Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore s2

“FORMULATION AND EVALUATION OF FAST DISSOLVING ORAL FILMS CONTAINING LAMOTRIGINE”

MASTER OF PHARMACY DISSERTATION PROTOCOL, SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.

BY SRIRAM SOMAYAJI.B M.PHARM – I

Under The Guidance of

MR. SHRIPATHY.D M.Pharm ASST.PROFESSOR

DEPARTMENT OF PHARMACEUTICS. SRINIVAS COLLEGE OF PHARMACY, VALACHIL MANGALORE – 574143 2011-2013 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. Name of the candidate and Mr. SRIRAM SOMAYAJI.B address DEPARTMENT OF PHARMACEUTICS, SRINIVAS COLLEGE OF PHARMACY, VALACHIL, POST FARANGIPETE MANGALORE. 574143

2. Name of the institution SRINIVAS COLLEGE OF PHARMACY, MANGALORE.

3. Course of study & subject MASTER OF PHARMACY (PHARMACEUTICS)

4. Date of admission to course 31/10/2011

5. Title of the topic

“FORMULATION AND EVALUATION OF FAST DISSOLVING ORAL FILMS CONTAINING LAMOTRIGINE”

2 Brief Resume of the intended work

6.1 Need of the study:

Oral route is most preferred route by medical practitioners and manufacturer due to highest acceptability of patients. About 60% of all dosage forms available are the oral solid dosage form. The lower bioavailability, long onset time and dysphagia patients turned the manufacturer to the parenterals and liquid orals. But the liquid orals (syrup, suspension, emulsion etc) have the problem of accurate dosing mainly parenterals are painful drug delivery, so most patient incompliance.1

Fast dissolving tablets are also known as mouth-dissolving tablets, Oro- dispersible tablets, rapimelts, and porous tablets. Fast dissolving tablets dissolve or disintegrate within 60 seconds when placed in the mouth without drinking or chewing. The active ingredients are absorbed through mucous membranes in the mouth and GIT and enter the blood stream.

But due to certain disadvantages like their physical solid form, psychological fear of swallowing, chewing or choaking, friability of wafer like porous and low pressure moulded tablet fabricated by various manufacturing processes and expensive packaging cost to protect the dosage form, a new technology was developed as mouth dissolving film.2

Fast dissolving oral films (FDOFs) are the most advanced form of oral solid dosage form due to more flexibility and comfort. It improve the efficacy of APIs by dissolving within minute in oral cavity after the contact with saliva without chewing and no need of water for administration. It gives quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa is 4- 1000 times greater than that of skin. FDOFs are useful in patients such as pediatric, geriatrics, bedridden, emetic patients, diarrhea, sudden episode of allergic attacks, or coughing for those who have an active life style. It is also useful whether local action desired such as local anesthetic for toothaches, oral ulcers, cold sores or teething.1

Epilepsy is a neurological disorder which requires quick management of seizures in order to avoid the risk of permanent brain damage.3 Pharmacotherapy with antiepileptic drugs remains the major treatment modality for epilepsy. Management of epilepsy differs from the treatment of other chronic disease in that a single breakthrough event has a major negative effect on quality of life. Complete control of seizures is necessary as a single seizure impacts negatively on patient quality of life and independence.4

The development of new antiepileptic drugs for epilepsy over the last decade has been spurred by the fact that the available antiepileptic drugs did not provide optimal care for patients with epilepsy. Lamotrigine (LMN) is a new antiepileptic drug, widely used in epilepsy. It is also used in simple and complex partial seizures and secondary generalized tonic-clonic seizures. Lamotrigine, 3,5-diamino-6-(2,3-dichlorophenyl)-

1,2,4-triazine, C9H7Cl2N5, mol. Wt. 256 g, is chemically unrelated with other antiepileptic drugs in current use, differing in structure and pharmacology. Lamotrigine has a broad spectrum in antiepileptic activity.5 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.6

Literature survey revealed the absence of published work on fast dissolving films of lamotrigine. Hence lamotrigine has been selected for the present research work. It is a bitter drug7 and therefore taste masking will be done adopting suitable methods. It has poor aqueous solubility (0.17 mg ml-1 at 250C) which could be the rate limiting step for its efficient absorption8. Therefore improvement of solubility will be made by complexation with various cyclodextrins which in addition mask the bitter taste of the drug. Thus to control the epileptic seizures in the shortest possible time, an attempt will be made to develop and evaluate fast dissolving films of lamotrigine with improved bioavailability and palatability. 6.2 Review of literature

 Sandeep DJ, Rahul NK, Chetan NJ, Bharat WT, Vijay RP have formulated and evaluated fast dissolving oral films of levocitrizine dihydrochloride by selecting hydroxy propyl methyl cellulose (HPMC) and sodium carboxy methyl cellulose as polymer. The films were optimized based on thickness folding endurance, weight variation, content uniformity, tensile strength, percentage elongation and surface pH.9  Francesco C, Irma EC, Buratti S, Chiara GM, Luisa M have developed the taste masked fast dissolving films of Diclofenac sodium using mint and licorice flavours. The films were prepared by casting and drying aqueous mixtures of maltodextrin(DE=6), glycerin, sorbitanoleate and diclofenac sodium. Films were characterized in terms of thickness, tensile properties, film disintegration time and drug dissolution time.10  Shelke PV, Dumbare AS, Gadhave MV, Jadhav SL, Sonawanne AA, Gaikwad DD have formulated and evaluated rapidly disintegrating films of amlodipine besylate. Fast dissolving film of Amlodipine Besylate was prepared using sodium alginate as film forming polymer. To decrease the disintegration time of formulations, sodium starch glycolate was used as disintegrating agent. The formulations were evaluated for their thickness, folding endurance, drug content, in vitro disintegration time and in vitro dissolution studies.11  Vijaykumar G, Ajaykumar P, Karunasri Sk, Raghavendar K, Priya P have

4 formulated and evaluated fast dissolving films of Montelukast sodium by solvent casting method using HPMC as film base with different concentrations of superdisintegrants like microcrystalline cellulose and crospovidone using PEG 400 as plasticizer. The physicochemical parameters of the fast dissolving films were evaluated. In vitro dissolution studies and mechanism of drug relase were identified.12  Nidhi PS, Vaishali AK, Anwar SD, Minal NB have developed fast dissolving oral thin films of Ambroxol Hydrochloride and effect of formulation variables like concentration of film forming polymer was investigated. Also the effect of emulsifying agent and plasticizer on physicochemical properties and in vitro dissolution studies were identified. HPMC was used as a film former, tween 80 as emulsifying agent and PEG 400 as plasticizer.13  Arun A, Amish C, Vijay S, Kamla P reported on formulation and design of fast dissolving drug delivery system and stated its advantage over other oral drug delivery system. They also studied the conventional techniques used in the preparation of fast dissolving drug delivery systems.14  Joshi PK, Harsha P, Vishnu P, Panchal R have formulated and evaluated mouth dissolving films of Domperidone. The solid dispersions of domperidone were prepared with the use of β-cyclodextrins in various ratios(1:1,1:2,1:3)and solubility study was performed to determine in which domperidone solubility was highest. The film was prepared by solvent casting technique utilizing HPMC E15 as film forming agent and PEG 400 as plasticizer. The formulations were evaluated for their thickness, folding endurance, drug content, in vitro disintegration time and in vitro dissolution studies.15  Deshmukh G, Deepti R, Seth AK, Jitendra P, Tejas G, Sharad K et al have formulated and developed fast disintegrating tablets of Lamotrigine using Microcrystalline cellulose and Lactose monohydrate IP as diluents and Aspartame as sweetening agent along with three different levels of two super disintegrants i.e. sodium starch glycolate and Kyron T-314. The tablets were evaluated for weight variation, friability, hardness, thickness, wetting time, disintegration time and dissolution study.16  Raju S, Sandeep R, Anirudh K, Deepthi A, Sreeramulu R, Madhava R have formulated and evaluated flash release oral films of metoclopramide hydrochloride. Two metoclopramide film formulations naming F1 and F2 were prepared by solvent casting technique using two water soluble polymers HPMC and CMC. The prepared films were evaluated for their thickness uniformity, folding endurance, weight uniformity, content uniformity, surface pH and in- vitro release. F1 released 99.40% of drug within 30 sec and was considered as best formulation.17

 Aditya D, Mangal N have formulated and evaluated fast dissolving films for the delivery of triclosan to the oral cavity. Film forming agents like HPMC, xanthan gum, xylitol were used. The potential of poloxamer407 and hydroxypropyl-β- cyclodextrins to improve the solubility of triclosan was investigated. The films were evaluated for in-vitro dissolution profile and in-vivo microbiological assay.18  Doaa A, Nevine S have formulated the orodispersible film of antidepressant drug tianeptine sodium using film former lycoat NG73 (granular hydroxyl propyl starch) along with different film-forming agents like HPMC, hydroxyethylcellulose and polyvinyl alcohol. In addition to these three film modifiers; namely, Maltodextrin, polyvinylpyrrolidone K90 and lycoat RS780 were used. The films were prepared by solvent casting methods and were evaluated for their in-vitro dissolution characteristics, in-vitro disintegration time and their physico-mechanical properties.19

6.3 Objectives of the Study :

The objectives of the study are to formulate fast dissolving oral films containing Lamotrigine with the purpose of developing a dosage form for very quick onset of action.

Specific objectives of the present investigation are as follows: 1. To mask the bitter taste of lamotrigine and also to increase its solubility by adopting suitable techniques and to formulate fast dissolving films containing lamotrigine using ideal polymers by suitable methods. 2. Evaluation of formulated film strips using different parameters like surface pH, swelling studies ,drug content, film thickness, folding endurance of the film, in-vitro drug release studies, etc.

6 7. Materials and Methods:

Materials:

1. Drug : Lamotrigine 2. Polymers : HPMC K100M:, HPMC K15M, HPMC K 4M, Carbapol, Polyvinylalcohol, Maltodetrins,etc 3.Plasticizers : Glycerol, Polyethylene glycol, Dibutyl phthalate, Castor oil etc. 4. Saliva stimulating : Citric acid, Malic acid, Lactic acid etc. Agents 5. Super disintegrants : Crosspovidone, MCC etc. 6. Organoleptic additives : Coloring, flavoring and sweetening agents.

Methods: Fast dissolving films containing Lamotrigine can be prepared by any one of following method.

 Solvent casting  Semi solid casting  Rolling  Solid dispersion extrusion  Hot melt extrusion 7.1 Source of Data: 1. Review of literature from

a) Journals such as  Indian Journal of Pharmaceutical Sciences.  Drug Development and Industrial Pharmacy.  International Journal of Pharma and Bio sciences.  International Journal of Pharmacy and Pharmaceutical Sciences.  International Journal of PharmTech research.  Journal of Pharmacy and Pharmacology. b) Internet Browsing

c) CD-ROM Search

2. Laboratory based experiments and evaluation. 7.2 Method of collection of data :

1. From the available literature 2. An attempt will be made to increase the solubility of lamotrigine by complexation with various cyclodextrins7,15 and to formulate fast dissolving films containing lamotrigine.9,12,13,15 3. Prepared films are evaluated for: a. Thickness.11,13 b. Weight variation.9,12 c. Folding endurance.9,15,17 d. Tensile strength and Percentage elongation.13 e. Drug content and content uniformity.12,13 f. In vitro drug release pattern by using USP dissolution test apparatus.7 g. To carry out stability studies as per ICH guidelines for the selected formulations.12 7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.

- Not applicable.

7.4 Has ethical clearance been obtained from your institution in case of 7.3? - Not applicable.

8 8. List of reference 1. Nehal S, Garima G, Pramod KS. A short review on Novel Approach in Oral Fast Dissolving Drug Delivery System and their patents. Adv Bio Res 2011;5(6):291-303.

2. Vivek C, Sunil B, Bhushan R, Nayan G, Sunil P. Fast Dissolving Tablets: An Overview. Int J Pharm Sci Review and Res 2012;12(1):35-41.

3. Patil RR, Shende AJ, Devarajan PV. Microemulsion of lamotrigine for nasal delivery. Indian J Pharm Sci 2007;65(5):721-2.

4. Werz MA. Pharmacotherapeutics of epilepsy: use of lamotrigine and expectation for lamotrigine extended release. Therapeutic & clinical risk management 2008;4(5):1035-46.

5. Magda TM, Clesio SP, Martin S. LC and UV methods for Lamotrigine determination in Pharmaceutical Formulation. Chromatography Res Int 2011;1:1-8.

6. Martindale S – The complete drug reference. Antiepileptics. 34th ED. Pharmaceutical Press, London 2005;363-5.

7. Prakash G, Shivam HS, Doddaya H. Development and Characterization of Lamotrigine Orodispersible Tablets: Inclusion complex with Hydroxy propyl β cyclodextrin. Int J Pharmacy & Pharm Sci 2011;3(3):208-14.

8. Parmar KR, Patel KA, Shah SR, Sheth NR. Inclusion complexes of lamotrigine and hydroxyl propyl β- cyclodextrine: solid state characterization and dissolution studies. J Incl Phenom Macrocycl Chem 2009;65:263-8.

9. Sandeep DJ, Rahul NK, Chetan NJ, Bharat WT, Vijay RP. Formulation and evaluation of fast dissolving oral film of levocitrizine dihydrochloride. Int J Pharm & Pharm Sci 2012;4(1):337-41.

10. Francesco C, Irma EC, Buratti S, Chiara GM, Luisa M. Diclofenac fast-dissolving film: Suppression of bitterness by a taste-sensing system. Drug devp & Industrial pharmacy 2011;37(3):252-9.

11. Shelke PV, Dumbare AS, Gadhave MV, Jadhav SL, Sonawanne AA, Gaikwad DD. Formulation and evaluation of rapidly disintegrating film of Amlodipine Besylate. J drug deli & Therapeutics 2012;2(2):72-5.

12. Vijaykumar G, Ajaykumar P, Karunasri Sk, Raghavendar K, Priya P. Development and evaluation of fast-dissolving film of Montelukast sodium. World J Med Pharm and Bio Sci 2011;1(1):6-12.

13. Nidhi PS, Vaishali AK, Anwar SD, Minal NB. Development of fast dissolving oral thin films of Ambroxol hydrochloride: Effect of formulation variables. J Adv Pharm Res 2011;2(2):102-9.

14. Arun A, Amish C, Vijay S, Kamla P. Fast dissolving oral films: An innovative Drug Delivery System and Dosage Form. Int J Chem Tech Res 2010;2(1):576-83.

15. Joshi PK, Harsha P, Vishnu P, Panchal R. Formulation development and evaluation of mouth dissolving film of Domperidone. J Pharm Bioall Sci 2012;4:108-9.

10 16. Deshmukh G, Deepti R, Seth AK, Jitendra P, Tejas G, Sharad K et al. Formulation and Development of Lamotrigine fast disintegrating tablet. Pharma Science Monitor, An Int J Pharm Sci 2011;2(3):7-15.

17. Raju S, Sandeep R, Anirudh K, Deepthi A, Sreeramulu R, Madhava R. Flash release oral films of metoclopramide hydrochloride for pediatric use: Formulation and in-vitro evaluation. J Chem Pharm Res 2011;3(4):636-46.

18. Aditya D, Mangal N. Formulation and evaluation of fast dissolving films for the delivery of Triclosan to the oral cavity. AAPS Pharm SciTech 2008;9(2):349-56.

19. Doaa A, Nevine S. Formulation of a novel Tianeptine sodium orodispersible film. AAPS Pharm SciTech 2010;11(3):1018-25.

20. Sathish D, Shayeda. Formulation and in-vitro evaluation of mucoadhesive buccal patches of Ondansetron Hydrochloride. Int J Pharm Sci & Nanotech 2010;3(1):860-66.

21. Patil C, Das S. Effect of various superdisintegrants on the drug release profile and disintegration time of Lamotrigine orally disintegrating tablets. Afr J Pharm Pharmcol 2011;5(1):76-82. 9. Signature of candidate

(SRIRAM SOMAYAJI.B) 10. Remarks of the guide The above given information is true and this work will be done under my guidance.

11. Name & Designation of Mr. SHRIPATHY.D M.Pharm (in block letters) Asst. Professor 11.1 Guide Department of pharmaceutics, Srinivas College of Pharmacy, Valachil, Mangalore-543143

11.2 Signature

11.3 Co-Guide (if any) ---

11.4. Signature ---

11.5 Head of Dept. Dr. A.R. SHABARAYA

M.Pharm,Ph.D. H.O.D and Principal, Srinivas College of Pharmacy, Valachil, Mangalore-574143 11.6 Signature

12. 12.1 Remarks of the Above mentioned information Principal is correct and I recommend the same for approval. 12.2. Signature

12 (DR. A.R. SHABARAYA)