INTRODUCTION:

Vaginal drug delivery systems are traditionally used to deliver contraceptive and drugs to treat vaginal infection. However, vaginal drug delivery is not limited to these drugs as vagina has promise as a site to topically deliver drugs which will be absorbed systemically, because of the dense blood vessels network in vaginal wall.¹

Vaginal drug delivery has more advantage over other routes of transdermal and transmucosal drug delivery. Vaginal drug delivery has also more advantages over oral route, because intra-vaginal drug delivery avoids hepatic first-pass metabolism, gastrointestinal side-effects and improves the user compliance also.²

Mucoadhesive polymers are used to increase the contact time between the vaginal gel and vaginal mucous membrane, so it provides the drug release from formulation for longer period of time in vagina.³

In recent years vaginal bioadhesive preparations have been developed as a new type of controlled release form for the treatment of both topical and systemic diseases. The greatest advantage of such dosage forms is the possibility of maintaining them in the vagina for extended period of time including day hours and night, thereby enabling lower dosing frequencies.³

A gel is an apparently solid, jelly-like material from a colloidal solution. By weight, gels are mostly liquid, yet they behave like solids due to the addition of a gelling agent.⁴

TYPES OF GELS⁴:

There are three types of gels used for vaginal therapy, these are Hydrogels, Organogels and Xerogels.

MATERIAL AND METHODS:

MATERIALS:

1) Selection of Drugs⁵:

For the preparation of micro-particulated intra-vaginal gel, the drug should have the following characteristics:

· Drugs having short half- life are suitable for the preparation of vaginal gel.

· Drugs having hepatic first-pass metabolism are suitable for vaginal gel.

· Drugs having hepato-gastric side effects are suitable for the preparation of gel.

· For the preparation of gel drugs should have better lipid as well as water solubility.

2) Selection of Polymers³:

An ideal polymer for mucoadhesive drug delivery system should have the following characteristics:

· The polymer and its degradation products should be non-toxic and non-absorbable from the GI tract.

· It should be non-irritant to the mucous membrane.

· It should preferably form a strong non-covalent bond with the mucin-epithelial cell surfaces.

· It should adhere quickly to moist tissue and should possess some site specificity.

· It should allow easy incorporation of the drug and offer no hindrance to its release.

· The polymer must not decompose on storage or during the shelf-life of the dosage form.

· The cost of the polymer should not be high so that the prepared dosage form remains competitive.

METHOD OF PREPARATION OF MICRO-PARTICLES^6,7,9,12:

There are so many methods are given here for the preparation of micro-particles:

· Single emulsion – solvent evaporation method.

· Double emulsion – solvent evaporation method.

· Particle precipitation by solvent partitioning.

· Spray drying method.

· Supercritical fluid extraction method.

· Ionic gelation method.

· Coacervation method.

· Cross-linking method.

From above these methods, solvent evaporation is the best method for the preparation of micro-particulates, because it provides more yield as compare to others. This method produces reproducible micro particulates with better micromeritic analysis.

EVALUATION OF MICRO-PARTICULATES:

For the evaluation of micro-particulates some of the parameters are given below:

· Percent yield estimation.

· Particle size analysis.

· Drug content estimation.

· Drug entrapment efficacy.

· Micromeritic analysis.

· In-vitro drug release study.

· In-vivo drug release study.

· Drug interaction studies.

1) Percent yield estimation^8,9:

For the estimation of percent yield following relationship used:

% Yield = Micro-particles from each batch (W₁) / Total weight of drug and polymers used (W₂) x 100.

2) Particle size analysis⁹:

For the analysis of micro-particulates optical microscopy method should be used, because all micro-particles follow the micron range means within the range of 50nm-2mm. Equation for the determination of micro-particles size distribution using calibrated stage micrometer (µm) in optical microscopy method:

Xg = 10 x [(n_i x log X_i) / N]

Where, Xg is geometric mean diameter, n_i is the number of particles in micron range, X_i is mid point of range and N is the total number of particles.

3) Drug content estimation^8,9:

Drug loaded micro-particles (50 mg) were powdered and suspended in 50 ml of dissolution medium and kept for 24 hrs. Then stir for 5 minutes and filter. Drug content in the filtrate should be determining spectrophotometrically (UV-Spectroscopy).

Percent drug content = Conc. of Drug x Pipette ml x Dilution factor x 100.

4) Drug Entrapment efficiency^8,9:

Drug Entrapment Efficiency (DEE) should be estimated by using following relationship:

Drug Entrapment Efficiency (DEE) = Practical Content (PC) / Theoretical Content (TC) x 100.

5) Micromeritic Analysis:

The terms angle of repose, Carr’s index, Bulk density and Hausner’s ratio comes under the micromeritic analysis.

· Angle of Repose (θ)⁹:

For the determination of angle of repose funnel method should be used. In this method firstly micro-particles poured through a funnel that can raised vertically until a maximum cone height (h) was obtained. Radius (r) of the heap was measured and angle of repose (θ) should be calculated by using following relation:

θ = tan^-1 (h / r)

· Bulk Density⁹:

Tap the product using bulk density apparatus for 100 times in a cylinder and measured the volume changes. Calculate the Carr’s index and Hausner’s ratio by using formula:

Carr’s Index (%) = [Tapped Density (D_f) – Poured Density (D_o) / Tapped Density (D_f)] x 100

Hausner’s ratio = Tapped (D_f) / Poured Density (D_o)

Where, Poured Density (D_o) in g/cc and Tapped Density (D_f) in g/cc.

In Carr’s index, value below 15% indicates good flow characteristics of powder, whereas above 25% indicates poor flow ability. Lower Hausner’s ratio (< 1.25) indicates better flow properties than higher Hausner’s ratio (> 1.25).

· In-vitro Drug Release Study^9,10:

In-vitro drug release study should be carried out by using Basket type apparatus (i.e.USP Type-I apparatus) using acetate buffer pH 4.7 as dissolution medium. For dissolution purpose volume should used 900 ml and temperature should maintained at 37±1˚C. Rotating speed should maintain at 50 rpm and 5 ml of sample should withdraw and replaced with 5 ml in the interval of 1 hr. After filtration of sample, should analyzed by using UV-Visible spectrophotometer at scanned wavelength of drug.

· In-Vitro Drug Release Kinetic Study^9,10:

In order to study exact mechanism of drug release from micro-particles, drug release data was analyzed according to zero order, first order, Higuchi square root model and Korsmeyer- peppas model. Selection of most appropriate model should be based on goodness of fit test.

· Drug Interaction Study^9,10:

For dug interaction (Drug-Polymer interaction) study Fourier Transform Infrared Radiation (FTIR), Differential Scanning Calorimetric (DSC), Differential Thermal Analysis (DTA), UV-spectroscopy, etc. should be used.

· Scanning Electron Microscopy (SEM)¹⁰:

This study is used to find out surface characteristics of micro-particles.

ELECTION OF MICRO-PARTICLES^13,15:

Selection of micro-particles should be on the basis of best In-vitro drug release kinetic study, micromeritic analysis of drug and drug interaction study.

PREPARATION OF MICRO-CAPSULATED GEL^13,15:

Selected batches of drug micro-particles were incorporated in gels by mechanical stirring method using different types of bioadhesive polymers like carbopol 934, carbopol 940, HPMC, chitosan, etc. with other formulation additives. Prepared gel should be packed in wide mouth glass bottles or wide mouth plastic should be jars covered with screw capped plastic lid after covering mouth with an aluminum foil. It should be kept in cool place for further study.

EVALUATION OF MICRO-CAPSULATED GEL:

For the evaluation of micro-particulated gel different parameters should be covered:

· Estimation of drug in vaginal gel.

· Drug content uniformity.

· Determination of pH of vaginal gel.

· Determination of spreadability.

· Extrudability study.

· Swelling index.

· Vaginal irritation test.

· In-vitro drug diffusion studies of micro-capsulated vaginal gel.

· Drug release kinetic study.

· Vaginal bioadhesion measurement.

· In-vivo drug diffusion studies of micro-capsulated vaginal gel.

· Stability studies.

1) Estimation of Drug in Vaginal Gel¹¹:

Accurately weighed vaginal gel (1g) suspended into 100 ml of suitable vaginal fluid (SVF). Then filter it after constant stirring and analyzed by using UV-Visible spectrophotometer after suitable dilution at scanned wavelength.

2) Drug Content Uniformity^9,11:

Initially the formulations should be tested for homogeneity by visual inspection. To further ensure homogeneity of drug content in formulation of gel, six tubes samples from different locations in mixer and assayed for the drug content using UV-Visible spectroscopy. Each test should be repeated atleast for three times.

3) Determination of pH^11,15:

Digital pH meter is used for the determination of pH. Dissolve the one gram of vaginal gel in 25 ml of distilled water and then dip the electrodes into this gel formulation for some time and note the constant reading. The measurements of pH of each gel formulation should be repeated for three times.

4) Determination of Spreadability¹⁵:

For the determination of spreadability excess of sample apply in between two glass slides and compress to uniform thickness by placing 100 gm weight for 5 minutes. Weight (50 gm) adds to the pan. The time require to separate the two slide, i.e. the time in which the upper glass slide moves over the lower plate is take as measure of spreadability(s).

S = ml / t

Where, m = Weight tide to upper slide, l = length move on the glass slide, t = time taken.

5) Extrudability Study¹⁶:

In this test, a closed collapsible tube containing above 20 grams of gel pressed firmly at the crimped end and clamp applied to prevent any roll back. Remove the cap and extrude the micro-particulated gel until pressure dissipated.

6) Swelling Index^9,11:

Swelling index plays an important role in drug release pattern as greater the swelling, easily the drug will release from the gel microspores. Determine dynamic swelling property of vaginal gel of different drug: polymer ratios in suitable vaginal fluid (SVF). Weigh 1 gm of vaginal gel and place in SVF for 6 hrs, then scrap the gel with filter paper and weigh the wet swollen gel. First blotting gels with filter paper to remove absorbed water on surface and then it immediately weigh on the balance. Time interval for weight taken should be predetermining (i.e. 0.5, 1.0, 2.0, 4.0 and 6.0 hrs). For calculation of swelling index formula is:

Swelling Index (Sw) % = [(Wt - Wo) / Wo] x 100

Where, (Sw)% = is percentage of swelling of vaginal gel,

Wt = is weight of swollen gel after time t,

Wo = is initial weight of gel at zero time.

Test for swelling index of all formulations should be repeated for three times.

7) Vaginal Irritation Test^14,15:

For vaginal irritation study rabbits (like New-Zealand white female rabbits) are suitable animal having large size of vagina and easily available. All gel samples should be tested for vaginal irritancy for atleast 48 hrs. After removing gel from vagina, site of vaginal epithelium should be tested. Then note if any irritancy sign observed on vaginal epithelium by using vaginal gel.

8) In-vitro drug diffusion studies of micro-particulated vaginal gels^11,15:

KC-Diffusion cell is used for in-vitro drug release study of gel by using suitable vaginal fluid (SVF) as diffusion medium. The processed cellophane membrane should be used, simulating the vaginal in-vivo condition like vaginal epithelial barrier. Withdraw the sample and estimate the drug content present in the gel by using UV-Visible spectrophotometer at scanned wavelength. Same method should be used for batch of micro-particulated vaginal gel.

9) Drug Release Kinetic Study^11,13:

In order to study exact mechanism of drug release from micro-particulated gels, drug release data should be analyzed according to zero order, first order, Higuchi square root and Korsemeyer-Peppas equations. Selection of most appropriate model should be on the basis of goodness of fit test.

10) Vaginal Bioadhesion Measurements¹⁷:

For the bioadhesive measurement of vaginal gel modified balance method should be used intact with mucosal membrane of goat vagina for in-vitro study.

11) In-vivo drug diffusion studies of micro-capsulated vaginal gel¹⁴:

For in-vivo drug diffusion studies rabbits (like New-Zealand white female rabbits) should be used, because the size of rabbit vagina is large and easily available. For this study apply vaginal gel on rabbit vagina with the help of applicator. Withdraw blood samples in predetermined interval of time and then estimate the concentration of drug in blood plasma by using C₁₈ column in HPLC.

12) Stability Studies¹⁵:

Formulated gel preparations should be kept at different temperature condition like ambient temperature (room temperature), 8 ± 1˚C, (refrigerator temperature), 45 ± 2˚C at 75% ± 5% R.H. ( condition of accelerated stability testing) for span of three months. The following parameters of the gel such as color, pH, viscosity and drug content should be test.

CONCLUSION:

The present study gives an overview of definition of gel, types of gel, selection of drug and selection of polymers as necessary for an understanding of function of mucoadhesive intra-vaginal gel. The present study gives an overview of preparation and evaluation of intra-vaginal gel. All the parameters used for evaluation of intra-vaginal gel are discussed here. Selection of microcaparticulate formulation on the basis of different evaluation parameters is discussed. Preparation of intra-vaginal gel by using different types of bioadhesive polymers is also discussed. Different types of parameters are also discussed here used for in-vivo and in-vitro study of intra-vaginal gel. In conclusion, intra-vaginal gel drug delivery is the best for drug delivery into vagina, method of preparation and evaluation of intra-vaginal gel is easier. This intra-vaginal gel drug delivery has more advantage over other routes, it avoids hepatic first-pass metabolism of drug, and it also avoids the hepato-gastrointestinal side effects and improves the user compliance. Drugs given as intra-vaginal gel drug delivery are more effective over oral route of drug administration, because this intra-vaginal gel drug delivery has more advantage over others.

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Received on 17.11.2008 Modified on 28.12.2008

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 48-51