1.0 Brief resume of intended work:

1.1 Need for study:

Oral drug delivery is the simplest and easiest route of administrating drugs because of smaller bulk, accurate dosage, and easy production. Solid dosage forms have many advantages over other types of oral dosage forms. Therefore, most of the new chemical entities (NCE) under development these days are intended to be used in a solid dosage form that originate an effective and reproduciblein vivo plasma concentration after oral administration.1However, the formulation of poorly water-soluble drugs has always been a challenging problem faced by pharmaceutical scientists and it is expected to increase because approximately 40% or more of the NCE being generated through drug discovery programs have problem in water- solubility.2

Consequently, if these drugs are not completely released in the gastrointestinal area, they will have a low bioavailability.Therefore, drug release is a crucial and limiting step for drug bioavailability particularly for drugs with low gastrointestinal solubility and high permeability. By improving the drug release profile of these drugs, it is possible to enhance their bioavailability and reduce side effects. So the aim of the present work is to increase the solubility of a poorly water-soluble drug and dissolution rate.

Solid dispersions are one of the most successful strategies to improve drug release of poorly water-soluble drugs. The term solid dispersion has been utilized to describe a family of dosage forms, whereby the drug is dispersed in a biologically inert matrix, usually to enhance the oral bioavailability.3Several hydrophilic carriers like polyethylene glycol (PEGs), polyvinyl pyrrolidone(PVP), hydroxypropyl cellulose (HPC), β-cylodextrin etc have been investigated as inert matrices for enhancing solubility and dissolution rate.

In biopharmaceutical classification system (BCS) drugs with low aqueous solubility and high permeability drugs are categorized as class-II drugs. Mefenamic acid, a non-steroidal anti-inflammatory drug (NSAIDS) belongs to BCS class-II having low solubility and high membrane permeability.4,5 The bioavailability of mefenamic acid is low to elicit the required pharmacological effect, hence making it a suitable candidate for the proposed research work with an aim of improving its bioavailability.

1.2 Review of literature:

Sheen et al6studied the formulation of poorly water-soluble drug in solid dispersion to improve bioavailability. The results concluded that the bioavailability of poorly water-soluble drug was increased from water-soluble carrier and was further improved by the addition of a surfactant.

Derleet al7 studied in vitro and in vivo evaluation of mefenamic acid and its complexes with β-cylodextrin and HP-β-cyclodextrin. The studies indicated that the dissolution rate of the mefenamic acid with β-CD and HP-β-CD was much higher than that of mefenamic acid alone as a consequence of increased solubility and decreased crystallinity due to complexation and also reduced side effects.

Zerrouk et al8studied invitro and invivo evaluation of carbamazipine-PEG 6000 solid dispersions. The results showed an improvement in bioavailability profile of carbamazipine with solid dispersions.

Tantishaiyakulet al9studied the properties of solid dispersion of piroxicam in polyvinyl pyrrolidone K-30.The results concluded that solid dispersion exhibited better dissolution rates due to increase in drug wettability and the drug-PVP interaction.

Kim et al10studied preparation of a solid dispersion of felodipine using solvent wetting method. The dissolution rate of felodipine from PVP, HPMC, and poloxamer by solid dispersion was markedly improved.

Shararanet al11 studied dissolution enhancement of drugs, technologies and effect of carriers. It was concluded that the dissolution enhancement was due to complexation of the drug with suitable carrier alters the solubility and dissolution characteristics due to extremely highly aqueous solubility of the carrier.

Leonardi et al12studied development of prednisone-polyethylene glycol 6000 fast-release tablets from solid dispersion. They further evaluated effect of formulation parameters on solid state characterization and dissolution behavior. Solid dispersion of prednisone prepared with PEG-6000 by the solvent evaporation method resulted in greater increase in drug dissolution rate.

Torrado et al13studied preparation, dissolution and characterization of albendazole solid dispersion. The results showed enhancement of dissolution and the solubility coefficient of albendazole.

Sammour et al14studied formulation and optimization of mouth dissolving tablets containing rofecoxib solid dispersion. The study showed that the amorphization of rofecoxib offered a better dissolution rate from its solid dispersion.

1.3 Objective of study:

The objectives of the proposed study are:-

1.Preformulation study of the mefenamic acid and hydrophilic carriers

2.Investigation of the effect of carriers,and excipients concentrationon solubility and dissolution rate.

3.Effect of incorporation of co-exipicents on solubility and dissolution rate.

4.Stability studies of the selected solid dispersion as per ICH guidelines.

2.0 Materials and methods:

2.1 Source of data:

Preliminary data required for the experimental study would be obtained from scientific journals, books available at National College of Pharmacy library.

2.2 Method of collection of data:

Data on drug and excipients will be collected from the drug information center, standard books, catalogs etc. On the basis of extensive preformulation trials on he drug and exicipents, the final formulation will be developed.

i.Materials:

The materials required for the study like mefenamic acid, hydrophilic carriers or naturally derived polymers like chitoson or others will be selected based on preformulation studies, and other exicipents will be procured from commercial suppliers.

ii. Methodology

The solvent evaporation technique will be used for preparation of solid dispersion of mefenamic acid:-

In this method, drug is either dissolved or dispersed in solution of selected hydrophilic carrier in a suitable solvent and then the solvent is removed by evaporation. Solid dispersion obtained will be stored in air tight container until further use.

iii) Evaluation of prepared solid dispersion:

The prepared solid dispersion will be evaluated for solubility, drug content anddissolution. Drug-carrier interactions will be investigated using sophisticated procedures like Differential Scanning Calorimetry (DSC)and Fourier Transform Infrared Spectroscopy (FTIR).

2.3 Does this study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly.

No studies are intended to be performed on humans or animals.

2.4 Has ethical clearance been obtained from you in case of 2.3.

Not applicable.

3. References:

1Tiwari R, Tiwari G, Srivastava B, and Rai A.K. Solid dispersion: An overview to modify bioavailability of poorly water-soluble drugs. Int. J. Pharm. Tech.. Res., 2009;1:1338-1349.

2Kumar N, Jain A.K, Singh C, Agarwal K, Nema R.K. Development, characterization and solubility study of solid dispersion of terbinafine hydrochloride.Int. J. Pharma Sci and Nanotech., 2008;1:171-176.

3Choudhary D, Kumar S, Gupta G.D. Solubility enhancement of glipizide by solid dispersion (kneading) technique. Asian J. Pharm., 2009;3:245-251.

4Fruiitwala‌ M.A, Dondeti‌ P, Alkhawam‌ E, Ahmed S. Rationales in the development of dissolution testing for solid oral dosage forms - an industrial, biopharmaceutical and regulatory perspective. Clin. Res. Reg. Aff., 1998;15:187-207.

5Taub M.E, Kristensen L, Frokjaer S. Optimized condition for MDCK permeability and turbidimertic solubility studies using compounds representative of BCS class I-IV. Eur. J. Pharm. Sci., 2002;15:331-340.

6Sheen P, Khetarpal V.K, Cariola C.M, Rowlings C.E. Formulation studies of a poorly water-soluble drug in solid dispersion to improve bioavailability. Int. J. Pharm., 1995;118:221-227.

7Derle D.V, Bele M, Kasliwal M. In vitro and in vivo evaluation of mefenamic acid and its complexes with β-cylodextrin and HP-β-cyclodextrin. Asian J. Pharm., 2008;30-34.

8Zerrouk N, Chemtob C, Arnaud P, Toscani S, Dugue J. In vitro and in vivo evaluation of carbamazipine-PEG-6000 solid dispersions. Int. J. Pharm., 2001;225:49-62.

9Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of solid dissolution of piroxicam in polyvinyl pyrrolidone K-30. Int. J. Pharm., 1996;143:59-66.

10Kim E, Chun M, Jang J, Lee I, Lee K, Choi H. Preparation of a solid dispersion of felodipine using solvent wetting method. Eur. J. Pharm. Bio.,2006;64:200-205

11Shararan V.A, Kulkar V, Katara M, Gera M, Choudhury P.K. Dissolution enhancement of drugs. Part 1: Technologies and effect of carriers. Int. J. Hea. Res., 2009;2:107-124.

12Leonardi D, Barrera M.G, Lamas M.C, Salomon C.J. Development of prednisone-polyethylene glycol 6000 fast-release tablets from solid dispersion: solid-state characterization, dissolution behavior, and formulation parameters. AAPS PharmSciTech., 2007;8:108:E1-E7.

13Torrado S, Torrado J, Cadorniga R. Preparation, dissolution and characterization of albendazole solid dispersion., Int. J. Pharm., 1996;140:247-250.

14Sammour O.A, Hammad M.A, Megrab N.A, Zidan A.S. Formulation and optimization of mouth dissolving tablets containing rofecoxib solid dispersion. AAPS PharmSciTech., 2006;7:55:E1-E9.

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