PREPARATION, CHARACTERIZATION AND IN VITRO EVALUATION OF SOLID DISPERSIONS CONTAINING NEVIRAPINE

ENCLOSURE – I

6) BRIEF RESUME OF THE INTENDED WORK:

6.1)NEED FOR THE STUDY :

Oral drug delivery is the simplest and easiest way of administering drugs. But the major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility.Hence the formulation of poorly soluble compounds for oral delivery is the most challenging aspectsin the pharmaceutical industry. In case of poorly water soluble drugs, dissolution is the rate limiting step in the process of drug absorption. So, bioavailability problems are prevalent with extremely hydrophobic drugs (aqueous solubility < 0.1 mg / ml at 370 C) due to erratic or incomplete absorption from GIT.1Thus improvement of aqueous solubility in such case is valuable goal to effectively formulate them into bioavailable drugproducts. Various techniques have been used to improve the solubility/dissolution rate of poorly water soluble drugs.2,3 Amongthem, the solid dispersionsareone of the most attractive techniques to improve the poor aqueous solubility of drugs.

Nevirapine isan antiretroviral drugthatis currently used in the treatment of human immunodeficiency virus type1 (HIV-1)infections.4,5The model drug belongs to Biopharmaceutical Classification System (BCS) class II (low solubility/high permeability), poses a challenge in achievement of optimal dissolutionkinetics from the dosage form.6 Drug release is a crucial and limiting step for oral drug bioavailability,particularly for drugs with low gastrointestinal solubilityand high permeability. Hence this work is planned to improve dissolution characteristicsof the model drug by increasing its release and solubility through solid dispersion technique.

ENCLOSURE – II

6.2)REVIEW OF LITERATURE :

1)Serajuddin ATM, 3 reviewed various literatures in an attempt to bring together the various publications and ideas associated with solid dispersion techniques. He gave details of recent approaches such as the use of surface active carriers and use of melt extrusion of PVP dispersions as a means of manufacturing viable dosage forms using solid dispersion technology.

2)Moneghini M et al 7 designed atenolol tablets using solid dispersions of atenolol and different polymers such as povidone (PVP), crosspovidone (PVP-CL), polyvinylpyrrolidone/vinylacetate (PVP/VA), and Eudragit®E. The physical properties of solid dispersions and physical mixtures were analyzed using X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubility and the release rate of atenolol from solid dispersions were compared to the drug alone. The influence of various parameters (type of polymer, drug to polymer ratio, pH) on the solubility and dissolution rate of the drug was also evaluated. They reported that dissolution rates were considerably improved from solid dispersions of atenolol with PVP and PVP-CL.

3)Mohammed GA et al 8coprocessedtwo activepharmaceutical ingredients (APIs), nevirapine (NVP) and stavudine(STV), by spray drying technique to overcome the respective problemsof poor solubility and poor content uniformity. The coprocessedproduct (NVP-STV CP) and untreated APIs werecharacterized by powder X-ray diffraction (PXRD), differentialscanning calorimetry (DSC), scanning electron microscopy (SEM),particle size, surface area analysis, compressibility, and solubility.Coprocessing enhanced NVP solubility by ∼1.5 fold over that of the pure NVPand STV demonstrated content uniformity in the powder blend.The coprocessed product was then formulated into 3 drug fixeddose combination (FDC) tablets with lamivudine (LMV), whichgave an enhanced in vitroNVP drug release compared with the control formulation toassure a quality antiretroviral formulation.

4)Maria DV and Fakhrul A 9studied the dissolution behaviour of tolbutamide–β-cyclodextrin inclusion complex in demineralised water and in aqueous solution of different surfactants like polysorbate 20, poloxyl 23-lauryl ether, and sodium lauryl sulphate. The study revealed that the presence of surfactant with proper shape and structure in the dissolution media or in the formulation containing tolbutamide–β-cyclodextrin inclusion complex could give rise to an unexpected dissolution profile.

5)Van Eerdenbrugh B et al 10prepared, characterized and evaluated sucrose co-freeze–dried nanopowders ofpoorly soluble anti-HIV agent loviride to improve the dissolution and absorption properties. Tween 80/poloxamer 188-stabilized nanosuspensions were produced on a laboratory scale using media milling.The study revealed that dissolution rate of loviride from the nanopowders was excellent. Based on the results, they reported that a Caco-2 experiment on the nanopowder showed a significantly higher cumulative amount transported after 120 min (1.59±0.02 μg) compared to the physical mixture (0.93±0.01µg) and the untreated loviride (0.74±0.03µg).

6)Van Gyseghem E et al11developed powders for reconstitution of TMC278,rilpivirine (the next-generation non-nucleoside reverse transcriptase inhibitor, NNRTI) to providepotential dry formulations by spray drying. They formulated TMC278 as solid dispersions using one or more water-soluble carriers like HPMC 2910 5 mPa s, PEG 6000, PVP-VA 64, PVP K-25 and Kollicoat IR.After the initial developmentof six selected powders for reconstitution, two formulations werepreferred based on the results of ease of applicability and dissolution:TMC278/PVP-VA 64 1:9 (w/w) (PFR3) and TMC278/PVP-VA64/Cremophor EL 1:8.5:0.5 (w/w/w) (PFR6). Both powders showed ease of suspendability, nearly complete dissolution of the drug(around 93%) andacceptable stability after one month storage at 25 and 40C.

ENCLOSURE – III

6.3)OBJECTIVES OF THE STUDY :

The present work is planned with the following objectives:

  1. To prepare solid dispersion system consisting of model drug, carrier (water soluble polymer) in different drug-polymer ratios by employing different methods.12
  2. To study the physicochemical properties of prepared solid dispersions.
  3. To study invitro drug release profiles.
  4. To study the influence of polymers on drug release characteristics.
  5. To study the effect of thedrug-polymer ratioon dissolution characteristics.
  6. To study the effect of the preparation methods on dissolution characteristics.
  7. To study the influence of nature of a surfactant in the dissolution media over release behaviour of the model drug from its solid dispersions.

ENCLOSURE – IV

7) MATERIALS AND METHODS:

7.1) SOURCE OF DATA:

The data will be collected by conducting various experiments and investigations in the laboratory and recording the observations. The secondary data will be collected by referring various national and international journals, books, Pharmacopoeiae and professional websites like helinet, pubmed etc.

ENCLOSURE –V

7.2) METHOD OF COLLECTION OF DATA

1)Instruments like dissolution apparatus, SEM, UV Spectrophotometer will be used to record the observations.

2) Drug – excipients (polyethylene glycols, polyvinyl pyrrolidine, mannitol etc.) compatibility will be studied using novel techniques such as DSC, FT-IR etc.

3) Solubility and phase equilibria studies will be studied using standard methodology.

4) Solid dispersions will be prepared using different water soluble carriers and surfactants (polysorbate-20, polysorbate-80 etc) adopting suitable techniques. (melting method, solvent evaporation method etc)

5) The drug and its solid-dispersions shall be characterized for their physico-chemical properties using standard techniques.

6) In vitro release profiles of drug in simulated physiological fluid will be studied using USP dissolution apparatus (Electrolab, 6 basket). The in vitro data shall be analyzed statistically and kinetics of drug release shall be studied.

ENCLOSURE –VI

7.3) N0

ENCLOSURE –VII

8) LIST OF REFERENCES:

  1. Patel MM, Patel DM. Fast dissolving Valdecoxib tablets containing solid dispersion of Valdecoxib.Ind J Pharm Sci.2006; 68(2): 222-226.
  1. Craig DQM. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002; 231: 131-144.
  1. Serajuddin ATM. Solid dispersions of poorly water soluble drugs: Early promises, subsequent problems and recent breakthroughs. J Pharm Sci. 1999; 88(10); 1058–1066.
  1. Nelson M, Waters L, John L. Non-nucleoside reverse transcriptase inhibitors: a review.Int J Clin Pract.2007; 61 (1): 105–118.
  1. Kusum VD, Roopa SP. Antiretrovirals: Need for an Effective Drug Delivery. IJPS. 2006; 68(1):1-6.
  1. Kasim NA, et al. Molecularproperties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2004;1(1):85–96.

7. Moneghini M, Carcano A,Zingone G, Perissutti B. Studies in dissolution enhancement of atenolol. PartI.Int J Pharm.1998; 175 (2): 177-183.

8. Mohammed GA, Vibha P, Arvind K B. Coprocessing of Nevirapine and Stavudine by Spray Drying. Pharm Dev and Tech.2008; 13: 299–310.

9. Maria DV, Fakhrul A. Influence of surfactants (present in the dissolution media) on the release behaviour of tolbutamide from its inclusion complex with β-cyclodextrin. Eur J Pharma Sci. 2000; 9: 291–299.

10. Van Eerdenbrugh B, Froyen L, Martens JA, BlatonN, Augustijns P, Brewster M, Van den Mooter G. Characterization of physico-chemicalproperties and pharmaceutical performance of sucrose co-freeze-dried solidnanoparticulate powders of the anti-HIV agent loviride prepared by mediamilling. Int J Pharm. 2007; 338:198–206.

11. Van Gyseghem E et al. powder for reconstitution of the anti-HIV-1 drug TMC278-Formulation, development, stability and animal studies. Eur J Pharm Bio Pharm.2008, (In press; DOI: 10.1016/j.ejpb.2008.06.030.)

12. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000; 50: 47–60.

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