desired fluidity of the formulation before administration and when administered, results into gelation when comes in contact with stomach fluids. The potential of an orally administered in situ gelling pectin formulation for the sustained delivery of Paracetamol has been reported22.

3.2 Xyloglucan:
Xyloglucoan is a class of polysaccharide derived from tamarind seeds. The polymer backbone is mainly comprises of a (1-4)-β-D-glucan backbone chain, which has (1-6)-α-D-xylose branches that are partially substituted by (1-2)-β-D-galactoxylose23. Xyloglucan is itself not a gel, dilute solutions of xyloglucan which has been degraded by galactosidase exhibit a thermally reversible sol-gel transition on heating. The sol-gel transition temperature varies with the degree of galactose elimination. Xyloglucan gels have been used for oral, intraperitoneal, ocular, and rectal drug delivery23, 24, 25, 26. Itoh K et al reported the gelation and release characteristics of mixtures of xyloglucan, which has thermally reversible gelation characteristics, and pectin (gelation is non-responsive), with the aim of formulating an in situ gelling vehicle for oral sustained drug delivery27.

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