6. / Brief resume of the intended work
6.1. Need for the study:
Transdermal drug delivery (TDD) patches are designed to deliver atherapeutically effective amount of drug across a patient’s skin. Transdermal patches typically involve a liquid, gel, solid matrix, or pressure-sensitive adhesive carrier into which the drug is incorporated. The earliest TDD systems were reservoir-type devices that used membranes to control the rate of drug release. Today, a drug is more commonly dispersed or dissolved in a pressure-sensitive adhesive (PSA) matrix1.
The transdermal drug delivery route is believed to have greater therapeutic benefits compared with the oral and Parenteral routes, including decreased drug degradation due to gastrointestinal metabolism and first-pass metabolism in the liver, maintaining the therapeutic drug concentration over a long period of time, avoiding fluctuations in drug concentration and thus decreasing adverse reactions2.
Transdermal patches control the delivery of drugs in a controlled manner by employing an appropriate combination of hydrophilic and lipophilic polymers3. In case of matrix controlled systems the drug is dissolved or suspended in a hydrophilic or lipophilic matrix4.
Diabetes mellitus is a major and growing health problem worldwide and an important cause of prolonged ill health and early death. It is a chronic metabolic disorder characterized by a high blood glucose concentration (hyperglycemia) caused by insulin deficiency and it is often combined with insulin resistance. Because antidiabetic drugs are usually intended to be taken over a long period transdermal delivery systems may provide a useful drug therapy with regard to patient compliance5.
Repaglinide is a oral insulin secretagogue of the Meglitinide class. It stimulates insulin release by closing ATP–dependent potassium channels in pancreatic β cells6.
Intensive research has showed that transdermal route is potential mode of delivery of lipophilic drugs in the systemic circulation. Repaglinide is a lipophilic drug used for lowering the blood glucose level by stimulating the insulin secretion. After oral administration peak plasma concentrations of repaglinide is reached within one hour. It possesses low oral bioavailability (56%) due to hepatic first pass metabolism after oral administration and has a short biological half-life of ~1h (Hardman et al., 2001), Which makes frequent dosing necessary to maintain the drug within the therapeutic blood level for long periods7.
Nateglinide is an orally effective insulin secretagogue derived from D-
Phenylalanine. It stimulates insulin secretion by blocking ATP–sensitive potassium channels in pancreatic β cells6. This lipophilic drug has an oral bioavailability of 73%, but a relatively short elimination half life of 1.5 hours, thereby requiring thrice daily dosing in large number of patients8.
Glipizide an oral hypoglycemic agent belonging to the class of sulfonylureas6. It is practically water-insoluble, but the absolute bioavailability is close to 1. Glipizide has a relatively short elimination half-life (2–4 h), thereby requiring twice daily dosing in large number of patients which often leads to non-compliance. Thus, there is a strong clinical need and market potential for a dosage form that will deliver Glipizide in a controlled manner to a patient needing this therapy, thereby resulting in a better patient compliance9.
The objective of the present investigation is to develop a matrix type transdermal system for a suitable antidiabetic agent and subject the formulation for characterization and evaluation.
6.2 Review of literature: -
  1. Guang-Ming KE et al., had developed a new Clonidine Transdermal Patch called as KBD-transdermal therapeutic system. In vitro release, penetration, and in vivo pharmacokinetics in rabbits were investigated. The transdermal penetration rate of clonidine was mainly controlled by the ethylene vinyl acetate membrane used in the patch2.
  1. Biswajit Mukherjee et al., had designed & developed a suitable matrix type transdermal drug delivery system(TDDS) of dexamethasone using blends of two different polymeric combinations, povidone (PVP) and ethylcellulose (EC) and Eudragit with PVP. Physical studies including moisture content, moisture uptake, flatness to study the stability of the formulations and in vitro dissolution of the experimental formulations were performed to determine the amount of dexamethasone present in the patches. Drug–excipient interaction studies by FTIR spectroscopic technique & skin permeation study using modified Franz’s diffusion cell were done. It was concluded that PVP–EC polymers are better suited than PVP–Eudragit polymers for the development of TDDS of dexamethasone3.
  1. Claudia Valenta et al., reviewed the use of polymers for skin preparations. They had reported that, polymers used on skin belong to various classes like: cellulose derivatives, polyacrylates, polyvinyl alcohol, polyvinyl pyrrolidone and silicones4.
  1. Srinivas Mutalik et al., had prepared Membrane-moderated transdermal systems of glipizide using drug-containing carbopol gel as drug reservoir and ethyl cellulose, as well as Eudragit RS-100, Eudragit RL-100 and ethylene vinyl acetate as rate-controlling membranes. The prepared patches were subsequently evaluated for in vitro: drug content and drug permeation studies and in vivo for:acute and long-term hypoglycemic activity, effect on glucose tolerance, biochemical and histopathological studies, skin irritation test & pharmacokinetic studies in mice5.
  1. G.D. Gupta et al., had prepared matrix type transdermal polymeric membrane systems of repaglinide by usingEudragit NE 30D as polymer. Various formulations were prepared using oleic acid, tween-60, span-80, & iso proply myristate as permeation enhancers. Prepared matrices were evaluated for their physico-chemical characteristics: weight variation, thickness uniformity, tensile strength and percent elongation at break, drug content uniformity,interaction studies and stability studies. In-vitro permeation profile across human cadaver skins using a modified Keshery-Chien diffusion cell was done. Different models were applied to evaluate release mechanism and kinetics7.
  1. Krishna D.R et al., had developed acrylate based transdermal drug delivery system for glibenclamide by mercury substrate method. Patches were evaluated for its hypoglycemic activity in normal and streptozotocin induced diabetic rats10.
  1. Shankar V et al., prepared drug free polymeric film of ethyl cellulose and film coating 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 vapour transmission, in vitro skin permeation studies and permeation enhancement studies11.
  1. Ikuhiro etal., had prepared matrix patches of formoterol fumarate using ethylene-vinyl acetate as the forming polymer, menthol as an forming enhancer, N- methyl -2- pyrrolidone as the solvent and hydrogenated rosin glycerol ester as the adhesive. Further they studied the permeability and stability of the Formoterol fumarate in matrix patches12.
  1. Ilbeyi Agabeyoglu etal., had developed a membrane controlled transdermal therapeutic system containing Isosorbide dinitrate by using ethylene vinyl acetate copolymer and polyethylene membrane as rate controlling membrane. A Carbomer gel was used as a drug reservoir. In vitro release of drug using FDA recommended method was carried out13.
  1. Olivier J C et al., compared two marketed transdermal matrix patches of nicotine by carrying out In-vitro release studies14.
  1. Cheong-Weon Choet al., had prepared matrix type transdermal patches of Atenolol using ethylene–vinyl acetate (EVA). Effect of penetration enhancer on the permeation of atenolol through the excised rat skin was studied. Among enhancers used such as glycols, fatty acids and non-ionic surfactants; polyoxyethylene 2-oleyl ether showed the best enhancement. This showed that for the controlled transdermal delivery of atenolol, the application of EVA membrane containing permeation enhancer could be useful in the development of transdermal drug delivery system15.
  1. Darshan K. et al., had checked the Feasibility of Transdermal Delivery of Fluoxetine using permeation enhancers like azone, SR-38 & ethanol. Permeation studies were done across human cadaver skin using Franz diffusion cells. Ethanol(65% vol/vol) was able to increase the permeation of fluoxetine the most21.

7. / 6.3 Objective of the study: -
  • To prepare transdermal matrix patches containing antidiabetic drug with various polymeric combination.
  • To characterize transdermal formulation for physicochemical properties.
  • To study the mechanism of release of drug from the patches and its skin permeation.
------Materials and methods:-
a) Materials: -
  • Drug : Repaglinide / Nateglinide / Glipizide etc.
  • Polymers : Different grades of Eudragit, Ethyl .
Cellulose, HPMC, Ethyl vinyl acetate etc.
  • Permeation enhancers : Any suitable class, if required.
b) Method: -
  • Solvent casting technique.
  • Drug and polymer are dissolved in suitable solvent at room temperature using magnetic stirrer.
2. Addition of suitable plasticizer and permeation enhancer.
3. The polymeric solution is then poured on mercury substrate petri dish and dried.
4. Films of specific size are cut, packed in aluminum foil and stored.

7.1. Source of data: -

Review of literature from :
a) Journals such as :
  • European Journal of Pharmaceutics and Biopharmaceutics
  • European Journal of Pharmaceutical Sciences
  • Journal of Controlled Release
  • International Journal of Pharmaceutics
  • Indian Journal of Pharmaceutical Sciences
  • Experimental Journal of Biology.
b)Internet browsing.
c)CD-ROM search
  1. Laboratory based studies.

7.2. Method of collection of data: -

  1. Formulation of transdermal patches of antidiabetic drug.
  1. Evaluation of transdermal formulation by:
a)Physicochemical evaluation:
  • Folding endurance
  • Thickness of the film
  • Percentage elongation
  • Weight variation
  • Drug content
b)Adhesiveness:
  • Thumb tack test
c)Drug excipients interaction:
  • By I.R. spectroscopy
d)In-vitro skin permeation studies:
  • Keshary-Chien diffusion cell using excised rat skin7, 16, 18
e)In-vitro drug release study:
  • USP Paddle method17, 19, 20

7.3. Does the study required any investigation or intervention to be conducted on patient or other humans or animals? If so, please describe briefly.
Yes, this study requires use of excised rat skin for evaluation of drug permeation.
------
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
Applied to institutional animal ethical committee.
------
8. / LIST OF REFRENCES:
  1. Adam S. Cantor and David J. Wirtanen.Novel Acrylate Adhesives for Transdermal Drug Delivery. Pharmaceutical Technology Jan 2002: 28-38.
  2. Guang-Ming KE, Li WANG, Hui-Yong XUE, Wan-Liang LU, Xuan ZHANG, Qiang ZHANG,and Hong-You GUO. In Vitro and in Vivo Characterization of a Newly Developed Clonidine Transdermal Patch for Treatment of Attention Deficit Hyperactivity Disorder in Children. Biol. Pharm. Bull. Vol 28(No 2) Feb 2005: 305—310.
  3. Biswajit Mukherjee, Sushmita Mahapatra, Ritu Gupta, Balaram Patra, Amit Tiwari, Priyanka Arora. A comparison between povidone-ethylcellulose and povidone-eudragit transdermal dexamethasone matrix patches based on in vitro skin permeation. Eur J Pharm & Bio Pharm. Vol 59 (2005): 475–483.
  4. Claudia Valenta, Barbara G Auner. The use of polymers for dermal and Transdermal delivery. Eur J Pharm & Bio Pharm 2004 (Vol 58): 279-289.
  5. Srinivas Mutalik and Nayanabhirama Udupa. Pharmacological evaluation of membrane-moderated transdermal system of Glipizide. ClinicalandExperimentalPharmacologyandPhysiology(2006) Vol 33: 17–26.
  6. L L Brunton, J S Lazo, K L Parker. Eds. Goodman & Gilman’s-The Pharmacological Basis of Therapeutics. 11th Edn. Mc Graw-Hill; 2006: 1637, 1638, 1634-1637.

7.G D Gupta, Parul Patel, Amit Chaudhary, Y S Tanwar. In-vitro permeation of repaglinide from polymeric membrane systems across human cadaver system. Priory Medical Journals, January 1995.

  1. Sean C Sweetman Editor. Martindale. The Complete Drug Reference. 35th Edition: 413.
  2. Rajan K Verma, Sanjay Garg.Development and evaluation of osmotically controlled oral drug delivery system of Glipizide. EurJ of Pharm & Biopharm. Vol 57 (2004): 513 – 525.
  3. Krishna DR, Sridevi S, Chary MG, Prakash V, Diwan. Pharmacodynamicevaluation of transdermal drug delivery system of Gilbenclamide in rats. Ind JPharmacol 2000;Vol 32:309-312.
  4. Shanker V, Benito Johnson D, Sivanad V, Ravichandran V, Raghuraman S, Velrajan G, Palaniappan R, Rajasekar S, Chandrashekaran A K. Design and evaluation of Nifedipine transdermal patches. Ind J Pharm Sci 2003; 65(5) : 510-515.
  5. Ikuhiro Kakubari, Norihiro Shinkal, Junji Kawakami, AkemiUruno, Toshiyuki Takayasu, Hitoshi Yamauchi, Satoshi Takayama, Kozo Takayama. Formulation and evaluation of ethylene-vinyl acetate copolymer matrix patches containing Formoterol fumarate. Biol Pharm Bull 2006; 29(3): 513-516.
  6. Ilbeyi Agaebyoglu, Figen Ocak. Development of a membrane controlled transdermal therapeutic system containing Isosorbide dinitrate. Int J Pharm 1999(180): 177-183.
  7. Oliver J C, Rabouan S, Couet.W. In vitro comparative studies of two marketed transdermal Nicotine delivery system: Nicopatch and Nicorette. Int J Pharm 2003(252): 133-140.
  8. Cheong-Weon Cho, Sang-Chul Shin. Enhanced transdermal delivery of atenolol from the ethylene–vinyl acetate matrix. Int J Pharm, Vol 287 (2004): 67–71.
  9. Dandagi P M, Manvi F V, Gadad A P, Mastiholimath V S, Jagadeesh T. Formulation of a transdermal drug delivery system of Ketotifen fumarate. Ind J Pharm Sci 2003; 65(3): 239-243.
  10. Amir Mehdizadeh, Taybe Toliate, Mohammad Reza Rouini, Sharyar Abash-Zadeh, Farid Dorkoosh. Design and In vitro evaluation of new drug in adhesive formulation of Fenatyl transdermal patches. Aact Pharm 2004; 54: 301-317.
  11. Malshe V C, Lalla J K, Bapat V R. Acrylate Adhesives for transdermal therapeutic system. Ind J Pharm Sci1994; 56(1): 5-9.
  12. Mohamed Aqil,Yasmin Sultana, Asgar Ali. Matrix type transdermal drug delivery system of Metaprolol tartarate: In –vitro characterization. AactPharm 2003; 53: 119-125.
  13. Biswajit Mukherjee, kanupriya, Sushmita Mahapatra, Surajit Das, Balaram Patra. Sorbiton Monolurate 20 as a potential skin permeation enhancer in transdermal patches. J App Res 2005; 5(1): 96-108.
  1. Darshan K Parikh and Tapash K Ghosh. Feasibility of Transdermal Delivery of Fluoxetine. AAPS PharmSciTech 2005; 6 (2) Article 22: 144-149.