Fast dissolving tablets of ritonavir m. Pharm dissertation protocol submitted to the



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FORMULATION AND EVALUATION OF

FAST DISSOLVING TABLETS OF RITONAVIR
M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES, KARNATAKA, BENGALURU.



BY

PADHIAR MAYURKUMAR RAOJIBHAI

B.Pharm.,

UNDER THE GUIDANCE OF



Prof. VENKATESH. J.S

B.sc, M.Pharm.,(Ph.D).



PROFESSOR AND HEAD

P. G. DEPARTMENT OF PHARMACEUTICS

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI-583131

2011-2012



Rajiv Gandhi University of Health Sciences,

Bengaluru, Karnataka.

Annexure – II




PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION



01

Name and Address of the Candidate

PADHIAR MAYURKUMAR RAOJIBHAI

paDHIAR RAOJIBHAI UDESINH

PRAMUKH SOCIETY, NEAR POLICE STATION, AT POST:-ANKLAV, TA:-ANKLAV, DIST:-ANAND,

ST:-GUJRAT

02

Name of the Institution
T. M. A. E. SOCIETY’S

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI:–583131

KARNATAKA.

03

Course of the Study Branch

M.PHARM. (PHARMACEUTICS)

04

Date of Admission to course

06/07/2011

05

Title of the Topic

FORMULATION AND EVALUATION OF

FAST DISSOLVING TABLETS OF RITONAVIR”

06

Brief resume of the intended work

6.1. Need for the Study



Enclosure – I


6.2. Review of the Literature

Enclosure – II

6.3. Objective of the Study

Enclosure – III

07

Materials and Methods

7.1. Source of data


Enclosure – IV



7.2. Methods of collection of data

Enclosure – V

7.3. Does the study require any

Investigations on animals?

If yes give details


No

7.4. Has ethical clearance been

obtained form your institution

in case of 7.3.


Not applicable

08

List of References

Enclosure – VI





09

Signature of the Candidate


(PADHIAR MAYURKUMAR.R.)

10

Remarks of the Guide

The work is well designed with best of my knowledge upon extensive literature review. This work will be carried out in the pharmaceutics laboratory by the above said student under my supervision.

11


Name and Designation of

(In Block Letters)

11.1. Guide

(ACA/CDC/PGT-M.Ph/SCS/02/20

05-06.Dated on 19.01.09)


11.2.Signature
11.3.Co-Guide (if any)

11.4.Signature


11.5. Head of the Department


11.6.Signature



Prof. VENKATESH. J.S

B.Sc., M.Pharm.,( Ph. D).



PROFESSOR AND HEAD

P.G.Department of Pharmaceutics

S.C.S. College of pharmacy,

Harapanahalli-583131, Karnataka.



Mr.SHANKRAYYA. M

M.Pharm., (Ph.D)



ASSISTANT PROFESSOR

P.G.Department of Pharmaceutics

S.C.S. College of pharmacy,

Harapanahalli-583131, Karnataka.



Prof. VENKATESH. J.S.

B.Sc., M.Pharm.,( Ph. D).



12


Remarks of the Principal

12.1. Signature


The present study is permitted to perform in the Pharmaceutics laboratory of our institution by above said student.

Dr.R.Nagendra Rao

ENCLOSURE: I
06. Brief resume of the intended work

6.1. Need for the study

Orally administered dosage forms e.g. tablets, capsules are convenient dosage forms for many drugs. But, they are challenging to formulate if the active substances have poor dissolution or low bioavailability. Polymer coating enables the formulation of mouth dissolving and taste masking of bitter taste drugs thereby giving better patient compliance1. Tablets that are fast disintegrate or dissolve rapidly in the oral, are convenient for young children, aged and patients with swallowing difficulties2. For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity3. The medication then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa, or it can be swallowed as a solution to be absorbed from the gastrointestinal tract(GIT) 4.


Fast dissolving tablets offer all advantages of solid dosage forms and liquid dosage forms

along with special advantages, which include:


  1. As FDTs are unit solid dosage forms, they provide good stability, accurate dosing, easy manufacturing, small packaging size and easy to handle by patients.

  2. No risk of obstruction of dosage form, which is beneficial for travelling patients who do not have access to water.

  3. Easy to administer for pediatric, geriatric and institutionalized patients (specially for mentally retarded and psychiatric patients)

  4. Rapid disintegration of tablet results in quick dissolution and rapid absorption which provides rapid onset of action.

  5. Medication as “bitter pill” has changed by excellent mouth feel property produced by use of flavors and sweeteners in FDTs.

  6. Bioavailability of drugs that are absorbed from mouth pharynx and esophagus is increased.

  7. Pregastric absorption of drugs avoids hepatic metabolism, which reduces the

dose and increase the bioavailability.5-6
Ritonavir is an antiretroviral drug from the protease inhibitor class used to treat HIV Infection and AIDS. Ritonavir is administered orally, half life of the drug is 3-4hours, and 98-99% is bound to plasma protein and inactive metabolite excreted through faecal matter. Ritonavir (center) bound to the active site of HIV protease. It is one of the most complex inhibitors. Ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. Ritonavir is poorly soluble in water. Its low solubility makes it a suitable candidate for fast dissolving tablets7

Hence, the present investigation was undertaken with a view to develop Fast-dissolving tablets of ritonavir.




ENCLOSURE: II

6.2 Review of the Literature



  • Ranch KM, et al., approach used in developing ODTs is maximizing pore structure of the tablets. Vacuum drying and freeze-drying techniques have been tried by researchers to maximize the pore structure of tablet matrix containing subliming agent. Among the soluble diluents, lactose was selected as a model soluble diluents considering its advantages in terms of easy availability, cost-effectiveness and relative moisture insensitivity.8



  • Sudhir Bhardwaj, et al., formulated fast dissolving tablets of Aceclofenac. Attempt had been made to prepare fast dissolving tablets of the drug using various super disintegrates sodium starch glycolate following by direct compression technique. The tablets were evaluated for hardness, friability, weight variation, disintegration time, water absorption ratio and wetting time, in vitro dissolution studies. All the formulation showed disintegration time in range of 12.2 to 27.5 seconds along with rapid in vitro dissolution.9




  • Vasanthkumar, et al., formulated Immediate Release Tablets of Telmisartan using Super disintegrant formuation. In this work the attempt has been made to prepare immediate release of telmisartan by using crospovidone at intragranular, extragranular and partly intra and extragranular level of addition to increase the rate of drug release from dosage form to increase the dissolution rate and hence its bioavailability. The prepared granules and tablets were evaluated for their physiochemical properties and in-vitro dissolution study was conducted for the prepared tablets. It was concluded that the immediate release tablets with proper hardness, disintegration , and with increase rate of dissolution can be made by using crospovidone. formulation-10 (F10) was selected for stability study and in-vitro dissolution study showed that was no difference in percent t of drug released between initial and sixth month sample.10



  • C.P. Jain, et al., formulated fast dissolving tablets of Valsartan were prepared by the direct compression method after incorporating superdisintegrants such as crospovidone in different concentrations. FDT’s were evaluated for physicochemical properties and in vitro dissolution. Effect of disintegrant on disintegration behaviour of tablet in artificial saliva, pH 5.8 was evaluated. Wetting time of formulations containing crospovidone was least and tablets showed fastest disintegration. The drug release from FDT’s increased with increasing concentration of superdisintegrants and was found to be highest with formulations containing crospovidone. The release of valsartan from FDT’s was found to be follow non-Fickian diffusion kinetics.11



  • Shailendra kumar Singh, et al., formulated fast disintegrating combination tablets of Omepraprazole and Domperidone. The tablets were prepared using mannitol as diluent and sodium saccharin as sweetening agent along with three different levels of disintegrant. The superdisintegrant used in this study were Kollidon CL, Ac-Di-Sol and SSG. The Tablets were evaluated for weight variation, hardness, friability, wetting time, water absorption ration, disintegration time dissolution study. Using the same excipients, the tablets were prepared by direct compression and were evaluated in the similar way. Omeprazole and Domperidone were well resolved and the retention times around 9.01 and 6.2 respectively. From the results obtained it can be concluded that the tablet formulation prepared with 4.76% Ac-Di-Sol (internally cross linked from sodium caboxymethylcellulose) ie. 10mg showed disintegration time of 15 seconds in vitro.12



  • Narmada GY, et al., formulated fast dissolving tablet of Amlodipine Besylate. All formulations of evaluated for pre-compression and post compression parameters. Wetting time and water absorption ratio. The results obtained showed that the quantity of starch potato, sodium starch glycolate, camphor significantly affect response variables. The results indicate that the optimized tablet formulation provides a short DT of 8 seconds with sufficient crushing strength and acceptable formulation is stable.13



  • Prashant Khemariya, et al., formulated and evaluated mouth dissolving tablets of Meloxicam. These tablets were prepared by wet granulation procedure. The tablets evaluated for % friability, wetting time and disintegration time. Sublimation of camphor from tablets resulted in better tablets as compared to the tablets prepared from granules that were exposing to vacuum. The systematic formulation approach helped in understanding the effect of formulation processing variables.14



  • Dali Shukla, et al., Review article on Mouth Dissolving Tablets II: An overview of Evaluation Techniques. This article attempts to present a detailed review regarding technological advances made so far in the area of evaluation of mouth dissolving tablets with respect to special characteristics of these unique dosage forms.15



  • Srivanas Babu, et al., Prepared solid dispersion of Piroxicam in five superdisintegrants namely primogel, microcrystalline cellulose, crospovidone, pregeletinzed starch, croscarmellose sodium with water soluble carriers polyvinyl pyrrolidone and polyethylene glycol. Solid dispersions of Piroxicam in super disintegrants gave a marked enhancement in its dissolution rate and dissolution efficiency. Solid dispersion in super disintegrants could be used as an effective and efficient technique for enhancing the dissolution rate Piroxicam a poorly soluble drug.16



  • Jyotsana Madan, et al., Research article on Fast dissolving tablets of Aloe Vera Gel. of nutraceutical, freeze-dried aloe vera gel were prepared by dry granulation method. The tablets were evaluated for crushing strength, disintegration time, wetting time, friability, drug content and drug release. A 32 full factorial design was applied to investigate the combined effect of two formulation variables amounts of microcrystalline cellulose and mannitol. The results of multiple regression analysis revealed that in order to obtain a fast dissolving tablet of the aloe vera gel, an optimum concentration of mannitol and higher content of MCC should be used. A response surface a plot was also provided to graphically represent the effect of the independent variables on the disintegration time.17


ENCLOSURE:III

6.3 Objectives of the study


  1. To develop Fast dissolving tablet of ritonavir.



  1. To evaluate for the pre-compression characteristics of powder mixture like bulk density, flow property, angle of repose, compressibility index etc.




  1. To evaluate the post-compression characteristics of the tablet like hardness, friability, disintegration time, dispersion time, wetting time and water absorption ratio etc.




  1. To carry out in-vitro dissolution studies of the tablet formulations.




5. To carry out stability studies according to ICH guidelines



ENCLOSURE: IV


7. Materials and methods.

7.1 Source of Data:

I. Review of Literature from

a. Journals - such as


  • Advanced Drug Delivery Reviews.

  • International Journal of Pharmaceutical Sciences.

  • Journal of Pharmaceutical Sciences.

  • European Journal of Pharmaceutical Science.

b. Internet Browsing.

www.google.com

www.pubmed.com

www.sciencedirect.com

c. CD-ROM Search.


II References from library:-

  • SCS COLLEGE OF PHARMACY, HARAPANAHALLI-583131.

  • Textbook and standard reference books.



ENCLOSURE: V



7.2 METHOD OF COLLECTION OF DATA-

PART-I:

1. Extensive literature survey.

2. Procurement of raw materials and drug.

3. Standardization of raw materials and drugs.


PART-II:

Preparation of fast dissolving tablets using different disintegrating and superdisintigrating polymers systems.



Disintegrating and Superdisintigrating Used:

1. Sodium starch glycolate.

2. Crosspovidon.

3. Crosscarmellose sodium.

4. Kyron-341.
PART-III: Evaluation of fast dissolving tablets:

1. Hardness

2. Friability

3. Disintegrating time

4. In-vitro dissolution studies
PART-IV:

1. Stability study.



PART-V: Statistical Analysis, Data Interpretation and Conclusions.

ENCLOSURE: VI

  1. References



  1. Birudaraj R, Berner B, Shen S, Li X. :Buccal permeation of buspirone:mechanistic studies on transport pathways. J Pharm Sci.2005;94:70-78.




  1. Ishihawa T, Koizumi N, Mukai B. Pharmacokinetics of acetaminophen from rapidly disintegrating compressed tablet prepared using microcrystalline cellulose (PH-M- 06) and spherical sugar granules. Chem. Pharm Bull(Tokyo).2001;49: 230-232.




  1. Price T.M., Blauer K.L., Hnasen M., Stancyzk F., Lobo R., Bates G. W. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17-beta-estradiol. Obset Gynecol.1997;89:340-345.




  1. Habib W., Khankari R., Hontz J. Fast-dissolving drug delivery systems, critical review in therapeutics, Drug carrier Systems, 2001;17:61-72.




  1. Jaccard TT, Leyder J, Une nouvelle forme galenique Ie Iyoc. Ann Pharm Fr, 1985;43:123-31.




  1. Doll G, Chevanne F, Le Corre P, Chemtob C, Le verge R, Bioavailability of phloroglucinol in man. J. pharm Belg, 1999;54:75-82.




  1. www.wikipedia.org.ritonivir




  1. Ranch KM, Koli AR. Formulation Design and Optimization of Orodispersible Tablets of Atenolol. International Journal of Pharma Tech Research. 2009; 1(4):1559-63.



  1. Sudhir Bhardwaj, Vinay Jain, Jat RC, Ashish Mangal, Suman Jain. Formulation and evaluation of fast dissolving tablet of aceclofenac. International Journal of Drug Delivery 2010;2:93-97.



  1. Vasanthakumar Sekar, Vijaya Raghavan Chellan. Immediate release Tablets of Telmisartan using Superdisintegrant-Formulation, Evaluation and Stability Studies. Chem Pharm Bull. 2008;56(4):575-575.



  1. Jain CP, Naruka PS. Formulation and Evaluation of Fast dissolving Tablets of Valsartan. International Journal of pharmaceutical Sciences. 2009;1(1).



  1. Shailendra Kumar Singh, Dina Nath Mishra, Rishab Jassal, Pankaj Soni. Fast Disintegrating Combination Tablets of Omeprazole And Domperidone. Asian Journal of Pharmaceutical and Clinical Research. 2009;2(3).



  1. Narmada GY, Mohini K, Prakash Rao B, Gowrinath DXP, Kumar KS. Formulation, Evaluation and Optimization of Fast Dissolving Tablets Containing Amlodipine Besylate by Sublimation Method. Ars Pharm. 2009; 50(3):129-44.



  1. Prashanth Khemariya, Kavita RG, Vikas Deep Vaidya, Rajesh Singh Jadon. Preparation and evaluation of mouth dissoloving tablets of meloxicam. International Journal of Drug Delivery. 2010;2:76-80.



  1. Dali shukla, Subhashis Chakraborty, Sanjay Singh, Brahmeshwar Mishra. Mouth Dissolving Tablets II: An Overview of Evaluation Techniques. Sci Pharm.2009; 77:327-41.



  1. Srinivas Babu P, Ramu A, Sasidhar R, Vidyadhara. Enhanceement of dissolution rate of Piroxicam by solid dispersion using newer carriers. The Pharma review 2007;163-6.



  1. Jyotsana Madan, AK Sharma, Ramnik Singh. Fast dissolving Tablets of Aloe Vera Gel. Trop J Pharm Res. 2009;8(1):63-70.

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