A. BRIEF RESUME OF THE INTENDED WORK:

A.1 NEED FOR THE STUDY:-

Oral route of drug administration is perhaps the most appealing route for the delivery of drugs.1 Of the various dosage forms administered orally, the tablets are the most preferred dosage form, because of its ease of manufacturing, convenience in administration, accurate dosage and compactness. However geriatric and paediatric patient experience difficulties in swallowing conventional tablets, which leads to poor patient compliance.2,3

Method to improve patient’s compliance has always attracted scientists towards the development of safer and new drug delivery systems. Among them, mouth dissolving drug delivery system (MDDS) have unique property of rapidly disintegrating, dissolving and releasing the drug as soon as they come in contact with saliva, thus obviating the requirement of water during administration.4The different approaches like Lyophilization, Moulding, Direct Compression, Cotton Candy Process, Spray Drying, Sublimation, Mass Extrusion, Nanonization and Fast Dissolving Films for manufacturing of MDDS.5

The fundamental principle used in the development of the fast-dissolving tablet is to maximize its pore structure. Researchers have evaluated spray dried materials and plastic materials for development of such tablets. Vacuum-drying and freeze drying techniques have been tried by researchers to maximize the pore structure of tablet matrix. Freeze drying is cumbersome and yields a fragile and hygroscopic product. Therefore, a vacuum drying technique was adopted in many investigations after addition of a subliming agent to increase porosity of the tablets.6

A wide range of drugs can be considered as a candidate for this dosage form. [E.g. Antiepileptic, Analgesic, Antiasthmatics, Antianginal, Antiarrhythmics, Antihypertensive, Antiemetics.]7

Lamotrigine (LMN) is an Antiepileptic drug, widely used in epilepsy. It is also used in simple and complex partial seizures and secondary generalized tonic-clonic seizures.It is poorly water soluble drug (0.17mg/ml at 250C). Lamotrigine is rapidly and completely absorbed after oral administration with negligible fast-pass metabolism (absolute bioavailability is 98%) and also bioavailability is not effected by food.

The objective of the present work is to improve the dissolution characteristics of the LMN solid dispersion using LMN inclusion complex with β-cyclodextrin and preparation of porous tablet by sublimation technique, to achieve reliable bioavailability and enhance patient compliance.

A.2 REVIEW OF LITERATURE:-

Literature survey on highly porous fast dissolving tablet by complexation is carried out by referring various scientific journals, internet and helinet facility. A survey of literature reveals that extensive work was conducted employing subliming agents & complexing agent to prepare fast dissolving tablets.

Mahapatra et al.,4have reported the development and characterization of mouth dissolving tablets of Levocetirizine hydrochloride using sublimation technique. In the formulation,different concentrations of Perlitol SD 200 (spray dried mannitol) and menthol were used for preparation of tablets. These formulations were evaluated for various parameters like hardness, friability, drug content, degradation and in vitro drug release studies.The compressed tablets with 30% menthol were rapidly dissolved within 15 seconds in mouth saliva. This may be attributed to the rapid wetting time or simulated saliva penetration, due to high porosity.

Ravi Kumar et al.,6 developed fast dissolving tablets of aceclofenac by wet granulation technique. Here camphor was used as subliming agent and sodium starch glycolate, croscarmellose sodiumwereused as superdisintegrants. It has shown improved aceclofenac dissolution and helped in rapid absorption, improved bioavailability and patient compliance. The sublimation was performed after compression rather than directly from the granules, which showed better results.

Rao et al.,8 have formulated fast dissolving tablets of poorly soluble carbamazepine by direct compression technique. In this formulation,β-cyclodextrin complex and various super disintegrants like Indion-414, croscarmellose sodium (CCS), crospovidone and sodium starch glycolate wereused to enhance the dissolution rate and the bioavailability. Among all the formulation, formulation with10% CCS, was better and satisfied all the criteria as a fast dissolving tablet.

Watanabeet al.,9developed the new method of high-porosity rapidly saliva soluble compressed tablets containing mannitol and camphor. Here camphor was used as subliming agent.These formulations are evaluated for various parameters like hardness, friability, drug content and in vitro drug release studies. The tablets with mannitol and camphor in a ratio of 7:3 and camphor with particle diameter from 355 to 500 μm was suitable for the preparation of rapidly saliva soluble tablets.

Pokharkar et al.,10 studied to improve the solubility and dissolution rate of carvedilol. In this formulationa ternary complex of drug with -cyclodextrin and citric acid was used. These would facilitate its absorption from the buccal cavity, to overcome its first-pass metabolism. In this formulation, ternary complexwere used in a molar ratio of 1:2:2 which showed improved bioavailability, by significant improvement in aqueous solubility.

Patelet al.,11developed fast dissolving tablets of etoricoxib by sublimation technique. In the formulationmenthol was used as subliming agent andcrospovidone was used as superdisintegrant.These formulations were evaluated for various parameters. Among all formulations, where sublimation was performed after compression, rather than directly from granules showed higher in vitro drug release and % dissolution efficiency than the marketed product.

Masareddy et al.,12studied the formulation of mouth dissolving tablets of clozapineby two different methods i.e. direct compression and sublimation whereexplotab was used assuperdisintegrant and camphor was used as subliming agent.These formulations were evaluated for various parameters like hardness, friability, drug content, degradation and in vitro drug release studies. It has been concluded that direct compression technique enhance the absorption which lead to increased bioavailability.

Ravi Kumar et al.,13developed and characterized mouth dissolving tablets of fenofibrate.In this study different subliming agents like camphor, thymol, ammonium bicarbonate and menthol were used in different concentrations.The tablet gives benefit in terms of patient compliance, low dosing, rapid onset of action, increased bioavailability, low side effect and good stability by enhancing the solubility. Based onin vitro and in vivo disintegration time and wetting time, the formulationhaving menthol as sublimating agent in the concentrationof 12.5 % was selected as the optimized formulation.

Shivakumar et al.,14 have formulatedcarbamazepineinclusion complex with β-cyclodextrin.These formulations were evaluated for various parameters like hardness, friability, drug content, degradation and in vitro drug release studies. Complexes of carbamazepine and β-cyclodextrin prepared in 1:2 molarratios by kneading method, showed enhanced solubility.

A.3 OBJECTIVES OF THE STUDY:

The present work is planned with the following objectives:

1.To prepare solid dispersion system of Lamotrigine inclusion complex with β-Cyclodextrin by employing

kneading method.

2.To study the physicochemical properties of Lamotrigine complex.

3.To develop fast dissolving tablets from Lamotrigine complex included with sublimationtechnique.

4.To study in vitro drug release profiles.

5.To study the effect of complexation and sublimation technique on dissolution characteristics.

6.To perform accelerated stability studies on selected formulations according to ICH guidelines.

B. MATERIALS AND METHODS:

B.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 & international journals, books, Pharmacopoeia,CIMS, Drug Index and other internet sources.

B.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 the drug and exicipents, the final formulation will be developed.

I. Materials:

The materials required for the study like Lamotrigine, complexing agent like β-cyclodextrin,subliming agent like camphor, menthol and other exicipents will be procured from commercial suppliers.

II. Methodology:

The proposed work is carried out in following stages:

A)Preformulation studies.

B)LMN inclusion complex.

C)Formulation of fast dissolving tablets.

D)Evaluation of prepared tablets.

A)Preformulation studies:

Compatibility between drug and excipients will be studied using standard techniques.

B)LMN inclusion complex:

1. LMN inclusion complex will be prepared by using β-cyclodextrinby employing kneading method.

  1. The drug and its inclusion complex shall be characterized for their physico-chemical propertiesusing

standard techniques.

  1. In vitro release profiles of drug in simulated physiological fluid will be studied using suitable dissolution

apparatus.

C) Formulation of fast dissolving tablets:

Fast dissolving tablets of LMN inclusion complex will be formulated by direct compression method using subliming agent such as menthol, camphor etc.in various ratios.

D) Evaluation of prepared tablets:

The formulated tablet will be evaluated for hardness, friability, weight variation, drug content uniformity, wetting time, disintegration time and dissolution studies.

B.3 Doesthis study requires any investigation or interventation to be conducted on patients or other humans or animals? If so, please describe briefly.

Not Applicable

B.4 Has ethical clearance been obtained from your institution in case of B3.

Not Applicable

C. LIST OF REFERENCES:-

  1. Martin A. Drug Product Design In Physical Pharmacy. 4th ed. PhiladelphiaPA: Lippincott Williams & Wilkins 2001:512-555.
  2. Banker GS, Anderson NR. Tablets In Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 3rd ed. PhiladelphiaPA: Lea & Febiger 1986;2:293-345.
  3. Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Sci 2005;8:76-93.
  4. Mahapatra AK, Murthy PN, Sahoo J, Biswal S, Sahoo SK. Formulation Design and Optimization of Mouth Dissolving Tabletsof Levocetirizine Hydrochloride Using Sublimation Technique. Indian J Pharm Educ Res2009;43(1):39-45.
  5. Bandari S, Mittapalli RK, Gannu R, Rao YM. Orodispersible tablets: an overview. Asian J Pharm2008;2:2-11.
  6. Kumar R, PatilMB, Patil1 SR, Paschapur MS, Mahalaxmi R. Development and Characterization of Orodispersible Tablets of Aceclofenac by Sublimation Technique.Int J Pharm Tech Res 2009;1(2):210-214.
  7. Shukla D, Chakraborty S, Singh S, Mishra B. Mouth Dissolving Tablets І, An Overview of Formulation Technology. Sci Pharm 2009;76:309–326.
  8. Rao NGR, Patel T, Gandhi S. Development and evaluation of carbamazepine fast dissolving tablets prepared with a complex by direct compression technique. Asian JPharm 2009;3:97-103.
  9. Koizumi K, WatanabeY, Morita K, Utoguchi N, Matsumoto M. New method of preparing high-porosity rapidly saliva soluble compressed tablets using mannitol with camphor a subliming material. Int J Pharm 1997;152:127-131.
  10. Pokharkar V, Khanna A, Venkatpurwar V, Dhar S, Mandpe L. Ternary complexation of carvedilolβ-cyclodextrin and citric acid for mouth-dissolving tablet formulation. Acta Pharm 2009;59:121–132.
  11. PatelDM,Patel MM. Optimization of fast dissolving etoricoxib tablets prepared by sublimation technique. Ind J Pharm Sci 2008;70(1):71-76.
  12. MasareddyRS, Kadia RV, Manvi FV. Development of mouth dissolving of clozapine using two different techniques.Ind J Pharm Sci 2008;70(4):526-528.
  13. Kumar R, Patil S, Patil MB, Patil SR, Paschapur MS. Formulation Evaluation of Mouth Dissolving Tablets of Fenofibrate Using Sublimation Technique.Int J ChemTech Res 2009;1(4):840-850.
  14. Suresh S, ShivakumarHN, Kumar GK. Effect of β-cyclodextrin complexation on the solubility and dissolution rate of carbamazepine from tablets. Ind J Pharm Sci 2006;68(3):301-307.

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