INTRODUCTION:

Insitu forming gels are the dosage forms which are liquid in nature outside the body and when they are instilled into the eye they are converted into gel upon the environmental changes like pH, temperature and upon ion activation [1]. The formation of the gel increases the residence time in the eye which is helpful in prolonging the corneal contact time, reducing the drainage of drug thus leading to an enhanced bioavailability. These formulations will also improve patient compliance by reducing the frequency of administration [2].

ADVANTAGES OF IN SITU FORMING GELS [1]:

· Mainly used to maintain for the prolonged and controlled release of the drug from the formulation.

· The formation of gel mainly increases the ocular contact time and residence time which is helpful for the enhancement of the bioavailability.

· Due to the secretion of the lacrimal fluids from the eye there will be rapid drainage of the drug which is a major drawback of the conventional dosage forms. This limitation can be overcome by the formation of gel.

· In situ forming gels will increase the patient compliance by reducing the frequency of administration.

· In situ forming gels are also helpful in the targeted drug delivery.

· Accurate dosing is possible which may not involve in the over dose and dose dumping.

· More comfortable with improved patient compliance when compared to other dosage forms like ocular inserts etc.

· Drug loss though naso-lacrimal duct is minimized as it can lead to unwanted side effects [3, 4].

VARIOUS APPROACHES OF IN SITU GELATION:

These are classified into four different mechanisms.

· Based on physiologic stimuli (pH, temperature, ionic strength or ion activation).

· Based on physical changes (swelling, diffusion).

· Based on chemical reaction (photo-polymerization, enzymatic cross-linking and chemical polymerisation).

Formation of in situ gel based on physiologic stimuli:

· pH:

In this the formation of gel is triggered due to the changes in the pH. The pH of the lacrimal fluids was found to be 7.4 at which formation of gel takes place. For example, cellulose acetate phthalate (CAP) is a polymer which exists in the form of a solution under pH of the solution 4.5 and forms gel when it is present at pH of lacrimal fluid[5,6]. The mechanism involved in this mainly deals with the ionizable groups of these polymers which can accept or release protons due to the changes in pH[7]. Some examples of polymers used are poly vinyl acetyl di-ethyl amino acetate (AEA), combination of polymethacrylic acid and polyethylene glycol and carbomer[8,9,10].

· Temperature:

The formation of gel or the conversion of sol to gel takes place due to the changes in the temperature. Generally the preparation is in the form of solution at the temperature around 20-25°C and it is converted into gel at the temperature of the eye which is around 35-37^oC. As the temperature increases there will be destruction of polymeric chains which helps in gel formation [11]. Pluronics are the widely used thermosetting polymers. These are having hydrophilic part (ethylene oxide) and hydrophobic part (polyoxy propylene) [12]. Pluronic F-127 is widely used for the preparation of colorless and transparent gels [13]. This type of solution upon instillation into eye due to increase in temperature it forms gel. The mechanism may be due to increased entanglement of the gel and also because of the intra molecular hydrogen bonding [14].

Classification of temperature sensitive systems:

1. Negatively thermo sensitive in situ gels:

These are the systems having lower critical solution temperature (LCST), it is the critical solution temperature below which the components of the mixture are miscible for all compositions. So formation of gel takes place above this temperature.

Example of such type of polymers is poly-(N-isopropylacrylamide). It is soluble in water at LCST and above this temperature it will be hydrophobic and starts precipitating from the solution.

2. Positively thermosensitive in situ gels:

These are having upper critical temperature (UCST), it is the temperature above which all the components of the mixture are miscible in all proportions. So on cooling this mixture below UCST it forms gel.

Examples of this type of polymers are poly (acrylic acid) (PAA), polyacrylamide.

3. Thermoreversible in situ gels:

These are normal free flowing systems upon change in temperature they form gel.

Examples of this type of polymers are poloxomers [8, 9, 10].

· Ion activation:

In this type initially the dosage form is in solution form but when it comes into contact with the monovalent or divalent ions which are present in the lacrimal fluids of the eye it forms gel. Concentration of sodium ions in eye is 2.6 g/L which is useful for the gel formation of some polysaccharide like Gelrite[1]. Alginates are also used as a gelling agents and they are used along with HPMC where HPMC acts as agent for increasing viscosity. The mechanism involved is the formation of gel or phase transition takes place in the presence of ions in the lacrimal fluid mainly because of the interaction of glucuronic acid in alginate chains [8, 15, 16].Some other examples of this type of polymers are hyaluronic acid, gellan gum, pectin, carrageenan.

In situ gel formation based on physical changes:

· Swelling:

Some substances like myverol 18-99 (glycerol mono-oleate) which is a having lipid like properties, it swells when it comes into contact with water which is helpful for the formation of gel like substance and also having the bio adhesive properties which further helps in increasing the contact time and helps in sustained release of the drug. After the action, it can be degraded by enzymatic activity [17].

· Diffusion:

In this mechanism, diffusion of the solvent from the matrix takes place which helps in the thickening or precipitation of the polymer matrix. The solvent used in such type of system is N-methyl-pyrrolidone (NMP) [18].

In situ gel formation based on chemical reaction:

· Enzymatic cross-linking:

In this approach the gel formation takes place due to interaction with enzymes. This is having large benefits when compared to other types because there is no need of using special monomers and other synthetic derivatives which will trigger the formation of the gel. A novel drug delivery in this approach is intelligent drug delivery system where, insulin and glucose oxidase is entrapped in a cationic pH sensitive polymer which can release insulin based on the glucose level in the blood. Here maintaining the level of the enzyme will be helpful for the formation of the gel.

· Photo- polymerisation:

This technique is helpful in the formation of in situ gel. Here some substances like monomers and some initiators are used which are helpful for the formation of the gel when electromagnetic radiation is applied. Certain functional groups like acrylate on the monomers undergo photo polymerisation when exposed to electromagnetic radiation or in the presence of photo initiator.

Usually longer wave lengths of light like UV-visible range can be used as shorter wavelength light is having higher energy and can be harmful to the biological tissues. Examples of some initiators used are 2,2 dimethoxy-2-phenyl acetophenone (gets polymerized when exposed to ultraviolet radiation), camphoroquinone and ethyl eosins (gets polymerized when exposed to visible light). These initiators and some of the polymers used can be biodegraded in the body with the use of the enzymes. These dosage forms can be introduced in the liquid and by the exposure to radiation they directly get polymerized to form a gel and these types of systems can also be formulated as inserts. Hence, this helps in attaining controlled drug delivery.

· Chemical cross linking:

Polysaccharides may undergo sol gel transition due to the presence of ions. k-carrageenan forms brittle and rigid gel in presence of K+ ions, whereas i-carrageenan mainly forms elastic gels with Ca2+. Gellan gum undergoes in situ gelling in the presence of various mono- and divalent cations like K+, Na+, Ca2+ and Mg2+. Similarly alginic acid and pectins undergo gelation in the presence of divalent/polyvalent cations. Due to the presence of Na+, Ca2+ and Mg2+ in tear fluids, the above polymers can undergo gelation in situ upon contact with tear fluids.

EVALUATION TESTS FOR IN SITU FORMING GELS:

· Viscosity and rheology:

Rheology studies should be done for the prepared formulation as it very much important for these types of formulations which undergo sol-gel transition. The viscosity of the dosage form can be determined with the help of Brookfield viscometer, Ostwald viscometer, cone and plate viscometer.

It is found that from the literature search that the viscosity of the formulation before the formation of the gel should be 5 to 1000 mP as and after the gelation in the eye the viscosity was found to be 50 to 50,000 mP as [19,20]. The samples should be analyzed in such a way that the viscosity of the preparation should be measured at room temperature (25^oC) and the sample is thermostat at 37±0.5^oC.This can be done by using a circulating water bath. It is generally found that the formulations generally exhibit newtonian and pseudo-plastic flow properties before and after the gelling of the formulation in the tear fluid b [21, 22]. Viscosity of the gel can also be measured by changing the formulation pH to 7.4 by adding simulated lacrimal fluid [23, 24].

· Sol-gel transition temperature and gelling time:

Sol-gel transition temperature is the temperature at which the formation of gel takes place. To determine this temperature the prepared formulation which is in the sol form is kept in a test tube and heated by increasing the temperature and the final temperature at which gel formation takes place is noted. The time required for the generation of gel is noted as gelling time [25].

· Gel-strength:

It can be assessed by using a device called rheometer. For the evaluation purpose initially the formation of the gel should be done by using appropriate mechanism [25]. Later into the beaker containing gel a probe is inserted. Then different loads are kept on the probe. The changes in the load on the probe can be measured as the function of depth of immersion of the probe below the surface [8, 26, 27].

· Gelling capacity:

It can be assessed by inserting the prepared formulation into the certain quantity of simulated lacrimal fluid and measuring the time required for the formation of the gel which gives the dosage form gelling capacity [5, 28].

· Texture analysis:

The consistency, cohesiveness and firmness of the dosage form can be determined by using texture analyzer. Texture analysis can be helpful in determining or assessing the syringe ability of the sol. Higher values of the adhesiveness of the gel is needed in order to attain intimate contact and to increase the contact time [29,30].

It is very important for the ophthalmic formulation to have proper spread ability and adhesive properties in order to easily spread on the conjunctival surface and the formed gel should properly adhere to the surface in order to enhance the retention time and helps in sustained drug release [31].

· Clarity:

Clarity of the prepared formulation can be estimated by visual observation. The prepared formulation is kept under light alternatively against black and white backgrounds for the particles [28]. When HPMC is used as a polymer, at high temperatures it will get precipitated so after autoclaving of HPMC containing formulation it forms a cloudy mass. It can be disappeared and retains original clarity after standing it for overnight and then the clarity of the formulation is visualized. And also, UV-visible spectro-photometer can also be used for the measurement of percentage transmission of the light through the formulation under the visible region at 490nm wavelength by using reference standard most preferably water.

· Isotonicity:

Isotonicity is the important parameter which should be measured properly especially for the ophthalmic preparations as the difference in isotonicity will lead to the damage of the tissue and it causes irritation to the eye. Hence, all the ophthalmic formulations should be tested for isotonicity measurement. Isotonicity of the ophthalmic preparation can be measured by mixing the small amount of the formulation in few drops of blood and it is observed under microscope at 45x magnification and compared with the standard ophthalmic marketed formulation [32, 23].

· Ocular irritancy test:

Ocular irritancy test should be done before marketing the product and the test used for knowing about the ocular irritancy is Draize irritancy test. With respect to the Draize test the amount of medicament applied in the lower conjunctival sac is about 100µL and after administration different criteria or several parameters are considered and the observations can be done at a time interval of 1,24,48,72 hours and one week respectively after the instillation of the dose.

For conducting this test healthy rabbits (male) three in number are chosen. Each rabbit weight is around 1.5 to 22 kilo gram. Then the dosage form is instilled into the eyes of the rabbit and the formulation should be in a sterilized form. The administration of the dose should be continued for one week by giving the dose in alternate days. Generally cross-over design is taken into practice. And the rabbits used for this design should be washed with saline for three days before the test is carried out. And the results can be evaluated by testing the rabbit eye or by visual inspection of the rabbit eye for the appearance of redness, swelling, inflammation and also can be checked for the excess secretions from the eye [33, 34].

· Anti-microbial efficacy:

The prepared ophthalmic formulations were tested for anti-microbial activity according the USP procedure one of such procedures used for ophthalmic in situ gels is USP 31<51> procedure in which it is mentioned effectively about the testing criteria for anti-microbial activity. In this test the samples are taken from the respective batches to be tested are selected and the test samples are inoculated with E.coli, Staphylococcus aureus, Pseudomonas aeruginosa, and these samples inoculated for one month (around 28 days) at 22.5±2.5^oC and the inoculum amount should be in the range of 10⁵-10⁶cfu/ml. Then for the time period of 7,14 and 28 days any indication for the growth of organisms or any increase in the turbidity is seen, by this we can notice effectiveness of the preservative.

The preservative used is said to be anti-microbially effective only if there is a 1-log decrease in the growth of the microorganisms and at the 7^th day of the incubation and also if there is a 3-log decrease in the concentration in the growth or concentration of the microorganisms in the 14^th day of incubation and from then there should be no much decrease in the growth from 14-28 days this is said according to USP 31<51>.

This antimicrobial efficacy tests can also be done by using simple procedure called cup and plate technique. In this test agar is used as nutrient medium in which the test organisms are inoculated and incubated for their growth later two solutions namely test and standard are prepared and the standard solution is the sterile solution of the drug whereas the test is the diluted solution to different concentrations from the test formulation. Later wait for around two hours which leads to the proper diffusion of the applied formulation later these plates are incubated for one day at 37^oC. Then the zone of inhibition of the organisms in the plate is tested and can be compared with the control. The study process should be done in the sterile area such as laminar air flow cabin. For obtaining proper results positive and negative controls should be maintained [35].

· Sterility studies:

After the formulation is prepared it is sent for sterilization and also sterilization is done if it is required in the intermediate steps of preparing the formulation. So for ophthalmic products the sterility testing is compulsory it is done in order to know about any viable bacteria is present in the final sterilized formulation. If it is found that any organism is present it can be again send back for sterilization or the batch should be cancelled.

· In vitro drug release studies:

These studies for the ophthalmic formulations can be assessed by using diffusion studies. Here, these studies can be performed by using dialysis cell apparatus (franz diffusion cell). This will be having donor compartment and receptor compartment and these two compartments can be separated by a cellulose membrane called cellulose membrane and this membrane is soaked in the simulated tear fluid overnight. The solution of the formulation can be incorporated into the donor compartment and the samples are taken from the receptor compartment and after the collection of the samples they are replaced with the same amount of simulated tear fluid [36]. The phosphate buffer oh pH 7.4 will acts as a simulated lacrimal fluid [37].

The conditions maintained are a proper magnetic stirrer is used for proper stirring and the temperature is maintained at 37±0.5^oC and the samples are collected for every one hour and the study is continued for six hours. And the obtained samples can be tested for the amount of drug or absorbance can be measured by using some spectrophotometric methods like UV-visible, HPLC etc. Dilutions of the obtained samples can be done if required and the dilution can be done by using some solvent. The amount of drug present is calculated by using the equation which is obtained from the calibration curve and from this the percentage cumulative drug release can be calculated. The information or data obtained can be fitted into the curves for drug release studies. The common plots used for this are fickian diffusion and korsmeyer -peppas model or kinetics [5, 8, 16, 38].

· Ex vivo studies:

This evaluation method is similar to the In vitro studies but here corneal membrane of goat is used instead of the synthetic semipermeable membrane. Cornea is removed from the eye of the goat carefully and washed properly with the cold saline and this tissue can be preserved in the simulated tear fluid prior to use. The test is carried out in the franz diffusion cell where donor and receptor compartments are present. The sample or the required quantity of the formulation is kept into the donor compartment. And the phosphate buffer of pH 7.4 is used as the simulated lacrimal fluid. Intimate contact should be maintained with the membrane and the fluid in the donor compartment. The temperature of the cell is maintained at 37⁰c and magnetic stirrer is used for continuous stirring and the samples are taken at specific time intervals and their absorbance can be measured [39].

· In vivo studies:

In this study the test animals used are rabbits the weight of each rabbit should be around 2.5 to 3kg. The rabbits should be healthy and should be devoid of any contamination. While using these test animals permissions should be taken and the guidelines of the ministry of social justice and empowerment and from the government of India should be followed. One eye of the rabbit can be served as the control and into the other eye the test sample is given which is around 50µL and the eye lids are closed for some time after the instillation into the eye mainly to avoid the drainage of the dosage form [40].

· In vivo scintigraphy studies:

In this study technique used is gamma scintigraphy. This technique is mainly used for the evaluation of the controlled release of ophthalmic formulation and to know about its retention time in the eye. Generally, the lab animals like rabbits are used in this study but preferably human volunteers can also be used as the physiology differences may exist when compared to human and other animals [41].

· Accelerated stability studies:

Accelerated stability studies can be done to know about half life and the stability of the formulation. In this the samples to be tested are selected from the respective batches and they are properly enclosed in the ambient colour container and these can be properly covered with aluminium foils. Accelerated stability studies can be done by maintaining the temperature at 40±2^°C and the percentage relative humidity is 75±5% as per ICH guidelines. Later the samples are taken and can be tested for all evaluation parameters like Appearance, pH, clarity, rheological studies, diffusion studies, drug content, gelling capacity etc.[42,8,43].

RESEARCH WORKS:

Following are the some of the works carried out on some of the drugs used to treat ophthalmic diseases based on in situ gel forming drug delivery:

· Moxifloxacin hydrochloride:

Moxifloxacin hydrochloride is the drug mainly used in the treatment of some infections occurred in the eye like conjunctivitis etc. It is formulated as the in-situ gel forming formulation by using sodium alginate and HPMC as polymers [44].

· Sesbania grandiflora:

It is an extract of flower which is also mainly used to treat some bacterial infections noticed in the eye. Here, the polymers used are pluronic F127 and chitosan where phase transformation takes place due to change in temperature [45].

· Dexamethasone and ciprofloxacin hydrochloride:

The use of ciprofloxacin is it acts as an antibiotic which is used to treat bacterial infections of the eye and dexamethasone is a potent anti-inflammatory drug used to treat inflammation caused during infection. To formulate this combination of drugs is gellan gum [46].

· Olopatadine hydrochloride:

Oloptadine HCl is the drug mainly used in the treatment of allergic reactions it is a class of anti-histaminic drug to formulate this drug as In-situ forming gel the polymers used are carbopol and HPMC E-50LV acts as a PH triggered system.

· Norfloxacin:

Norfloxacin is the drug which is mainly used to treat bacterial infections like conjunctivitis. The polymers used to formulate this drug are carbopol-940 and HPMC-E50LV and the formation of gel takes place due to pH change.

· Ketorolac:

Ketorolac is anon-steroidal anti-inflammatory drug. Here the polymers used are carbopol 940 and HPMC. Here also gel formation takes place due to the changes in Ph [47].

· Dorzolamide Hydrochloride:

This drug is mainly used in the treatment of glaucoma. The polymers used for formulating this drug are sodium alginate and Hydroxy propyl cellulose. The main mechanism involved in the formation of the gel is due to the presence of calcium ions in the lachrymal fluid [48].

· Ciprofloxacin:

Ciprofloxacin is mainly used for the treatment of eye infections like dacrocystitis, ulceration in cornea, conjunctivitis etc. The polymers used for formulating this drug are poly acrylic acid and HPMC [49].

· Voriconazole:

This drug is mainly used fungal keratitis which causes vision loss. It is a broad spectrum antifungal drug. the polymers used to formulate this drug are sodium alginate and HPMC K15M[50].

· Pilocarpine:

It is the drug which is used in the treatment of glaucoma. And the polymers used are sodium alginate which mainly consists of glucuronic acid residues which are helpful for the formation of gel in the presence of calcium ions [51].

Commercial formulation of ophthalmic drug based on in situ gel formation:

· Timoptic-XE:

This formulation is supplied from Merck and Co. Inc., which is sterile and buffered product and is isotonic with the eye. The drug present in this is Timolol maleate. It is mainly used to decrease the increased intra ocular pressure. Each ml of this solution contains 3.4mg of the drug. The other ingredients present in this are tromethamine, gellan gum, mannitol and water [52].

CONCLUSION:

In recent times several infections related to eye are rapidly increasing even though they are not so serious an action should be taken as the eye problems should need rapid recovery and relief from the symptoms. Hence, several types of dosage forms are formulated such that they should not cause any irritation to the eye and they should be comfortably administered as the eye is having secretions like lacrimal fluid which causes more loss of the drug and also naso-lacrimal drainage is present which leads to poor bio-availability and the contact time of the drug. So, in order to avoid these problems, the ophthalmic formulations can be generated as solution forms in which some polymers are included and these polymers can be useful for formation of gel when comes into contact with eye. Drugs used for several diseases like conjunctivitis; cataract can be formulated as In-situ gel forming dosage forms.

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Received on 01.08.2017 Modified on 22.08.2017

Research J. Pharm. and Tech. 2018; 11(1): 380-386.

DOI: 10.5958/0974-360X.2018.00069.0