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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA by c9t0f87l

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									RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
          KARNATAKA, BANGALORE.




                       M. PHARM SYNOPSIS

                  YEAR OF ADMISSION-JULY-2011



                     TITLE OF THE SYNOPSIS

  FORMULATION OF THERMALLY INDEPENDENT AQUEOUS BASED GELS OF
FLUCONAZOLE AND EVALUATION OF THEIR PHARMACEUTICAL PROPERTIES
                        AND STABILITY

                             BY
                       SANTOSH JOSHI
                      M. PHARM., PART-I
                DEPARTMENT OF PHARMACEUTICS



                   UNDER THE GUIDANCE OF
                     Dr. K. MANJUNATH. M.Pharm, Ph.D
                           PROFESSOR
                DEPARTMENT OF PHARMACEUTICS




                      INSTITUTION
      SREE SIDDAGANGA COLLEGE OF PHARMACY
              B. H. ROAD, TUMKUR-572 102
                      KARNATAKA
     RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA,
                           BANGALORE.

                             ANNEXURE-II

        PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION


1.    NAME AND ADDRESS OF     Mr. SANTOSH JOSHI
      THE CANDIDATE           I M. PHARMA
                              DEPARTMENT OF PHARMACEUTICS
                              SREE SIDDAGANGA COLLEGE OF PHARMACY
                              B.H. ROAD, TUMKUR- 572102
                              KARNATAKA




2.    NAME OF THE             SREE SIDDAGANGA COLLEGE OF PHARMACY
      INSTITUTION             B.H. ROAD, TUMKUR- 572102
                              KARNATAKA




3.    COURSE OF STUDY AND     MASTER OF PHARMACY IN PHARMACEUTICS
      SUBJECT




4.    DATE OF ADMISSION       JULY-2011




5.    TITLE OF THE TOPIC

    “FORMULATION OF THERMALLY INDEPENDENT AQUEOUS BASED GELS OF
 FLUCONAZOLE AND EVALUATION OF THEIR PHARMACEUTICAL PROPERTIES AND
                            STABILITY”



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6.0   BRIEF REVIEW OF THE INTENDED WORK

      6.1. NEED FOR THE STUDY

      The skin often has been referred to as the largest of the body organs. An average adults skin has
      surface area of about 2m2 and receives about one-third of the blood circulation through the body.
      Microscopically skin is composed of three main histological layers: epidermis, dermis and
      hypodermis (subcutaneous layer).

      Gels are semisolid systems that consist of either suspensions of inorganic particles or organic
      molecules interpenetrated by a liquid. Gels can either be water based (aqueous gels) or organic
      solvent based (organogels).1 Gels for dermatological use have several favorable properties such as
      being thixotropic, greaseless, easily spreadable, easily removable, emollient, nonstaining, compatible
      with several excipients, and water-soluble or miscible. Extensive studies on release properties have
      revealed that the active ingredients in gel based formulations are better percutaneously absorbed than
      cream or ointment bases.2 Within a major group of semisolid preparations, the use of transparent gels
      have expanded both in cosmetic and pharmaceutical preparations.3

      During course of studies different gel formulation of Fluconazole for topical application will be
      prepared by using different grades and proportions of fumed silica [colloidal silicon dioxide, Pharma
      Grade] and evaluated to give proper consistency. Many advantages of gels are there but a major
      limitation is in the delivery of poorly water soluble drugs like Fluconazole. So to overcome this
      limitation co-solvency based approach being used to improve the solubility so that even poorly water
      soluble drugs can enjoy the unique properties of gels.

      Fluconazole, a synthetic antifungal agent, is a triazole derivative. It is used in the treatment of
      oropharyngeal, esophageal, or vulvovaginal candidiasis as well as other serious systemic candidal
      infections. It is also effective against superficial fungal infections and dermatophytoses. Fluconazole
      is available commercially as tablets and injections only in spite of its well known adverse effects
      including nausea, vomiting, bloating and abdominal discomfort. Over the last decades gels formed
      from natural, semisynthetic or synthetic polymers have been confirmed as vehicles for different types
      of pharmaceutical applications. They have good viscosity, satisfactory bioadhesion, and are without
      irritating or sensitizing actions.4 A newly raised concern about the wide spread use of Fluconazole is
      the potential for development of azole resistant candia albicans and selection of non albicans candida
      species.



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Candidiasis is a fungal infection also commonly referred to as a yeast infection, candidiasis is also
technically known as candidiasis, moniliasis and oidiomycosis. Candidiasis encompasses infections
that range from superficial, such as oral thrush and vaginitis, to systemic and potentially life-
threatening diseases. Candida infections of the latter category are also referred to as candidemia and
are usually confined to severely immunocompromised persons, such as cancer, transplant and AIDS
patients as well as non-trauma emergency surgery patients. Superficial infections of skin and mucosal
membranes by Candida causing local inflammation and discomfort are common in many human
populations.5

Currently available gels like hydrogel or other gels have their physical stability issues as the
polymers tend to coagulate or degrade during storage in a temperature country like ours. It is also not
practical insist on storing such external preparations in refrigerator or cold condition. Formulation of
                                                                    6,7
gels using fumed silica considered to be thermally independent            as such gels do not change their
rheological properties even at high temperature.

The present formulation of gels is to overcome the stability problems associated with emulsion based
gel formulation like heat stability problem, cracking, phase separation, breaking. The aim of present
research work is to investigate the thermally independent gel and avoid need for emulsification.

The objective of present investigation is to develop thermally independent Fluconazole gel and study
effect of fumed silica (Colloidal silicon dioxide, Pharma grade) as a gelling agent on the stability,
parameters (e.g. Rheological stability, spreadability, performance in collapsible tubes and chemical
stability of drug ) adopting short term accelerated storage stability and challenged condition protocols
and during formulation studies co-solvency phenomenon will be studied to improve the aqueous
solubility of Fluconazole to the desired level suitable for external use.




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6.2. Review of Literature

Different amphiphilogel formulations of Fluconazole for topical application were prepared by using
sorbitan monostearate (span 60), tween80, tween20 and isoprpyl myristate. The formulated
Fluconazole were evaluated for physico-rheological characteristic drug content, pH, spredability.
Stability studies were carried out and results showed no separation of gel indicated overall stability.3

Colloidal silicon dioxide is widely used in oral and topical pharmaceutical products because of its
prominent function such as glidant, binder, suspending agent, thickening agent and adsorbent. Since
colloidal silicon dioxide is formed in the oxygen/hydrogen flame at temperature about 1800 C, it has
lower micro organism contamination and possesses higher thermal stability than other gelling
agents.6

Basic ferric sulphate or hydrated aluminium chloride solution used as haemostatic agent and is made
to easier to handle and apply by gelling with colloidal silicon dioxide. A gel for topical application as
a haemostatic agent containing essentially of a solution in water of basic ferric sulphate at a
concentration within the range 6 to 20% w/v Fe(III) and sufficient for haemostatic activity, the said
solution having a sufficient sulphate and colloidal silicon dioxide to gel the solution. In the presence
of silicon dioxide gel showed greatly reduced tendency to crystallize even on prolonged standing at
reduced temperature and also showed a reduced tendency to dry out.7

Formulation comprised of the mixture of complex colloidal magnesium aluminium silicate and
fumed silica dioxide powder in 10 to 1 ratio, comprises only about 11% by weight of the resultant
fluoride gel because of the apparent high viscosity imparted to the resultant composition by the
thixotropic gum constituent. It has been found that lesser quantity of this agent need to be employed
to obtain the desired degree of set up of the gel in mouth as compared to conventional non thixotropic
gelling agent.8

The microemulsion based topical drug delivery system of antifungal drug Fluconazole (0.5% w/w) in
order to bypass its gastrointestinal adverse effects and to improve patient compliance. The pseudo-
ternary phase diagrams were developed for combinations of isopropyl palmitate or light liquid
paraffin as the oil phase. The developed microemulsion based gel was characterized for pH,
spreadability, refractive index and viscosity. Optimized formulation was then subjected to in vitro
antifungal screening in comparison to available marketed gel formulation of Fluconazole (Flucos gel
0.5%). Centrifugation studies were carried out to confirm the stability of the developed formulation.


                                                                                                5
Formulation was thickened with a gelling agent carbopol 940, to yield a gel with desirable properties
facilitating the topical application.9

Topical gel formulation of terbinafine hydrochloride were prepared by using different types of
chitosan of different molecular weight and the antifungal inhibitory activity was evaluated to suggest
an effective formulation for treatment of fungi infection. The characteristics of gel formulation were
determined with viscosity measurement and texture profile analysis. Stability studies were performed
at different temperature during 3 months. The antifungal inhibitory activity of formulation on candida
species and filamentous fungi was also examined with agar method. A higher drug release and the
highest zone of inhibition were obtained from gels prepared with the lowest molecular weight.10

Topical formulations of griseofulvin than can deliver the drug locally in effective concentration,
various hydrogels formulation were prepared using carbomer (940NF) as base; essential oils,
propylene glycol (PG), N-methyl -2 pyrolidone (NMP) as penetration enhancer. Further combination
of PG with varying amount of NMP in the hydrogel formulations exhibited significantly greater
increase in the flux on comparison with the control and formulation containing PG alone. Further
these formulations were found to be stable at three different temperature 4, 25 and 40 c with respect
to percent drug content, release characteristics, pH, transparency, feel and viscosity.11

A stable aqueous hydrogen peroxide gel dentifrice for oral antijunjuvitis application having an acid
pH of about 3 to 6 were formulated with combination of hydrophilic and hydrophobic fumed silica
gelling agent, hydrogen peroxide, PEG, humectants, flavor, sweetening agent, sodium benzoate and
non ionic surfactant as essential ingredient.12

Gel based formulations of coal tar were developed with fumed silica effective for topically treating
skin conditions mainly psoriasis and excema. The gel prepared by weighing appropriate quantity of
crude coal tar which is then admixed with glcerylcocoate, retinoic acid and glycerin. The resultant
mixture as stirred into a beaker and colloidal silica and coecyl heroine are added. The stirring
continued for 30 minutes and a smooth uniform gel was obtained.13




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      6.3. Objective of the Study

      Following are the objectives of the present study

         1) The main objective of the present study is to formulate thermally independent aqueous based
             topical gel containing Fluconazole for antifungal action.
         2) To improve the aqueous solubility of Fluconazole by co-solvency phenomenon.
         3) To evaluate the formulated dosage form for their pharmaceutical properties.
         4) The best formulation will be subjected for stability studies.

7.0   MATERIALS AND METHODS

      Materials
      Drug                      : Fluconazole
      Solvent                   : Purified water
      Co solvents               : Sorbitol, glycerine etc.
      Gelling agent             : Different Grades of Fumed silica [Colloidal silicon dioxide, Pharma grade]

      Method.
      Fluconazole will be dissolved in different ratios of polyhydric alcohols like sorbitol, glycerine etc
      (co-solvent) with water and find out the highest solubility. Fluconazole thus dissolved to get desired
      percentage will be incorporated with different grades/ proportions of fumed silica (colloidal silicon
      dioxide), then disperse to get the intended gel.


      7.1. Source of Data

         a) Journals such as,
                1) International Journal of Pharmaceuticals.
                2) Egypt Journal of Biomed Science.
                3) American Association of Pharmaceutical Scientists.
          b) Indian drugs
          c) US Patents
          d) J-gate@Helinet
          e) Library: Siddaganga College of Pharmacy
          f) E-library: Siddaganga College of Pharmacy



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7.2. Method of collection of data


    1. Evaluation of solubility of Flucanazole by co-solvency phenomena using sorbitol, glycerine
      etc.
    2. Formulation of thermally independent aqueous based topical gel containing Fluconazole.
    3. Evaluation of the various pharmaceutical properties of prepared topical gel
      a) Physical examination
      b) pH
      c) Rheological properties ( Viscosity, Spreadability, Performance in collapsible tube,
         caking/hardening/softening at challenge temperature on storage)
       d) Drug content
     4. Best Formulation will be subjected for short term accelerated storage stability studies
      (As per ICH guide lines)
      a) Room Temperature
      b) 15-25C ± 2C
      c) 40C ± 2C and 75% RH ± 5%
      d) 50C ± 2C and 75% RH ± 5%
After completion of storage period all the samples will be analysed for all pharmaceutical properties
mentioned above 3.




7.3 - Does the study require any investigations or interventions to be conducted on patients or
        other humans or animals? If so, please describe briefly.


                                       “NOT APPLICABLE”




7.4 - Has ethical clearance been obtained from your institution in case of 7.3?



                                       “NOT APPLICABLE”



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8.0   REFERENCES

        1. Anand B, Pisal SS, Paradkar AR, Mahadik KR. Applications of organogels in
           pharmaceuticals. J Sci Ind Res 2001;60:311-8.
        2. Paranjothy KLK. Gels as topical application. Ind Drug 1994;31:224-8.
        3. Shivkumar L, Aakash SP, Gajanan D, Dinesh KJ. Formulation and evaluation of fluconazole
           amphiphilogel. Der Pharma Lett 2011;3:125-31.
        4. Mottaleb MMA, Mortada ND, Elshamy AA, Awad GAS. Preparation and evaluation of
           fluconazole gels. Egy J Biomed Sci 2007;3:1-21.
        5. Candidiasis. www.wikipedia.com. [updated 2011 May 20; cited 2001 Nov 7]. Available from:
           http://en.wikipedia.org/wiki/Candidiasis
        6. Toprasri P. Factors affecting physical properties and drug release from hydrophilic and
           hydrophobic colloidal silicon dioxide gels [Dissertation]. Univ of Silpakorn 2003.
        7. Whitefield M. Haemostatic agents. US patent 5,011,693. 1991 Apr 30.
        8. Weitzman S, Archibald RD. Thixotropic topical fluoride phosphate gel compositions useful
           for the prevention of dental caries. US patent 4,267,167. 1981 May 12.
        9. Jadhav KR, Shetye SL, Kadam UJ. Design and evaluation of microemulsion based drug
           delivery system. Int J Adv Pharm Sci 2010;1:156-66.
        10. Ozcan I, Abacl O, Uztan AH, Aksu B, Boyacloglu H, Guneri T et al. Enhanced topical
           delivery of terbinafine hydrochloride with chitosan hydrogels. AAPS Pharm Sci Tech
           2009;10:1024-31.
        11. Shishu, Agarwal N. Preperation of hydrogels of griseofulvin for dermal application. Int J
           Pharm 2006;326:20-24.
        12. Mei-King NS, DiTomasso DM. Stable hydrogen peroxide dental gel containing fumed silicas.
           US patent 4,839,157. 1989 Jun 13.
        13. Klein RW, Foxx ME. Coal tar gel composition. US patent 4,178,373. 1979 Dec 11.




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9.    SIGNATURE OF CANDIDATE




10.   REMARKS OF GUIDE                       RECOMMENDED


11.   NAME AND DESIGNATION
      OF

      11.1 GUIDE                  Dr. K. MANJUNATH, M. Pharm., Ph.D.
                                               Professor
                                       Department of Pharmaceutics


      11.2 SIGNATURE


      11.3 CO-GUIDE (If any)                   ------------------


      11.4 SIGNATURE                            -----------------


      11.5 HEAD OF                         Dr. Suresh V. Kulkarni,
           DEPARTMENT                         M. Pharm., Ph.D.
                               Professor & Head, Department of Pharmaceutics


      11.6 SIGNATURE




12.   12.1 REMARKS OF THE           Forwarded to university for approval.
           CHAIRMAN AND
           PRINCIPAL



      12.2 SIGNATURE


                                              (Dr. S. Badami)
                                                  Principal
                                    Sree Siddaganga College of Pharmacy
                                                   Tumkur


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