6. / Brief Resume of the intended work:
6.1 – Need for the study:
Transdermal drug delivery systems (TDDS) allow delivery of contained drug into the systemic circulation via permeation through skin layer at a controlled rate. These systems are easy to apply and remove as and when desired. This approach of drug delivery is more pertinent in case of chronic disorders, such as hypertension, which required long term dosing to maintain therapeutic drug concentration.1
The transdermal route offers many advantages over the oral dosage forms, such as improving patient compliance in long term therapy, bypassing first-pass metabolism, sustained drug delivery, maintaining a constant and prolonged drug level in plasma.2
Hypertension is the most common cardiovascular disease involves elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. As a consequences, hypertension is the principle cause of stroke, is a major risk factor for coronary artery diseases and its attended complications. Myocardial infarction and sudden cardiac death, is a major contribution to cardiac failure, renal insufficiency and dissecting aneurysm of the aorta.3
Lercandipine is a new 1, 4-dihydroperydine derivative with potent long lasting and vascular selective calcium channel blocking agent. It is subjected to extensive first pass metabolism with an elimination half life of 2 hrs, has and poor bioavailability of 10 % having plasma protein binding of 98 %.4
Nicorandil is a potassium channel activator characterized by its arterial vasodilator properties, used in the treatment of angina pectoris. It is subjected to hepatic first pass metabolism with systemic bioavailability of about 75 %, has and having a short half life of 1 hr.5
The objective of the present investigation is to develop transdermal patches and subject them for characterization and evaluation studies.
6.2 – Review of literature:
1. Aqil M.et al. had prepared monolithic matrix type transdermal drug delivery system of metoprolol using Eudragit RL-100 and PVP-30 as polymers, aluminum foil backing membrane and plasticizer-PEG 400 and DMSO as permeation enhancer, further they characterized in-vitro drug release, skin permeation and drug excipients interaction analysis.1
2. Ubaidulla U.et al. had prepared different matrix patches with various ratios of hydrophilic and hydrophobic polymer combinations such as (a) ethyl cellulose (EC) and polyvinylepyrolidone (PVP), and (b) ERL 100 and ERS 100 containing carvidilol as a model drug. They evaluated the efficacy of transdermal patches against hypertension-induced albino rats.2
3.Krishnaiah YSR et al. prepared hydroxypropyl methyl cellulose gel drug reservoir with 70% v/v ethanol-water solvent system containing 10% w/w of nerodilol. It was effective in promoting the in-vitro transdermal delivery of nicorandil. The fabricated nerodilol based transdermal therapeutic system (TTS) of nicorandil provide a steady state plasma concentration of 25.5 ng/ml up to 24 hr, with minimal fluctuation and improved bioavailability.5
4. Kannikkannan N.et al.had prepared pre treated skin with laurocapram and iontophoresis on the pharmacodynamic effect of timolol maleate in-vivo in albino rabbits. In conculation, intophoresis in combination with laurocapram can increases the transdermal delivery of timolol maleate.6
5. Sankar V et al. prepared drug free polymeric film of ethyl cellulose and film containing nifedipine as model drug by casting on a glass plate. Both the films were evaluated for folding endurance, percentage moisture absorbance, percentage moisture loss, water vapor transmission, in-vitro skin permeation studies and permeation enhancement studies.7
6. Mehdizadeh A.et al. Designed different matrix and reservoir formulations of fentanyl transdermal patches using ethyl cellouse & cabomer 90 as polymer. The formulations were subjected to peel adhesion test, thumb lack, creep resistance test and for in-vitro release
study using USP paddle method.8
7. Mukherjee B.et al. had prepared transdermal matrix patches containing diclofenac diethylamine with various polymeric combinations of polyvinylpyrrilidone and ethyl cellulose. Sorbiton monolurate 20 was added as skin permeation enhancer. In-vitro drug release studies were carried out using USP paddle method, permeation of the drug was studied through excited rat skin using Keshary- Chien diffusion cell and drug polymer interaction was also studied using I.R.spectroscopy.9
6.3 Objectives of the study :
  1. To prepare transdermal patches containing a drug with various polymers.
  2. To evaluate transdermal formulations for physicochemical characters.
  3. To study the mechanism of release of drug from the patches using dialysis membrane and excised porcine skin.
  4. To evaluate antihypertensive activity in wistar albino rats.
7. Materials and Methods :
a)Materials:
  1. Drug: Modelantihypertensive drug ( Ex: Nicorandil/
Lercandipine / Prazosine).
2 Polymers:Eudragit RL-100 & RS-100, different grades of hydroxypropyl methylcellulose, Ethyl cellulose.
  1. Plasticizers: Di-n-butyl- phthalate, Tetra ethyl citrate.
4.Permeationenhancers: suitable class of permeation enhancers if
required.
b) Methods:
1)Solvent casting technique.
a)Drug and polymers were dissolved in suitable solvent at room temperature using magnetic stirrer.
b)Addition of suitable plasticizer and permeation enhancers.
c)The polymeric solution was then poured on mercury substrate into the Petri dish and dried.
d)Films of specific size were cut, packed in an aluminum foil and stored in desscicator.
7.1 Source of Data :
1. Review of literature :
a) Journals such as :
European Journal of Pharmaceutical Sciences
European Journal of Pharmaceutics and Biopharmaceutics
Journal of Controlled Release
International Journal of Pharmaceutics
Indian Journal of Pharmaceutical sciences
Indian Journal of Experimental Biology
b) Internet Browsing
c) CD-ROM Search
2. Laboratory Based Studies
7.2Method of collection of Data :
1. Formulation of transdermal patches with antihypertensive drug.
2. Evaluation of transdermal formulation by:
a) Physicochemical evaluation:
  • Folding endurance.7
  • Thickness of the film.7
  • Weight variation.7
  • Percentage elongation.10
  • Drug content.11
  • Stability studies as per ICH guidelines.13
b) Adhesiveness :
  • Thumb tack test.8
c) Drug exipients interaction:
  • By FT-I.R spectroscopy.2, 12
  • By Differential Scanning Calorimetry (DSC).2
d) In-vitro skin permeation studies:
  • Keshary-Chien diffusion cell using dialysis membrane and excised porcine skin.
e) In-vitro release study.
  • USP-2dissolution apparatus Paddle method.1, 8, 9.
g) In-vivo study in hypertensive Wistar albino rats.1, 2.
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.
- YES, Skin permeabilitystudy will be done on porcine ear skin and in vivo antihypertensive activity will be done on hypertension induced Wistar albino rats.
7.4 - Has ethical clearance been obtained from your institution in case of 7.3?
- Applied to Institutional Animal Ethical Committee.
8.List of references:
  1. Aqil M, Ali A, Sultan Y, Dubey K: in vivo characterization of monolithic matrix type transdermal drug delivery system of pinacidil monohydrate.AAPS pharmsciTech 2006; 7 (1):E1-5.
  1. Ubaidulla U, Reddy M V S: Transdermal therapeutic system of carvidilol: Effect of hydrophilic and hydrophobic matrix on in-vitro and in-vivocharacteristics:AAPS PharmSciTech 2007:8(1):E1-8.
  1. Goodman & Gilman’s- The Pharmacological Basis of Therapeutics. 11th Edn. Delhi.Mc Graw-Hill; p.845.
  1. Martindale the complete drug reference 35th edition, Lercandipine 1189-90.
  1. Krishnaiah YSR, Al-saidan S.M, Chandresekhar D.V, Satyanarayana V: Bioavailability of nirodilol-based transdermal therapeutic system of nicorandil in human volunteers: J of controlled release 106 (2005) 111-22.
  1. Kanikkannan N, Sing J, Ramarao J: Transdermal ionotophorotic delivery of timolol maleate in albino rabbits. Int J Pharm 197(2000) 69-76.
  1. Sanker V, JohnsonD B, Sivanad V, RavichandranV,RaghuramanS, Velrajan G, Palaniappan R, Rajasekar S, Chandrashekaran A.K : Design and evaluation of nefidipine transdermal patches. Indian J Pharm Sci 2003; 65 (5): 510-15.
  1. Mehdizadeh A, Toliate T, Rouini M R, Abash-Zadeh S, Dorkoosh F. Design and in vitro evaluation of new drug in adhesive formulation of fentanyl transdermalpatches. Acta Pharm 2004; 54:301-17.
  2. Mukherjee B, Kanupriya, Mahapatra S, Das S, Patra B. Sorbiton Monolurate 20 as a potential skin permeation enhancer in transdermal patches. J App Res 2005; 5(1): 96-108.
  1. Dandagi PM, Manvi FV, Gadad AP, Mastiholimath VS, Jagadeesh T. Formulation of a transdermal drug delivery system of Ketotifen fumarate. Indian J Pharm Sci 2003; 65 (3):239-43.
  1. Guyot M, Fawaz F, Design and in-vitro evaluation of adhesive matrix of transdermal delivery of propanolol. Indian J Pharm 200; (58): 278-89.
  1. Malshe VC, Lall JK, Bapat VR, Acrylate: Adhesive for transdermal therapeutic system. Indian J Pharm Sci 1994; 56 (1): 5-9.
  1. Panchagnula R, Bokalial R, Sharma P, Khandavilli S. Transdermal delivery of naloxone: skin permeation, pharmacokinetic, irritancy and stability studies. Int J Pharm 2005; 293:213-23.