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     Need of Study:
             The design of effective formulations for drugs has long been a major
     challenge, because drug efficacy can be severely limited by instability or poor
     solubility in the vehicle. Colloidal dispersed systems are one of the most promising
     technologies, which are being applied to enhance the solubility and bioavailability of
     lipophilic drugs1.
             Colloidal systems have attracted wide attention as novel drug carrier systems
     and are being enthusiastically pursued by both academia and industry since the early
     1990s. Colloidal drug carriers such as micro- and nanoemulsions combine the
     advantages of polymeric nanoparticles, fat emulsions and liposomes simultaneously,
     at the same time avoiding some of their major disadvantages. They have great
     potential of drug delivery applications, particularly for certain chronic therapies,
     where controlled release, maintenance of therapeutic plasma drug level for prolong
     time results in reduction in frequency of dosing, increased patient compliance,
     increased safety and improved therapeutic efficiency2.
             Poor bioavailability can be due to poor solubility, degradation in GI lumen,
     poor membrane permeation and presystemic elimination. By many estimates up to
     40% of new chemical entities (NCEs) discovered by the pharmaceutical industry
     today and many existing drugs are poorly soluble or lipophilic compounds that leads
     to poor oral bioavailability, high intra- and inter-subject variability and lack of dose
     proportionality. Most of these drugs have been classified into BCS Class II. They
     have high epithelial permeability, but suffer from dissolution rate limited
     bioavailability problems, primarily due to their poor solubility3.
              Hence, in the envisaged investigation, we will try to design, formulate and
     evaluate a suitable colloidal dispersed system in the form of micro-/nanoemulsion /
     micellar systems / cubic phases of model drug(s) such as carbamazepine /carvedilol/
     ketoconazole /pyroxicam/ketoprofen/ibuprofen/flurbioprofen/naproxen etc.

     Objective of Study:

             The aim of the present work is to design and develop a colloidal dispersed
     system of a model BCS class II drugs.
            Broadly, the work would attempt to-
          Screen the excipients for the formulation of the proposed drug delivery
          Preparation of the colloidal dispersion system.
          Evaluation of colloidal dispersion system, in vitro.
          Predicting the release pattern as per the pharmacokinetic need.
          Optimize the formulation using suitable experimental design, w.r.t particle
            size, stability, release characteristics, surface properties, charge, lipid loading,
          Short-term stability study of the optimized formulation.
          If time permits, the developed formulation would be subjected to in vivo
            studies in appropriate animal models.
Review of Literature:

        With the cost of new drug development skyrocketing, focus is being
increasingly shifting to development of new delivery system to rejuvenate the so-
called older drugs. It appears that one of the best strategies to develop novel delivery
systems in order to improve the efficacy, specificity, tolerability and therapeutic
index of existing therapeutic agents are colloidal dispersed systems4.

        Many therapeutically active molecules are chemically and biologically
fragile, so they need to be encapsulated in a drug carrier system. These systems
protect the loaded drug against degradation and the active molecule can be
transported effectively in biological media. The research impetus in this field is
presently concentrated on colloidal dispersed systems. The development of such
systems including micelles, liposomes, micro and nanoparticles, micro and nano
emulsions, etc., aims to improve the bioavailability and the therapeutic efficacy of
active molecules against their targets like carbamazepine, ramipril, furosamide,
ubiquinone, nimesulide,etc5.

        In recent years, attention has been focused on emulsions with sub
micrometer droplet size that is with sizes between those of conventional emulsions
and microemulsions. These emulsions have been termed mini-emulsions, nano-
emulsions, fine-disperse emulsions, submicron emulsions, unstable microemulsions,
translucent emulsions, and so forth. Because of their small droplet size (typically
between 20 and 500 nm), nanoemulsions may appear transparent and are stable
against sedimentation or creaming. They have the appearance of microemulsion;
however, require far less surfactant concentration for their preparation6.

        Nanoemulsions can be defined as oil-in-water (o/w) emulsions with mean
droplet diameters ranging from 50 to 1000 nm. Usually, the average droplet size is
between 100 and 500 nm, particles can exist as water-in-oil and oil-in water forms.
They do not show the problems of inherent creaming, flocculation, coalescence
sedimentation and also are non-toxic, non-irritant hence can be easily applied to skin
and mucous membranes without damage to healthy human and animal cells hence
are suitable for human and veterinary therapeutic purposes7.

         The influence of the vehicle on the release and permeation of fluconazole, a
topical antifungal drug dissolved in Jojoba oil was evaluated. Series of
Cutinalipogels like cetyl palmitate, mixture of glyceryl stearate, cetearyl alcohol,
cetyl palmitate, and cocoglycerides, glyceryl stearate, and glyceryl monostearate in
different concentrations as well as gel microemulsion were prepared. In-vitro drug
release in Sorensen's citrate buffer (pH 5.5) and permeation through the excised skin
of hairless mice, using a modified Franz diffusion cell, were performed8.
         The potential application of highly biocompatible o/w microemulsions as
topical drug carrier systems for the percutaneous delivery of anti-inflammatory
drugs, i.e. ketoprofen, was investigated. Microemulsions were made up of
       triglycerides as oil phase, a mixture of lecithin and n-butanol as a surfactant/co-
       Surfactant system and an aqueous solution as the external phase. To evaluate the
       Percutaneous enhancing effect of oleic acid, this compound was used as a component
       of some o/w microemulsions. The topical carrier potential of lecithin-based o/w
       microemulsions were compared with respect to conventional formulations, i.e. a w/o
       emulsion, an o/w emulsion and a gel9.

              Baboota S et al.10 have developed celecoxib nano-emulsion to improve
       transdermal penitrarion trough skin using sefsol 218 and triacetin as oily phase,
       tween-80 and transcutol-p as a surfactants and double distilled water as a continuous

               Self-nanoemulsifying drug delivery systems (SNEDDS) are isotropic
       mixtures of oil, surfactant, co-surfactant and drug that form fine oil-in-water
       nanoemulsion when introduced into aqueous phases under gentle agitation and there
       are several other methods of preparing nanoemulsion. e.g. Date AA and his friends11
       have formulated self emulsifying drug delivery system (SNEDDS) for a poorly
       soluble (400 µg/ml) and poorly bioavailable (50%) antibiotic cefpodoxime proxetil.
       Also they evaluated potential of submicronic emulsions of medium chain mono-, di-
       and tri-glycerides in improving the oral bioavailability of CFP.

               The systemic use of colloidal carriers is limited by the presence of the
       reticulo endothelial system (RES), which recognizes them as foreign products and
       quickly removes them from blood circulation [e.g. hydrophobic polymeric
       nanoparticles are efficiently cleared from circulation (about 90% in a few minutes)].
       Various attempts have been made to achieve long blood circulation times by
       avoiding RES recognition, mainly by attaching or adsorbing appropriate hydrophilic
       polymers (pegylation) or molecules at the particle surface to minimize the interaction
       with opsonins to provide so called stealth mechanism12.

Materials & Methods:

       Source of Data:
               Data will be obtained from Pubmed, Science Direct, Medline, US patent
       office website and other Internet facilities, literature search and related articles from
       library of Krupanidhi College of Pharmacy and Drug Information Centers.
Method of Collection of Data (including sampling procedure, if any):
        Data on drugs will be collected from drug information center, standard
books, physicochemical database and literature search. Extensive Preformulation
trial provides the basis of selecting the excipients and system for final formulation
development. Experimental design assisted replicated experiments would generate
other data pertinent to the formulation under investigation.
Such methodology will be -
     1. Selection proposed formulation technique.
     2. Selection of lipid, emulsifier(s), and co-emulsifier(s) in suitable molar /
        weight percentage ratio, dispersion medium from different physiologically
        accepted and GRAS listed excipients.
     3. Formulation of proposed colloidal dispersion system.
     4. Evaluation of physicochemical parameters of the colloidal dispersion – like
        particle size, zeta potential, drug loading and entrapment efficiency, drug
        release, stability study etc.
     5. Optimization of the system based on above physicochemical data.
     6. ICH guidelines will be followed for carrying out the stability studies.
     7. Rat / mice models will be used to assess the PK/PD of the formulation.

7.3 Method of Screening:
Does the study require any investigations or interventions to be conducted on
patients or other human or animals ? If so please describe briefly:

        Yes. The study needs evaluation of colloidal dispersed system managed by
     Model bcs class II drugs. If time permits test will be carried out on isolated
     intestine of Rat/mice.

Has the Ethical Clearance been obtained from your Institution in case of above?

        YES, Form B has been submitted to the institutional animal ethics committee
     for necessary clearance.


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      Formulation Development and Optimization Using Nanoemulsion
      Technique: A Technical Note. AAPS PharmSciTech 2007; 8(2) Article 28.
   2. Vyas SP, Khar RK. Nanoparticles In Target And Controlled Drug Delivery.
      1st ed. New Delhi: CBS Publishers & Distributors; 2004.
   3. Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M.
      Development and Bioavailability assessment of ramipril nanoemulsion
      formulation. Eur J Pharm Biopharm 2006 [Article in Press].
   4. Date AA, Joshi MD, Patravale VB. Parasitic diseases: Liposomes and
      Polymeric nanoparticles versus Lipid nonoparticles. Advance drug delivery
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5. Shahgaldiana P, Quattrocchia L, Gualberta JM, Colemana AW. AFM
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7. http://www.pharmainfo.org/pharma-student-magazine/nanoemulsions.
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    PharmSciTech 2002;3(4):E35.
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    microemulsions for the topical administration of ketoprofen: percutaneous
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    celecoxib. Acta Pharm 2007;57: 315–32.
11. Date AA, Nagarsenkar MS. Design and evaluation of self-nanoemulsifying
    drug deliverysystems (SNEDDS) for cefpodoxime proxetil. Int J Pharm
    2007; 329:166–72.
12. Bocca C, Caputo O, Cavalli R, Gabriel L, Miglietta A, Gasco MR. Phagocytic
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    Pharm 1998;175:185-93.

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