in situ gel a novel drug delivery system

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Indo American Journal of Pharmaceutical Research, 2014 ISSN NO: 2231-6876

IN SITU GEL: A NOVEL DRUG DELIVERY SYSTEM

P.R. Patil*, S.S.Shaikh, K.J.Shivsharan, S.R.Shahi Department of Pharmaceutics, Government College of Pharmacy, Opposite Govt. Polytechnic, Osmanpura, Aurangabad-(431005),

Maharashtra, India.

Corresponding author

P.R.Patil

Assistant Professor,

Government College of Pharmacy,

Opposite Govt. Polytechnic,

Osmanpura, Aurangabad (431005),

Maharashtra, India

[email protected]

Copy right © 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical

Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history

Received 11/11/2014

Available online

30/11/2014

Keywords

In Situ Gel,

Thermally Trigged System,

Ph Triggered Systems,

Photo-Initiated

Polymerization,

Polymers, Application,

Evaluation Etc.

The environmental factors like change in pH, ionic concentration, temperature, osmolarity or

irradiations etc physical state of formulation can change from free flowing solution to viscous

gel form. This kind of phase transition from ‘sol to gel’ because of above mentioned reasons

is called as in situ gelling. In situ gel is very much useful technique for improving the

bioavailability of such formulations which are easily washed away from their site of

administration, eg. Eye drops (in solution form) or Nasal drops. As compared to other drug

delivery systems like Parenteral, Nasal, Rectal and Vaginal etc use of in-situ gel in

Ophthalmic drug delivery is extensive. The intention of this new paper is to enlight the all

possible areas where in-situ gel technique can be used to improve bioavailability including

ophthalmic drug delivery. Therefore we have discussed here the applications of in-situ gel

technique in Nasal, Oral, Rectal and Vaginal drug delivery. The most important thing

required in in-situ gel is availability of suitable and compatible biodegradable polymer. Hence

we have given the list of polymers (biodegradable and non-biodegradable) that may be

helpful for investigators.

Please cite this article in press as P.R.Patil et al. In Situ Gel: A Novel Drug Delivery System. Indo American Journal of Pharm

Research.2014:4(11).

mailto:[email protected]

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Vol 4, Issue 11, 2014. P.R.Patil, et al. ISSN NO: 2231-6876

INTRODUCTION In situ gel formulations applied as solutions or suspensions that undergo gelation after instillation. This new concept of

producing a gel in situ was suggested for the first time in the early 1970s. [12]

These systems are more acceptable for the patients. They

are administered into the eye as a solution and undergo an immediate gelation when in contact with the eye. Studies have shown that

the precorneal residence time of some in situ gelling for several hours. The in situ gelation has been the most attractive feature of these

systems. Various polymeric combinations have been successfully used for fabrication. [1]

Hence, they are promising means for

overcoming the limitation of conventional topical ophthalmic dosage forms like eye drops, suspensions and ointments. In situ

activated gel forming systems are those which are when exposed to physiological conditions will shift to a gel phase. Gelation occurs

via the cross-linking of polymer chains that can be achieved by covalent bond formation (chemical cross-linking) or non-covalent

bond formation (physical cross-linking).The progress that has been made in gel technology is in the development of a droppable gel. [2]

In situ gel-forming systems can be described as low viscosity solutions that undergo phase transition to form viscoelastic gels due to

conformational changes of polymers in response to the physiological environment. The rate of in situ gel formation is important

because between instillation in the eye and before a strong gel is formed; the solution or weak gel is produced by the fluid mechanism

of the eye. [21]

ADVANTAGES 1. Generally more comfortable than insoluble or soluble insertion. Less blurred vision as compared to ointment.

2. Increased bioavailability due to increased precorneal residence time.

3. Decreased naso-lacrimal drainage of the drug which causes undesirable side effects arising due to systemic absorption of the drug

through naso-lacrimal duct is reduced.

4. Drug effect is prolonged hence frequent instillation of drug is not required.

5. The principle advantage of this formulation is the possibility of administering accurate and reproducible quantities, in contrast to

already gelled formulations and moreover promoting precorneal retention. [4]

METHODS OF DRUG DELIVERY :

Physiological Stimuli: [1,3,5]

Thermally Trigged System :

Temperature-sensitive hydrogels are probably the most commonly studied class of environment-sensitive polymer systems in

drug delivery research. The use of biomaterial whose transitions from ‘sol to gel’ is triggered by increase in temperature is an

attractive way to approach in-situ formation. The ideal critical temperature range for such system is ambient and physiologic

temperature and no external source other than that of body heat is required to trigger gelation. A useful system should be endurable to

account for small differences in local temperature, such as it might be encountered in appendages in the oral cavity.

Three main strategies are exists in engineering of thermoresponsive sol to gel polymeric system. For convenience,

temperature-sensitive hydrogels are classified as fallows.

Table 1: Classification of Hydrogels (Thermally Trigged System).

Types of

Hydrogels Characteristics Polymers

Negatively

Thermosensitive

Have Lower Critical Temperature (LCST) and

Contract upon heating above the LCST.

Poly-(N-isopropylacrylamide) (PNIPAAm). PNIPAAm is

a water soluble polymer at its low LCST, but hydrophobic

above LCST, which result on precipitation of PNIPAAm

from the solution at the LCST.

Positively

Thermosensitive

Have Upper Critical Temperature (UCST) and

Contract upon cooling below UCST.

Poly-(acrylic acid) (PAA) and Polyacrylamide (PAAm) or

Poly-(acrylamide-co-butyl methacrylate). They have

positive temperature dependence of swelling.

Thermally

Reversible

Polymer solution is a free flowing liquid at

ambient temperature and gels at body

temperature. When injected as a solution into the

body, the material forms a firm, stable gel within

minutes.

Poly-(ethylene oxide)-b-poly (propylene oxide)-b-poly

(ethylene oxide) (Pluronics®, Tetronics®, poloxamer).

pH Triggered Systems :

The second approach of in situ gel formation is based on Change in pH. Certain polymers such as PAA (Carbopol®,

carbomer) or its derivatives, polyvinylacetal diethylaminoacetate (AEA), Mixtures of poly (methacrylic acid) (PMA) and poly

(ethylene glycol) (PEG) shows change from sol to gel with change of pH. 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.

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Chemical Reactions : [1,7,12]

Ionic cross-linking :

Certain ion sensitive natural polysaccharides such as Carrageenan, Gellan gum, Pectin, Sodium alginate undergo phase

transition in presence of various ions such as K+, Ca

2+, Mg

2+, Na

+ eg. Alginic acid undergoes gelation in presence of

divalent/polyvalent cations e.g. Ca2+

due to the interaction with glucoronic acid block in alginate chains.

Enzymatic cross-linking :

Certain natural enzymes operate efficiently under physiologic conditions without need for potentially harmful chemicals such

as monomers and initiators. They provide a convenient mechanism for controlling the rate of gel formation, which allows the mixtures

to be injected before in situ gel formation.

Physical Changes In Biomaterials : [1,9,14]

Swelling :

In situ formation may also occur when material absorbs water from surrounding environment and expand. One such

substance is myverol 18-99 (glycerol mono-oleate), which is polar lipid that swells in water to form lyotropic liquid crystalline phase

structures. It has some bioadhesive properties and can be degraded in vivo by enzymatic action.

Diffusion :

This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or

solidification of polymer matrix. N-methyl- pyrrolidone (NMP) has been shown to be useful solvent for such system.

Photo-Initiated Polymerization : [1,11,13]

A solution of monomers such as acrylate or other polymerizable functional groups and initiator such as 2,2 dimethoxy-2-

phenyl acetophenone, camphorquinone and ethyl eosin can be injected into a tissues site and the application of electromagnetic

radiation used to form gel designed readily to be degraded by chemical or enzymatic processes or can be designed for long term

persistence in vivo. Typically long wavelength ultraviolet and visible wavelengths are used. A photopolymerizable, biodegradable

hydrogel as a tissue contacting material and controlled release carrier is reported by Sawhney.

POLYMERS:

Ideal Characteristics [1]

:

It should be biocompatible.

It should have pseudo plastic behavior.

It should have good tolerance.

It should be capable of adherence to mucus.

Polymer should be capable of decreasing viscosity with increasing shear rate there by lowering viscosity during blinking.

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Table 2: Examples of Polymer.

Type of Drug Delivery Polymers Drugs

1) Oral Carbopol-934, Chitosan, Gellan gum, Gum

karaya, HPMC, Hyaluronic acid esters, MC,

Methylpyrrolidinone Chitosan, Pectin,

Poloxamer, Pluronic F-127, Sodium-

Alginate, Trimethyl Chitosan, Xyloglucan,

etc.

Ambroxol,

Articaine HCl,

Benzydamine HCl,

Cimetidine,

Indomethacin,

Paracetamol,

Theophylline, etc.

2) Nasal Acacia, Carbomer, Carbopol-934,

Carrageenan, Chitosan, CMC, Gellan gum,

Gum karaya, HEC, HPMC, Pectin, PEG,

Poloxamer, PVA, PVP, Sodium-Alginate,

Tragacanth, etc.

Acetaminophen,

Chloramphenicol,

Insulin,

Ketorolac,

Melatonin,

Metaclopramide,

Midazolam,

Oxymetazoline,

Oxytocin,

Salbutamol,

Zolmitripan, etc.

3) Ocular Carbomer, Carbopol-940, Carrageenan,

Chitosan, Gelatin, Gellan gum, HPMC,

HEC, Sodium-Alginate, Pluronic F-127,

Poloxamer, PVA, PVP, Xanthan gum,

Xyloglucan, etc.

Aceclofenac,

Ciprofloxacin,

Diclofenac,

Dorzolamide,

Fluconazole,

Indomethacin,

Methazolamide,

Ofloxacin,

Pilocarpine,

Timolol,

Voriconazole, etc.

4) Rectal and Vaginal Carbopol, Chitosan, Gelatin, HEC, HPC,

HPMC, MC, PEG, Pluronic F-127,

Poloxamer, Polycarbophil, PVP, Sodium-

Alginate, Sodium-CMC, Starch, etc.

Acetaminophen,

Acyclovir,

Chloramphenicol,

Clotrimazole,

Doxorubicin,

5-Flurouracil,

Insulin,

Metronidazole,

Nimesulide,

Oxybutynin,

Oxytocin,

Quinine, etc.

5) Parenteral Cellulose acetate, Chitosan, Gelatin, PEG,

Poloxamer, Sodium-Alginate, Sodium-

Hyaluronate, etc.

Doxorubicin,

5-Flurouracil,

Palcitaxel, etc.

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Oral Nasal Ocular Rectal and

Vaginal

Parenteral

Carbopol

Cellulose derivatives

Chitosan

Gelatin

Gellan gum

Hyaluronic acid derivatives

Pectin

PEG

Pluronic F-127

Poloxamer

PVA

PVP

Sodium alginate

Tragacanth

Xanthan gum

Figure 1: Plot of polymers in different kind of drug delivery:

APPLICATIONS IN DRUG DELIVERY :

Oral :

Pectin, xyloglucan and gellan gum are the natural polymers used for in situ forming oral drug delivery systems. The

potential of an orally administered in situ gelling pectin formulation for the sustained delivery of paracetamol has been

reported. The main advantage of using pectin for these formulations is that it is water soluble, so organic solvents are not

necessary in the formulation. In situ gelling gellan formulation as vehicle for oral delivery of theophylline is reported. 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. [1]

Nasal :

An in-situ gel system for nasal delivery of mometasone furoate was developed and evaluated for its efficacy for the treatment

of allergic rhinitis. Gellan gum and xanthan gum were used as in situ gel forming polymers. Animal studies were conducted using an

allergic rhinitis model and the effect of in situ gel on antigen induced nasal symptoms in sensitized rats was observed. In-situ gel was

found to inhibit the increase in nasal symptoms as compared to marketed formulation nasonex (mometasone furoate suspension

0.05%). Intact ciliated respiratory epithelium and normal goblet cell appearance indicated from histopathology of rat nasal cavity

proved that these formulations were safe for nasal administration.Wu et al. designed a new thermosensitive hydrogel by simply mixing

N-[(2-hydroxy-3-methyltrimethylammonium) propyl] chitosan chloride and poly (ethylene glycol) with a small amount of α-β-

glycerophosphate; for nasal delivery of insulin. The formulation was in solution form at room temperature that transformed to a gel

form when kept at 37o C. Animal experiments demonstrated hydrogel formulation to decrease the blood-glucose concentration by 40-

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50% of the initial values for 4-5 h after administration with no apparent cytotoxicity.Therefore, these types of systems are suitable for

protein and peptide drug delivery through nasal route. [1, 16]

Ocular :

For in situ gels based ocular delivery, natural polymers such as gellan gum, alginic acid and xyloglucan are most commonly

used polymers. Local ophthalmic drug delivery has been used for various compounds such as antimicrobial agents, anti-inflammatory

agents and autonomic drugs used to relieve intraocular tension in glaucoma. Conventional delivery systems often result in poor

bioavailability and therapeutic response because high tear fluids turn over and dynamics cause rapid elimination of the drug from the

eye. So, to overcome bioavailability problems, ophthalmic in situ gels were developed much of the interest in the pharmaceutical

application of gellan gum has concentrated on its application for ophthalmic drug deliver. Drug release from these in situ gels is

prolonged due to longer precorneal contact times of the viscous gels compared with conventional eye drops. Miyazaki et al. attempted

to formulate in situ gels for ocular delivery using Xyloglucan (1.5%w/w) as the natural polymer. These in situ forming polymeric

systems were observed to show a significant mitotic response for a period of 4 h when instilled into lower cul-de-sac of rabbit eye.

The formulation and evaluation of an ophthalmic delivery system for indomethacin for the treatment of uveitis was carried out. A

sustained release of indomethacin was observed for a period of 8 h in-vitro thus considering this system as an excellent candidate with

the water- soluble Carbopol system has been reported. [1, 17]

Rectal And Vaginal :

In situ gels also possess a potential application for drug delivery by rectal and vaginal route. Miyazaki et al. investigated the

use of xyloglucan based thermoreversible gels for rectal drug delivery of indomethacin. Administration of indomethacin loaded

xyloglucan based systems to rabbits indicated broad drug absorption peak and a longer drug residence time as compared to that

resulting after the administration of commercial suppository. For a better therapeutic efficacy and patient compliance, mucoadhesive,

thermosensitive, prolonged release vaginal gel incorporating clotrimazole-β-cyclodextrin complex was formulated for the treatment of

vaginitis. In addition, a significant reduction of drug Cmax was observed after administration of in situ polymeric system thus

indicating the avoidance of adverse effects of indomethacin on nervous system. [1, 18]

Parenteral :

The development of injectable in-situ forming drug delivery systems has received a considerable interest over the last decade.

A novel, injectable, thermosensitive in situ gelling hydrogel was developed for tumor treatment. This hydrogel consisted of drug

loaded chitosan solution neutralized with β-glycerophosphate. Local delivery of paclitaxel from the formulation injected

intratumorally was investigated using EMT-6 tumors implanted subcutaneously on albino mice. Ito et al. designed and synthesized

injectable hydrogels that are formed in situ by cross-linking of hydrazide modified hyaluronic acid with aldehyde modified versions of

cellulose derivatives such as carboxymethylcellulose, hydroxypropylmethylcellulose and methylcellulose. These in situ forming gels

were used for preventing postoperative peritoneal adhesions thus avoiding pelvic pain, bowel obstructions and infertility. For a better

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therapeutic efficacy and patient compliance, mucoadhesive, thermosensitive, prolonged release vaginal gel incorporating clotrimazole-

β-cyclodextrin complex was formulated for the treatment of vaginitis. [1, 13]

EVALUATION AND CHARACTERIZATION :

Sol to gel Transition Temperature and Gelling Time:

For in situ gel forming systems, the sol to gel transition temperature and pH should be determined. Gelling time is the time

required for first detection of gelation of in situ gelling system. Thermosensitive in situ gel should be checked for in situ gelling at

body temperature. [1,2]

Clarity:

The clarity of formulated solutions can be determined by visual inspection against black and white background. [1,3]

Texture Analysis:

The firmness, consistency and cohesiveness of formulation 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. [1,2,4]

Gel Strength:

A specified amount of gel is prepared in a beaker, from the sol form. This gel containing beaker is raised at a certain rate, so

pushing a probe of rheometer 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. [1,9,25]

Viscosity and Rheology:

This is an important parameter for the in situ gels, to be evaluated. The viscosity and rheological properties of the polymeric

formulations, either in solution or in gel made with artificial tissue fluid (depending upon the route of administrations) were

determined with different viscometer. The viscosity of these formulations should be such that it should be patient complient. [1,2,7]

Fourier Transform Infra-Red Spectroscopy and Thermal Analysis:

Fourier transform infra-red spectroscopy is performed to study compatibility if ingredients. 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.

[1,4,12]

Drug Content:

Uniform distribution of drug is important to get good bioavailability. The content of drug is estimated by simultaneous

method by UV-Visible spectrophotometer. Method involves dilution of 1 ml of formulation with 100 ml of ATF solution pH 7.4.

Aliquot of 1 ml was withdrawn and further diluted to 10 ml of ATF solution. Then concentration is determined by UV-Visible

spectrophotometer. [1,5,22]

In-Vitro Drug Release Studies:

The drug release studies are carried out by using the plastic dialysis cell. 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 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. [1,12,26]

Histopathological Studies:

Two mucosa tissue pieces (3 cm2) were mounted on in vitro diffusion cells. One mucosa was used as control (0.6 mL water)

and the other was processed with 0.6 mL of optimized organogel (conditions similar to in vitro diffusion). The mucosa tissues were

fixed in 10% neutral carbonate formalin (24 hours), and the vertical sections were dehydrated using graded solutions of ethanol. The

subdivided tissues were stained with haematoxylin and eosin. The sections under microscope were photographed at original

magnification ×100. The microscopic observations indicate that the organogel has no significant effect on the microscopic structure of

the mucosa. The surface epithelium lining and the granular cellular structure of the nasal mucosa were totally intact. No major changes

in the ultra structure of mucosa morphology could be seen and the epithelial cells appeared mostly unchanged. [1,13,23]

Accelerated stability Studies:

Formulations are placed in ambient colour 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 (ICH) states Guidelines. Samples are analyzed every

month for clarity, pH, gelling capacity, drug content, rheological evaluation, and in vitro dissolution. [1,6,10]

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Ocular irritancy test:

The Draize irritancy test was designed for the ocular irritation potential of the ophthalmic product prior to marketing.

According to the Draize test, the amount of substance applied to the eye is normally 100μl placed into the lower cul-de-sac with

observation of the various criteria made at a designed required time interval of 1hr, 24hrs, 48 hrs, 72hrs, and 1week after

administration. Three rabbits (male) weighing 1.5 to 2kg are used for the study. The sterile formulation is instilled twice a day for a

period of 7 days, and a cross over study is carried out (a 3 day washing period with saline was carried out before the crossover study).

Rabbits are observed periodically for redness, swelling, watering of the eye. [1,7,24]

Table 3: Some Examples of Marketed Formulations:

Sr. No Type of Drug Delivery Name of Drug Marketed Formulation

1) Oral Betamethasone Celestone®

,

Celestone soluspan®

2) Nasal Fluconazole Diflucan®

Zinc gluconate, Zinc acetate Zicam®

3) Occular Ganciclovir Zirgan®

Lidocaine Akten®

Loteprednol etabonate Lotemax Gel®

Pilocarpine Pilostat®, Carpine

®

Timolol Timoptic®

4) Rectal & Vaginal Diazepam Diastat®

Dinoprostin Prostin E®

Metronidazole Metrogel Vaginal®

Nonoxynol-9 Advantage S®

Conceptrol®

Gynol II®

Oxyquinoline sulphate, Ricinolic acid Acid jelly®

Progesterone Crinone®

5) Parenteral Ganciclovir Vitrasert®

Doxycycline Atridox®

Atrisorb D®

Leuprolide acetate Eligard®

Lupron depot®

CONCLUSION In situ gels are wonderful amalgamation of two pharmaceutical forms one solution and second gel. Both have their own

advantages like solution provide ease of handling and administration while gel helps to increase the contact period with targeted

tissue. This not only improves the bioavailability but also reduces the frequency of dosing which ultimately leads to patient

compliance.

Use of biodegradable polymer will help to improve the utility of in-situ gel. Due to flexible nature of in-situ gel, formulator

can play with its release properties. Formulator can mold it into controlled, sustained or prolong release as per the needs.

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