By

KARTHEEK THUMULURIM.Pharm(3rd semester)

External GuideDr. K. Raghupathi, M.Pharm., Ph.D

Senior General ManagerGenovo Development Services Ltd.

Internal GuideMr. M.Srikanth Reddy,

M.Pharm., (Ph.D)

Department of PharmaceuticsSt.Peter’s Institute of Pharmaceutical Sciences

Hanamkonda

CONTENTS INTRODUCTION

LITERATURE SURVEY

DRUG PROFILE

OBJECTIVE

PLAN OF WORK

MATERIALS AND METHODS

REFERENCES

INTRODUCTION The Oral route of administration still continues to be the most preferred

route due to its manifold advantages including ease of administration, accurate dosage, self-medication, versatility and most importantly patient compliance.

However, many patient groups such as the elderly, children, mentally retarded, uncooperative, nauseated, or on reduced liquid intake diets have difficulty in swallowing these dosage forms, because many of them are required to consume medicines on a regular basis to maintain their quality of life. Children may also have difficulty ingesting these dosage forms because of their underdeveloped muscular and nervous system. Swallowing conventional tablets will be further hindered by conditions such as unavailability of water, allergic reactions, and episodes of coughing.

The aforementioned problems can be solved by developing rapidly disintegrating and dissolving tablet dosage forms for oral administration because they dissolve in saliva and does not require water for swallowing.

United States Food and Drug Administration (FDA) defined ODT as

“A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue.” The disintegration time for ODTs generally ranges from several seconds to about a minute.

Oro-dispersible tablets are also known as fast dissolving tablets, melt-in-mouth tablets, rapimelts, porous tablets, Mouth dissolving tablets, quick dissolving tablets or rapidly disintegrating tablets.

The bioavailability of some drugs may be increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover the amount of drug that is subjected to first pass metabolism is reduced as compared to standard tablets.

ADVANTAGES• Superior taste of the tablet helps to change the basic view of medication as the

“bitter pill” particularly for pediatric patients. An increased bioavailability, particularly in cases of insoluble and

hydrophobic drugs, due to rapid disintegration and dissolution. To achieve increased bioavailability/ rapid absorption through pregastric

absorption of drugs from mouth, pharynx, and esophagus as saliva passes down.

Free from the risk of suffocation due to physical obstruction when swallowed, thus offering improved safety.

Convenient for administration and patient compliance for disabled, bedridden patients and for travelers and busy people, who do not always have access to water.

As ODT’s are solid unit dosage form, they provide good stability, accurate dosing, easy manufacturing, small packaging size, and easy to handle by patients.

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

IDEAL PROPERTIES An ideal Oro-dispersible tablet should meet the following criteria: Does not require water for oral administration yet disintegrates and

dissolve in the mouth within a few seconds. Has sufficient strength to withstand the rigors of the manufacturing

process and post manufacturing handling. Has a pleasing mouth feel. Exhibit low sensitivity to environmental conditions such as humidity

and temperature. Allows high drug loading. Be compatible with taste masking. Does not leave any residue in the mouth after disintegration. They can be manufactured using conventional tablet processing and

packaging equipment at low cost.

MANUFACTURING TECHNOLOGIESVarious technologies used in the manufacture of mouth dissolving tablets

include: Freeze drying/ lyophilization Molding Cotton – candy process Spray drying Mass extrusion Compaction

1. Melt granulation

2. Phase transition process

3. Sublimation

4. Conventional methods

a. Dry granulation

b. Wet granulation

c. Direct compression Disintegrant addition

PATENTED TECHNOLOGIES• Zydus Technology

• Lyoc

• Quick Solv

• Nanocrystal Technology

• Flashtab Technology

• Orasolv Technology

• Durasolv Technology

• WOW Tab Technology

• Dispersible Tablet Technology

• Pharmaburst Technology

• Frosta Technology

• Oraquick

• Ziplets/Advatab

• Flashdose Technology

LITERATURE REVIEW

S Jeevanandham et al.,(2011) prepared Oro Dispersible Tablets of Naproxen sodium by wet granulation technique using camphor as a subliming agent and SSG together with CCS as super disintegrants. Camphor was sublimed from granules by exposing them to vacuum. The porous granules were then compresses into tablets. Alternatively, tablets were prepared and later exposed to vacuum. Sublimation of camphor from tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum.

M.D.Kshirsagar et al.,(2010) developed Doxilamine oro-dispersible tablets with considerable increase in drug release as compared to marketed formulations. To prevent bitter taste and unacceptable odour of the drug, the drug was taste masked with weak cation exchange resins like Indion 234, Indion 204 and Indion 414.Among the three, Indion 234 was found to have high drug loading capacity.

Taizia D. Silva et al.,(2010) prepared solid dispersions (SD) of SIM with inert carriers in an attempt to improve the release profile. Here , SIM SD with polyethylene glycol (PEG 6000) or polyvinylpyrrolidone (PVP K15) in different ratios were prepared and their stability and dissolution properties were investigated. Tablets containing SD SIM : PEG 6000 were developed and their dissolution profile evaluated. Drug release from all SD was significantly improved when compared to their corresponding physical mixture or SIM alone. SD SIM:PVP showed drug degradation. The tablets gradually released SIM with a final quantity greater than 80% in 60 minutes. SIM SD with PEG are more advantageous over the dispersions prepared with PVP because they do not show drug degradation during preparation.

Debjit Bhowmik et al.,(2009) prepared Fast Dissolving tablets of Telmisartan by using Superdisintegrants–Crosspovidone, Ac-de-sol, and sodium starch glycolate, level of addition to increase the rate of drug release from dosage form to increase the dissolution rate and hence its bioavailability. The tablets were prepared by Direct Compression methods and the prepared blend and tablets were evaluated for their physico chemical properties and In-Vitro dissolution study.

Priyanka Pandya et al.,(2008) enhanced the solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K3LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K3LV. Spray drying and rota evaporation method were applied for solvent evaporation. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM.

Synthon et al.,(2007) patented the invention that relates to an orally disintegratable pharmaceutical tablet comprising an effective amount of simvastatin, atleast 50 wt% of silicified microcrystalline cellulose, and a non alkali lubricant and is used for treating high cholesterol in a mammal.

DRUG PROFILEName : Simvastatin Synonyms: Simvastatina, Simvastatine, Simvastatinum Brand Names: Zocor IUPAC Name: [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-

oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-

hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate.

• Structure:

Chemical Formula: C25H38O5

Molecular weight: 418.559997 Appearance, odor and Color: white to off-white, non-hygroscopic,

crystalline powder. State: Solid Melting Point: 135-138°C. Water solubility: 0.76mg/L Log P: 4.7 Bioavailability: 5% approx. Protein Binding: 95% approx. Half Life: 3 hrs Route of Elimination: 13% in urine and 60% in feces. Category: HMG-CoA Reductase Inhibitor.

MECHANISM OF ACTION

Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus.

After oral ingestion, Simvastatin, which is an inactive lactone, is hydrolyzed to corresponding β hydroxyacid form. This is an inhibitor of HMG CoA reductase. This enzyme catalyzes the conversion of HMG CoA to mevalonate that is an early and rate-limiting step in the biosynthesis of cholesterol.

OBJECTIVETo Formulate and Evaluate Oro-Dispersible Tablets of

Simvastatin.

PLAN OF WORK Construction of standard graph . Preparation of Simvastatin Oral dispersible tablets containing

polymers, by wet granulation method. Evaluation of Blend

1. Angle of repose

2. Bulk density and tapped density

3. Compressibility index

4. Hausner’s Ratio

5. Drug content uniformity

Evaluation of tablets

1.Weight Variation

2. Hardness

3. Friability

4. Thickness

5.Wetting Time

6. Moisture Uptake

7. Disintegration Time

8.Mouth Dispersion Time Evaluation of in vitro release characteristics of all formulations using USP

dissolution apparatus 2 (paddle). Comparison of the test formulation with the marketed product. FTIR Studies. Stability studies of optimized formulation

MATERIALSDry Blending

Simvastatin (Ph.Eur)

Microcrystalline Cellulose PH 102

Aerosil

Ascorbic Acid

Citric Acid.

Granulating

PVP K30

HPMC e3 LV

BHA

IPA

Purified water.

Extra Granular

Microcrystalline Cellulose PH 102

Aerosil

Crospovidone XL 10

Peppermint

Asparteme

Iron oxide red

Stearic Acid.

REFERENCES Priyanka Pandya, Surendra Gattani, Pankaj Jain, Lokesh Khirwal and

Sanjay Surana. Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation. AAPS PharmSciTech, Vol. 9, No. 4, December 2008.

M.D. Kshirsagar , T.Y. Puttewar , A.V. Chandewar , R.V. Chikhale. Formulation and evaluation of oro-dispersible tablet of taste masked doxylamine succinate using ion exchange resin. Journal of King Saud University (Science) (2010) 22, 229–240.

Taízia D. Silva, Valquíria T. Arantes, Jackson A.L.C. Resende, Nivaldo L. Speziali, Renata B. de Oliveira and Cristina D. Vianna-Soares. Preparation and characterization of solid dispersion of simvastatin Preparation and characterization of solid dispersion. Drug Development and Industrial Pharmacy, 2010; 36(11): 1348–1355.

Debit Bhowmik, B.Jayakar, K.Sampath Kumar. Design And Characterisation of Fast Dissolving Tablet of Telmisartan. International Journal of Pharma Recent Research. IJPRR 2009, 1(1), 31-40.

Parikh SR, Gothoskar AR. A review of mouth dissolving tablet technologies. Pharm Tech 2003 Nov [Cited 2008 Nov 9]. Available from URL: http://www.pharmtech.com.

Kuchekar BS, Bhise SB, Arumugam V. Design of fast dissolving tablets. Ind J Pharm Edu 2001; 35(4): 150-52.

Kaushik D, Dureja H, Saini TR. Mouth dissolving tablets: a review. Indian Drugs 2004; 41(4): 187-93.

Bandari S, Mittapalli RK, Gannu R, Rao YM. Oro-dispersible tablets: an overview. Asian J Pharm 2008 Jan [Cited 2008 Nov 9]. Available from URL: http://www.asiapharmaceutics.info.