PREPARATION AND EVALUATION OFTRANSDERMAL PATCHES OF TERBUTALINE SULPHATE
M.Pharm Dissertation Protocol Submitted to the
RajivGandhiUniversity of Health Sciences,
Karnataka, Bangalore
By
Mr.MALAVI SHOBHARAJ BHARAT
B.Pharm
Under the esteemed guidance of
Dr.C.C. PATIL . M.Pharm., Ph.D
Professor and Head
Department of Pharmaceutics
B.L.D.E.A’S College of Pharmacy, Bijapur-586 103
2010-2011.
RajivGandhiUniversity of Health Sciences, Karnataka, Bangalore
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate andAddress(In block letters) / MR. MALAVI SHOBHARAJ BHARAT
2. / Name of the Institution / B.L.D.E.A’S COLLEGE OF PHARMACY,
B.L.D.E.A’S UNIVERSITY CAMPUS,
BIJAPUR-586 103
3. / Course of study and subject / M.PHARM (PHARMACEUTICS)
4. / Date of admission to Course / 17-06-2010
5. / Title of the Topic / PREPARATION AND EVALUATION OFTRANSDERMAL PATCHES OF TERBUTALINE SULPHATE
6. / Brief resume of the intended work :
6.1 Need for the study
6.2 Review of literature
6.3 Objectives of the study / Enclosure-I
Enclosure-II
Enclosure-III
7. / Material and Methods :
7.1 Source of data : ENCLOSURE-IV
7.2 Method of collection of data (including sampling procedure, if any)
: ENCLOSURE-IV
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.
: ENCLOSURE - V
7.4Has ethical clearance been obtained from your institution in case of 7.3
:YES
8. / List of References (about 4-6)
: ENCLOSURE-VI
9. / Signature of candidate
10. / Remarks of the guide / : ENCLOSURE-VII
11. / Name & Designation of
(in block letters)
11.1. Guide
11.2. Signature
11.3. Co-Guide (if any)
11.4. Signature
11.5. Head of Department
11.6. Signature / Dr. C.C.PATIL. M.Pharm.,Ph.D
PROFESSOR &HEAD
DEPARTMENT OF PHARMACEUTICS.
B.L.D.E.A’S COLLEGE OF PHARMACY, BIJAPUR-586 103
--
--
Dr. C.C.PATIL. M.Pharm.,Ph.D
PROFESSOR &HEAD
DEPARTMENT OF PHARMACEUTICS.
B.L.D.E.A’S COLLEGE OF PHARMACY, BIJAPUR-586 103
12. / 12.1. Remarks of the chairman & principal: This study can be carried out in our
laboratory
12.2. Signature Dr.N.V.KALYANE M.Pharm.,Ph.D
Principal
ENCLOSURE-I
6) Brief resume of the intended work
6.1 Need for the study
Transdermal rate controlled drug delivery offers one or more of the following potential biomedical benefits, avoids the risks and inconveniences of intravenous therapy, bypass the variation in the absorption and metabolism associated with oral administration, permit continuous drug administration and the use of drugs with a short biological half life, increase the bioavailability and efficacy of drugs through the bypass of hepatic first pass elimination, reduce the chance of over or underdosing through the prolonged, preprogrammed delivery of drug at the required therapeutic rate, provide a simplified therapeutic regimen leading to better patient compliance, permit a rapid termination of the medication, if needed, by simply removing the TDDS from the skin surface. 1
Terbutaline Sulphate is widely used for the therapeutic management of chronicas well as prophylaxis of asthma and nocturnal asthma in particular. It is a drug of choice for the treatment of asthma but it has several drawbacks such as short biological half-life of about 3.6 hours1, it is readily metabolized in the gut wall and liver when given orally. It has a short duration of action, low peak plasma level of 1.2 μg/ml and poor bioavailability of only 14.8%. These factors necessitated formulation of controlled release transdermal drug delivery system for terbutaline sulphate, as this route of drug administration would reduce the dosing frequency hence better patient compliance.2
Hence, the present work deals with the preparation and evaluation of transdermal therapeutic systems containing terbutaline sulphate.
ENCLOSURE-II
6.2. Review of literature
1. Bharkatiya M. et al., The present investigation was taken up to prepare and evaluate drug free polymeric patches using different polymers and to study the effect of different plasticizers on physicochemical properties of the patches to explore their feasibility for transdermal application. Polyethylene glycol (PEG 400), Dibutylphthalate (DBP) and Propylene glycol (PG) were used as plasticizers at a concentration of 40 % w/w of dry polymer weight. Drug free polymeric patches were prepared by the casting method on mercury surface and evaluated for weight variation, thickness, flatness, tensile strength, folding endurance, surface pH, hardness, swellability, water vapour transmission rate and skin irritation studies. The mercury substrate method was found to give thin uniform patches.The weight and thickness of the patches was found to be uniform. Tensile strength and folding endurance of the patches prepared with DBP as plasticizer was high compared to patches plasticized with PG and PEG. All the formulations show 100 % flatness. HPMC K4M: PVP patches plasticized with PEG 400 showed higher swellability and water vapour transmission rates. The patches were found to be free of any skin irritation. Based on the above observations, it can be reasonably concluded that plasticizers have a significant influence on the mechanical properties of the transdermal patches.3
2. Bhatnagar M. et al., Transdermal drug delivery systems are polymeric patches containing dissolved or dispersed drugs that deliver therapeutic agents at a constant rate to the human body. Matrix type transdermal patches containing Metoprolol tartrate were prepared by solvent casting method employing a mercury substrate by using the combinations of EC-PVP and Eudragit RL 100-PVP in different proporations. The transdermal patches were evaluated for their physicochemical properties like thickness, weight variation, flatness, tensile strength, hardness, folding endurance, drug content, swellability, surface pH, water vapour transmission, in vitro permeation and skin irritation studies. FTIR, DSC and UV studies indicated no interaction between drug and polymers. The permeability of Metoprolol tartrate was increased with increase in PVP content. The burst effect due to the incorporation of PVP was because of the rapid dissolution of the surface hydrophilic drug which results in the formation of pores and thus leads to the decrease of mean diffusional path length of the drug molecules to permeate into dissolution medium and higher permeation rates. The in vitro drug permeation followed higuchi kinetics as its coefficient of correlation values predominates over zero order and first order kinetics. Also the diffusion coefficient of release profiles (slope) had a value of nearly 0.5, which indicated fickian transport diffusion. The patches were found to be free of any skin irritation. Based on the above observations, it can reasonably concluded that Eudragit RL 100 PVP polymers are better suited than EC-PVP polymers for the development of transdermal patches of Metoprolol tartrate. 4
3. Prabhakara P. et al.,Transdermal patches of Papaverine hydrochloride were prepared by solvent casting method using ethyl cellulose: PVP, PVA: PVP and eudragit RL-100: eudragit RS-100 in different ratios. The physicochemical parameters like flex-ibility, thickness, smoothness, weight variation, moisture content, hardness and tensile strength were evaluated and found to be flexible, uniform thickness and weight, smooth, good drug content (92 to 96%) and little moisture absorption. The in-vitro diffusion studies were carried out using modified Keshery-Chein cell with cellophane as diffusion membrane and the formulation followed Higuchi diffusion mechanism. The formulation containing PVA:PVP as polymers showed faster release rate (hydrophilic polymers) compared to eudragit RL-100:eudragit RS-100 (hydrophobic polymers) or combination of hydrophilic and hydrophobic polymers (Ethyl cellulose and PVP). The stability studies indicated that all the patches maintained good physicochemical properties and drug content after storing the patches in different storage conditions. Compatibility studies indicated that there was no interac-tion between the drug and polymers.5
4. Chakraborty P. et al., Verapamil hydrochloride is a calcium ion influx inhibitor, which is used widely in the treatment of angina pectoris, hypertension and supraventricular tachyarrhythmias and used as conventional and sustained release dosage form. Present study is aimed at proper designing of the formulation parameters in terms of the excipient incorporation. Excipients include broadly hydrophilic and hydrophobic polymers, plasticizers and penetration enhancer. Polymers includes ethyl cellulose, hydroxyl propyl methyl cellulose K4M and polyvinyl pyrrolidone.Polyvinyl alcohol was used as to prepare backing membrane, Dibutyl phthalate was used as plasticizer and DMSO was used as transdermal penetration enhancer. After preparation of the transdermal patches, they were examined in respect to several physicochemical properties thickness, percent moisture content, percent moisture absorption, percent flatness, tensile strength, weight variation to satisfy the suitablephysicochemical criteria for transdermal patch. For all the formulations, invitro release and skin permeation of the drug with and without incorporation of penetration enhancer (DMSO) through abdominal skin of albino rat were studied using Keshary-Chien diffusion cell. Formulation containing increased proportion of hydroxyl propyl methyl cellulose K4M and polyvinyl pyrrolidone showed faster release of drug over a period of 24 hours where as increased proportion of ethyl cellulose produce a prolonged release of drug through transdermal route for a period of more than 24 hours. DMSO significantly increased the permeation of drug through abdominal skin of albino rat.6, 7
ENCLOSURE-III
6.3. Objectives of the study
The present work is planned with the following objectives.
1)To prepare transdermal therapeutic systems (TTS) using various polymers.
2)To evaluate the TTS for various physicochemical properties.
3)To study the nature of drug in the formulations.
4)To study the in vitro drug release/permeation through cellophane membrane.
ENCLOSURE-IV
7) MATERIALS AND METHODS
7.1. Source of data
The data will be collected by performing various laboratory experiments, referring journals, text books and other literature.
7.2. Method of collection of data
The whole data is planned to collect from laboratory experiments which includes the following,
1)Development of transdermal therapeutic systems (TTS) using different polymers like Cellulose Acetate, Ethyl Cellulose, PVP, Propylene glycol. etc. by solvent casting technique.
2) The physical characterization of the prepared TTS are evaluated for thickness, tensile strength, weight variation and water vapour permeation will be studied and data will be collected.
3) The nature of drug in the formulation will be studied by XRD and data will be
collected.
4) The in-vitro permeation studies were carried out using a modified Keshary- Chein
diffusion cell.
5)The stability studies will be carried out as per ICH guidelines and data will be
collected.
ENCLOSURE-V
7.3. This study is aimed to carry out the following animal studies.
1) Skin permeation studies: The excised abdominal skin of rats will be used to
perform the in-vitro skin permeation study (No of rats required: 10, Sex: Male, Weight: 150-200 gm).
4) Skin irritation study: The prepared transdermal systems will be evaluated for
skin irritation on rabbits (No of rabbits required = 10).
7.4. Animal ethical clearance has been obtained to carry out the above said animal
experiments.
ENCLOSURE-VI
8) List of References
1. Corbo M., Llu J.C., Chien Y.W.,1989 “Advances in Transdermal controlledDelivery System”. Pharm. Res., 6: 301-79.
2. Rathore R., Chauhan C., Naruka P., Tanwar Y., Chauhan L.,2006 “Transdermal Formulation of TerbutalineSulphate. ”PharmacyOn Line.
3. Bharkatiya M., Nema R.,Bhatnagar M.,2010 “Designing and Characterization of Drug Free Patches for Transdermal Application.”Int J of Pharma Sci and Drug Res., 2(1): 35-39.
4.BhatnagarM.,Bharkatiya M., Rajesh Kumar N, 2010 “Development and characterization of transdermal patches of Metapropol tartarate.” Asian J of Pharma and Clinical Research., 3(2):130-134.
5. Prabhakara P., Koland M., Vijaynarayana K., Harish NM., Shankar G., MohdGulzar Ahmed, NarayanaCharyulu R., Satyanarayana D., 2010 “Preparation and evaluation of Transdermal patches of Papaverine hydrochloride. ”Int. J. Res. Pharm. Sci., 3: 259-266.
6. Chakraborty P., Dutta D., Biplab Kumar D.,2010 “Effect of polymer blends in drug release kinetics from transdermal drug delivery system.”Int J of Drug Development & Research., 2(2):300-309.
7. Agarwal S.S., Munjal P.,2009 “ Permeation studies of Atenolol and MetaprololTartarate From Three different Polymer Matrices for Transdermal Delivery”.Ind.JPharm.Sci., 69: 535-39.
ENCLOSURE-VII
10) Remarks of the Guide
The present work is aimed to prepare and evaluate the transdermal formulation of terbutaline sulphate. Terbutaline sulphate is an important bronchodilator drug used in the treatment of asthma, bronchitis and other respiratory disorders. The drug has a shorter biological half-life of about 3-4 hours and it is readily metebolised in the gut wall and liver after oral administration. The drug has also a short duration of action and poor bioavailability. Therefore, it needs to be administered frequently in order to achieve constant plasma levels, but the frequent administration may leads to dose accumulation and toxicity. Hence, to conquer this limitation, preparationof transdermal drug delivery systemfor terbutaline sulphate,is planned.
The proposed study can be carried out in the laboratory.
Dr. C. C. PatilM.Pharm.,Ph.D
Professor&Head
Departement of pharamaceutics
Reserch Guide