“LERCANIDIPINE HYDROCHLORIDE MATRIX TYPE TRANSDERMAL DRUG DELIVERY SYSTEMS:IN-VITRO CHARACTERIZATION”

M. Pharm. Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Bangalore

Karnataka

By

Mr. IMRAN. SHAIK. MOHAMMADB.Pharm.

Under the Guidance of

VENKATARAJU M.P

Professor& HOD

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY

EAST WEST COLLEGE OF PHARMACY

BANGALORE – 560 091

2010-2012

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 / Name of candidate and address (In Block Letters) / IMRAN.SHAIK.MOHAMMAD
H.NO-45/24/180-A1,ASHOK NAGAR
KURNOOL, ANDHRA PRADESH-518002.
2 / Name of the Institute / EAST WEST COLLEGE OF PHARMACY, BANGALORE-560 091
3 / Course of study and subject: / M.PHARM
PHARMACEUTICAL TECHNOLOGY.
4 / Date of admission of course: / 13/10/2010
5 / Title of the topic:
“LERCANIDIPINE HYDROCHLORIDE MATRIX TYPE TRANSDERMAL DRUG DELIVERY SYSTEMS:IN-VITRO CHARACTERIZATION”
6 / Brief Resume of this intended work:
6.1 Need for the study Enclosure-I
6.2 Review of Literature Enclosure-II
6.3 Objectives of study Enclosure-III
7 / Materials and Methods:
7.1 Source of data Enclosure-IV
7.2 Method of collection of data (Including sampling procedure, if any)
Enclosure-V
7.3 Does the study require any investigation or interventions to be conducted on patients of humans or animals? If so, please describe briefly.
------NO------
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
------NOT APPLICABLE------
8 / List of References Enclosure-VI
9 / Signature of the candidate / (IMRAN. SHAIK.MOHAMMAD)
10 / Remarks of the Guide / The proposed research work is recommended for registration and approval
11 / Name and designation of (in block letters)
11.1 Guide
11.2 Signature / Dr. VENKATARAJU M.P
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICAL TECHNOLOGY,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.3 Co-Guide (if any)
11.4 Signature / Mr. SUBHASH P.G
11.5 Head of Department
11.6 Signature / Dr. VENKATARAJU M.P
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICAL TECHNOLOGY,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
12 / 12.1 Remarks of the Chairman / Principal
12.2 Signature / Prof. K. A. SRIDHAR
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091

ENCLOSURE-I

6) Brief resume of the intended work:

6.1) Need for the study:

Administration of drugs into systemic circulation via skin has generated a lot of interest during the last decade as transdermal drug delivery systems (TDDS) offers key advantages over the conventional dosage forms and oral controlled release delivery systems notably avoidance of hepatic first pass metabolism, decrease in frequency of administration, reduction in gastrointestinal side effects and improves patient compliance.1 Recognizing the advantages of transdermal drug delivery system in the recent past years, many such systems are marketed for some anti-arrhythmic drugs (isosorbide dinitratre), drugs to treat motion sickness (scopolamine), Angina pectoris (nitroglycerine), drugs to treat hypertension (clonidine), drugs used in the treatment of cancer (fentanyl) etc.2

The present work will be carried out with lercanidipine hydrochloride as a suitable drug candidate for the fabrication of matrix type transdermal drug delivery system. Poor oral absorption, short biological half life (2hrs) andvery low bioavailability of about 44% due to extensive first pass metabolism which made the drug choice for TDDS.3-4

ENCLOSURE-II

6.2) Review of Literature:

GuyotMet al.,have preparedPropranolol hydrochloride, a water-soluble drug, was incorporated in three transdermal delivery systems using three polymers such as hydroxypropylmethylcellulose, PIB and ucecryl®MC808. The influence of different factors (polymeric material, matrix thickness, drug content, thickness of the adhesive layer and presence of a dissolution enhancer) was investigated. The results of microscopic observations and DSC thermograms have permitted to demonstrate that propranolol was essentially dissolved in the HPMC matrix and dispersed in the two other matrix types. In-vitro dissolution study was carried out according to European Pharmacopoeia. They found that the release from HPMC matrices without adhesive coating was fast. Release from these matrices became slow when they are coated with a 12 mm thick ucecryl layer. Release from different PIB matrices was too slow to be suitable as TDDS for propranolol. The best release modulation was obtained from ucecryl matrices.1

Sang CSet al., were carried out to evaluate the possibility of using polymer EVA membrane as an EVA matrix system for transdermal delivery of atenolol. The effects of drug concentration, temperature, and plasticizers on drug release were studied from the atenolol-EVA matrix. They revealed that the release rate of drug from the EVA matrix increased with increased temperature and drug loading doses. The flux of atenolol versus the reciprocal of the loading dose yielded a straight line. The release of atenolol from the EVA matrix follows a diffusion-controlled model. Among the plasticizers used such as alkyl citrates and phthalates, tributyl citrate showed the best enhancing effects. The controlled release of atenolol system could be developed using the EVA polymer including the plasticizer.5

Biswajit M et al., have designed a matrix type TDDS of dexamethasone using blends of two different polymeric combinations, povidone (PVP) and ethylcellulose (EC) and Eudragit with PVP. They performed the physical studies such as moisture content, moisture uptake, flatness to study the stability of the formulations and in-vitro dissolution of the experimental formulations. Scanning electron microscopy (SEM) photographs of the prepared TDDS were taken to see the drug distribution pattern. Drug-excipient interaction studies were carried out using Fourier transform infrared (FTIR) spectroscopic technique. In-vitro skin permeation study was conducted in a modified Franz’s diffusion cell. All formulations were found to be suitable for formulating in terms of physicochemical characteristics and there was no significant interaction noticed between the drug and polymers used. In-vitro dissolution studies showed that the drug distribution in the matrix was homogeneous and the SEM photographs further demonstrated this. The formulations of PVP:EC provided slower and more sustained release of drug than the PVP:Eudragit formulations during skin permeation studies and the formulation PVP:EC (1:5) was found to provide the slowest release of drug. It can be reasonably concluded that PVP-EC polymers are better suited than PVP-Eudragit polymers for the development of dexamethasone.6

Roland Bet al.,have studied the adhesive properties of polyisobutene adhesives and acrylic adhesives in the formulation of crystal-free patches. They found that the drug release from those patches were independent of polyisobutene’s molecular weight distribution, probably because the drug release occurred mainly through fluid filled channels. On the other hand, the drug release from acrylic adhesives was independent of whether the patches contained pure drugs or drug adsorbates on to crospovidone. A higher degree of saturation in those systems resulted in a higher thermodynamic activity of the drugs and hence a higher drug release. The crystal-free acrylic and polyisobutene patches did not showed drug recrystallization after 3 months at 25 0C/60 RH and 40 0C/75 RH. The adhesive properties of polyisobutene patches were investigated in-vitro and in-vivo. From their studies, it can conclude that crospovidone contents ≤30% had no detrimental effect on the adhesive properties of the patches.7

Satyanarayan Pet al., have examined the influence of casting solvent on crystallinity of the ondansetron hydrochloride in transdermal polymeric matrix films fabricated using povidone and ethyl cellulose as matrix forming polymers. Various casting solvents like chloroform (CHL), dichloromethane (DCM), methanol (MET) and mixture of chloroform and ethanol (C-ETH) were used for fabrication of the transdermal films. Analytical tools like scanning electron microscopy (SEM), x-ray diffraction (XRD) studies, differential scanning calorimetry (DSC), etc. were utilized to characterize the crystalline state of ondansetron in the film. Recrystallisation was observed in all the transdermal films fabricated using the casting solvents other than chloroform. They found long thin slab-looking, long wire-like or spherulite-looking crystals with beautiful impinged boundaries were observed in SEM. Moreover, XRD revealed no crystalline peaks of ondansetron hydrochloride in the transdermal films prepared using chloroform as casting solvent. The significantly decreased intensity and sharpness of the DSC endothermic peaks corresponding to the melting point of ondansetron in the formulation (specifically in CHL) indicated partial dissolution of ondansetron crystals in the polymeric films. The employed analytical tools suggested chloroform as a preferred casting solvent with minimum or practically absence of recrystallization indicating a relatively amorphous state of ondansetron in transdermal films.8

Ashish Aet al., have formulated transdermal drug delivery system (TDDS) of carvedilol (CRV) and hydrochlorothiazide (HCTZ). They compared the bioavailability of these two study drugs from a TDDS with conventional immediate release oral tablets in healthy volunteers. This was an open-label, randomised, single centre, two treatment, two period, single dose, crossover pilot study of two formulations of cardiovascular agents. Subjects (n=10) were randomised to have a TDDS applied to their abdominal skin for 72 h or receive one oral tablet each of CRV and HCTZ respectively in period I, followed by 1-week washout period. They received the alternative treatment in period II. A significant improvement in bioavailability was observed with the transdermal patches over oral tablets.They have concluded from those observations that the TDDS meets the intended goal of at least 2 day management of stage II hypertension with application of a single transdermal patch.9

Aqil Met al., have performed monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate (PM) by film casting technique on mercury substrate and characterised in-vitro by drug release studies using paddle over disc assembly, skin permeation studies using Keshary and Chein diffusion cell on albino rat skin and drug-excipient interaction analysis.They developed with varied concentrations of polymers such as Eudragit RL-100 and PVP K-30. All the four formulations carried 20% w/w of PM, 5% w/w of plasticiser, PEG-400 and 5% w/w of DMSO in isopropyl alcohol: dichloromethane (40:60) solvent system.On the basis of in-vitro drug release and skin permeation performance, formulation B-4 was found to be better than the other three formulations and it was selected as the optimised formulation. The interaction studies carried out by comparing the results of assay, ultraviolet, infrared and TLC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipient.10

ENCLOSURE-III

6.3) Objective of the study:

The present study is planned with the following objectives:

•To evaluate the solubility of the drug.

•To carry out permeability studies using appropriate diffusion cell.

•To study the effect of different enhancers on the permeability of lercanidipine Hcl.

•To prepare the matrix type transdermal drug delivery system containing lercanidipine Hcl employing solvent casting technique or any suitable method.

•To study the in-vitro release of drug from developed transdermal drug delivery system across the synthetic semi permeable/biological membrane through appropriate diffusion cell.

ENCLOSURE-IV

7) Materials and Methods:

Materials:

Drug: Lercanidipine hydrochloride.

Polymers: Synthetic or semi synthetic or natural polymers or combination of these.

Plasticizer: n-dibutylpthalate/glycerine/castor oil/any other suitable plasticizer.

Enhancers: DMSO/DMF/sodium EDTA/Hyaluronidase or any other suitableenhancer.

Methods: The preparation of matrix type TDDS by solvent casting technique or any suitable method.

7.1) Source of data:

Data is collected from:

1 Science Direct & other internet facilities.

2 Pharmaceutical poster presentations.

3 Research publications.

4 International and Indian journals.

5 Textbooks and reference books.

6 RGUHS Library.

ENCLOSURE-V

7.2) Method of collection of data:

1.Identification of drug by

Using UV-Spectroscopy (Shimadzu 1800).

2. Preparation of TDDS.

3.Evaluation parameters

Thickness

Weight variation

Folding endurance

Tensile strength

Drug content

4.In-vitro drug release studies using suitable diffusion cell.

ENCLOSURE- VI

8) List of references:

  1. Guyot M, Fawaz F. Design and in-vitro evaluation of adhesive matrix for transdermal delivery of propranolol.Int J Pharm 2000;204:171-82.
  2. Anna MW, Suneela P, William HD, Ajaz SH, Lucinda FB. Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute. Eur J Pharm Biopharm 2006;64:1-8.
  3. Martindale, The complete drug reference. Pharmaceutical Press. 2007;35(1):1189.
  4. Barchielli M. Clinical pharmacokinetics of lercanidipine. J Card pharmacol 1997;29:S1- S15.
  5. Jin K, Sang CS. Controlled release of atenolol from the ethylene-vinyl acetate matrix. Int J Pharm 2004;273:23-7.
  6. Mukherjee B, Sushmita M, Ritu G, Balaram P, Amit T, Priyanka A.Comparison between povidone-ethylcellulose and povidone-eudragit transdermal dexamethasone matrix patches based onin-vitro skin permeation. Eur J Pharm Biopharm 2005;59:475-83.
  7. Martin S, Bernhard F, Roland B. Drug release and adhesive properties of crospovidone containing matrix patches based on polyisobutene and acrylic adhesives. Eur J Pharm Sci 2010;41:675-84.
  8. Satyanarayan P, Kalpana S, Subrata M, Zhiqun L. Effect of casting solvent on crystallinity of ondansetron in transdermal films. Int J Pharm 2011;406:106-10.
  9. Shyam SA, Ashish A.Randomised, cross-over, comparative bioavailability trial of matrix type transdermal drug delivery system (TDDS) of carvedilol and hydrochlorothiazide combination in healthy human volunteers:A pilot study Contemp Clin Trials. 2010;31:272-78.
  10. Aqil M, Asgar A. Monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: in-vitro characterisation. Euro J Pharm Biopharm. 2002;54:161-64.

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