EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEMS

Brief ppt on evaluation of TDDSs with diagrammatic representation & recent research reports.

1. PRESENTED BY: GUIDED BY: SANI SINGH Prof. VIKAS ANAND M. Pharm (Pharmaceutics) 2 nd Semester EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEMS SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH, BALAWALA, DEHRADUN, (UTTARAKHAND) SECOND SEMINAR (MPHR 120) 2016-17

2. ORGANISATION Introduction Evaluation Methods Physicochemical Evaluation In-vitro Evaluation In-vivo Evaluation Marketed Products Available In India FDA Approved TDDS Products Recent Research Report From Pubmed

3. Transdermal drug delivery systems (TDDS, “Patch”) are self-contained, discrete dosage forms that, when applied to intact skin, are designed to deliver the drug(s) through the skin to the systemic circulation. INTRODUCTION Vyas SP, Khar RK. Controlled drug delivery: Concepts and advances. 2 nd edition. Vallabh Prakashan . 2012, 397-398.

4. EVALUATION Physicochemical evaluation In – vitro evaluation In – vivo evaluation

5. Physicochemical evaluation Interaction studies Thickness of the patch Weight uniformity Drug content determination Content uniformity Folding endurance Flatness Moisture content Moisture uptake Water vapour permeability (WVP) evaluation Tensile strength Evaluation of adhesive Shear adhesion test Peel adhesion test Tack properties Thumb tack test Rolling ball test Quick stick (Peel tack test) test Probe tack test

6. Physicochemical evaluation 1. Interaction studies: Interaction studies ( drug and excipients ) are commonly carried out in Thermal analysis, Fourier transform infrared spectroscopy (FTIR), UV and chromatographic techniques by comparing their physicochemical characters such as assay, melting point, wave numbers, absorption maxima etc. 2. Thickness of the patch: * The thickness of the drug loaded patch is measured in different points by using a digital micrometer, dial gauge, screw gauge . 3. Weight uniformity: * The prepared patches are to be dried at 60°c for 4 hrs before testing . Individually weighing 10 randomly selected patches a specified area of patch is to be cut in different parts of the patch and weigh in digital balance. Lembhe Swapnil , Dev Asish . Trasdermal Drug Delivery System: An Overview. World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

7. 4. Drug content determination: * accurately weighed portion of film (about 100 mg) is dissolved in 100 ml of suitable solvent & shaken continuously for 24 h, then sonicated After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically 10 patches are selected, if 9 out of 10 patches have content between 85% to 115% and 1 has content not less than 75% to 125% of the specified value, patches pass the test 3 patches range of 75% to 125%, then additional 20 patches are tested . If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test. 5. Content uniformity test: * * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

8. 6. Folding endurance: # 7. Flatness test: * In flatness determination one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. 0 % constriction is equivalent to 100 % flatness. % constriction = I1 – I2 X 100 I1 I1 = Initial length of each strip I2 = Final length of each strip # Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American Journal Of Pharmaceutical Research.2015; 5(1):531-548. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

9. 8. Percentage Moisture content: The weighed films are to be kept in a desiccator containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs the films are to be reweighed and determine the percentage moisture content from the formula – Percentage moisture content = [Initial weight - Final weight/ Final weight] ×100 9. Percentage Moisture uptake: The weighed films are to be kept in a desiccator containing saturated solution of potassium chloride at room temperature for 24 hrs (84% RH). After 24 hrs the films are to be reweighed and determine the percentage moisture uptake from the formula – Percentage moisture uptake = [Final weight - Initial weight/ initial weight] ×100 Lembhe Swapnil , Dev Asish . Trasdermal Drug Delivery System: An Overview. World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610.

10. 10. Water vapour permeability (WVP) evaluation: WVP=W/A Where, WVP is expressed in gm /m 2 per 24 hrs, W is the amount of vapour permeated through the patch (gm/24 hrs) A is the surface area of the exposure samples ( m 2 ) Water vapour permeability can be determined by a natural air circulation oven. The WVP can be determined by the following formula: Lembhe Swapnil , Dev Asish . Trasdermal Drug Delivery System: An Overview. World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610.

11. weights are added to the pan attached with the hanging end of the thread. A pointer is used to measure the elongation of the film. The weight sufficient to break the film is noted. One end is fixed with the help of an iron screen & other end is connected to a freely movable thread over a pulley. P olymeric films are sandwiched separately by corked linear iron plates 11. Tensile Strength: * Tensile strength= F/ a.b (1+L/l) F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

12. 12. Evaluation of adhesive: a) Shear Adhesion test: Shear adhesion strength is determined by measuring ( cohesive strength of an adhesive polymer ) the time it takes to pull the tape off the plate. Shear strength test for adhesive evaluation Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

13. b) Peel Adhesion test: In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. Peel adhesion test for adhesive evaluation Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

14. c) Tack properties: It is ability of a polymer to adhere to a substrate with little contact pressure. Test is includes. Thumb tack test: It is a qualitative test and t he force required to remove thumb from adhesive is a measure of tack. Rolling ball tack test: In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive. Rolling ball tack test for adhesive evaluation T Himanshi , S Ruchika . Transdermal Drug Delivery System: A Review. International Journal Of Pharmaceutical Sciences And Research. 2016;7(6): 2274-90.

15. Quick Stick (peel-tack) test: The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min. Quick stick test for adhesive evaluation T Himanshi , S Ruchika . Transdermal Drug Delivery System: A Review. International Journal Of Pharmaceutical Sciences And Research. 2016;7(6): 2274-90. Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

16. Probe Tack test: The tip of a clean probe is contact with adhesive and bond is formed between probe and adhesive. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams . Probe tack test for adhesive evaluation Probe Force gauge T Himanshi , S Ruchika . Transdermal Drug Delivery System: A Review. International Journal Of Pharmaceutical Sciences And Research. 2016;7(6): 2274-90. Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

17. In – vitro evaluation

18. 1. In vitro drug release studies: * A number of mathematical model is describe the drug dissolution kinetics from controlled release drug delivery system e.g., Higuchi model, First order, Zero order and Peppas & Korsenmeyer model. The dissolution data is fitted to these models and obtained the release mechanism of the drug. There are various methods available for determination of drug release rate of TDDS. In–vitro evaluation * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

19. Higuchi model Peppas & Korsenmeyer model A=[D (2C-Cs) Cs x t] ½ Where , A – amount of drug released in time ‘t’ per unit area C – initial drug concentration Cs – drug solubility in the matrix media D – diffusivity of drug molecule in the matrix substance F = (M t /M) = K m t n Where, F – fraction of drug release at time ‘t’ M t - amount of drug release at time ‘t’ M – total amount of drug in dosage form K m - kinetic constant n – diffusion or release exponent t - time (hrs)

20. Paddle over disc: * (USP apparatus 5) This method the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

21. Cylinder modified USP Basket: * (USP apparatus 6) This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

22. Reciprocating disc: * (USP apparatus 7) In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method may be used. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

23. 2. In vitro skin permeation studies: * The transdermal system is applied to the hydrophilic side of the membrane (donor compartment) and then mounted in the diffusion cell with lipophilic side in contact with receptor fluid (receptor compartment, usually temprature 32±5°C for membrane ) in vertical diffusion cell such as Franz diffusion cell or Keshary-chien (K-C) diffusion cell and is continuously stirred at a constant rate. The samples are withdrawn at different time intervals and diluted appropriately then absorbance is determined spectrophotometrically . Then the amount of drug permeated per cm 2 at each time interval is calculated. * Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012; 5(1):447-456.

24. Franz diffusion cell: # Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American Journal Of Pharmaceutical Research.2015; 5(1):531-548.

25. In – vivo evaluation

26. 1. Animal models: # In-vivo animals models are preferred because considerable time and resources are required to carry out studies in humans. Some of the species are used : mouse, rat, guinea pig, rabbit, rat, cat, dog, pig, house, monkey small hairy animals (e.g. rat, rabbit) or rhesus monkey is most reliable or in vivo evaluation of transdermal patches standard radiotracer methodology used. The application site is generally the abdomen which are the least hairy site on the animals body. The compound is applied after light clipper showing of the site. In –vivo evaluation # Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American Journal Of Pharmaceutical Research.2015; 5(1):531-548.

27. 2. Human models: # It is first described by Fieldman and Maibach . They includes determination of percutaneous absorption by an indirect method of measuring radioactivity in excreta following topical application of the labeled drug. 14C is generally used for radio labeling . Determination of absorption of know amount of radioactivity retained in the body or excreted by routes. The percentage of dose absorbed transdermally is then calculated as. % Close absorbed = Total radioactivity exerted after topical Administration x 100 Total radioactivity exerted intervenes was Administration The procedure takes 5-7 days for completion. # Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American Journal Of Pharmaceutical Research.2015; 5(1):531-548.

28. # Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American Journal Of Pharmaceutical Research.2015; 5(1):531-548. (a) Reservoir technique : (b) Mass balance technique : It makes use of the relationship between stratum corneum reservoir function and in vivo percutaneous absorption to predict in vivo penetration. This method is involves a simple, short exposure of the skin to the compound under study followed by removal of the stratum corneum by tape stripping and analysis of the content of the compound in the stratum corneum . The application site is covered with an occlusive chamber , the chamber being replaced by a new one after a particular time interval. The site is also subjected to washing at these time. Radio labeling techniques are used and the chamber, washing and the faces and urine of the patients are subjected to analysis. In this technique include achievement of mass balance between the applied close and exertion level and measurement for predicting percutaneous .

29. 3. Biophysical Models: Models based on steady-state mass balance equation, solution of Fick’s second law of diffusion for the device, stratum corneum and viable epidermis, as well as linear kinetics have been described in the literature. It can be concluded that many techniques for in-vivo evaluation of transdermal systems have been put forward there is scope for further refinement. Some of the unresolved issues include the barrier function of the skin with age, skin metabolism, in-vivo functioning of penetration enhancers etc. Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

30. Stability studies: Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and 75±5% RH for 6 months . The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content. Regulatory requirements: * A transdermal patch is classified by U.S. Food and Drug Administration (FDA) as a combination product , consisting of a medical device combined with drug or biologic product that the device is designed to deliver. Prior to sale, any transdermal patch product must receive approval from FDA, demonstrating safety and efficacy for its intended use. Lembhe Swapnil , Dev Asish . Trasdermal Drug Delivery System: An Overview. World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610. Shinde Utkarsh P et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research. 2012;5(1):447-456. *

31. Marketed Products Therapeutic Agent Brand Name Manufacturer Name Indication Fentanyl Fendrop Sun Pharmaceutical Industries Ltd Moderate/severe pain Rivastigmine Alzamine Bliss GVS Pharma Limited Dementia Tulobuterol Astherol Bliss GVS Pharma Limited Anti-asthmatic Fentanyl F- TAN Bliss GVS Pharma Limited Moderate/severe pain Ketoprofen Ketopron Bliss GVS Pharma Limited Musculoskeleton pain and Inflammation Diclofenac Diethylamine Lofnac Bliss GVS Pharma Limited Musculoskeleton pain and Inflammation

32. Therapeutic Agent Brand Name Manufacturer Name Indication Fentanyl Fen-Touch Sparsha Pharma Moderate/severe pain Ketoprofen Artho -Touch Sparsha Pharma Musculoskeleton pain and Inflammation Diclofenac Diclo -Touch Sparsha Pharma Musculoskeleton pain and Inflammation Rivastigmine Memory-Touch Sparsha Pharma Dementia

33. Therapeutic Agent Brand Name Manufacturer Name Indication Diclofenac Nupatch Zydus Cadila Healthcare Ltd. Musculoskeleton pain and Inflammation Fentanyl Finrid Dr. Reddy’s Moderate/severe pain Fentanyl Trofentyl Troikaa Moderate/severe pain Fentanyl Durogesic Johnson & Johnson Moderate/severe pain http://www.drugsupdate.com/brand/brand_name/FENDROP http://www.blissgvs.com/products/pharma-products/transdermal-patches http://sparsha.com/fen_touch.html http://sparsha.com/diclo_touch.html http://sparsha.com/artho_touch.html http://sparsha.com/memory-touch.html http://www.drugsupdate.com/brand/brand_name/NUPATCH http://www.drugsupdate.com/brand/brand_name/FINRID http://www.drugsupdate.com/brand/brand_name/TROFENTYL http://www.drugsupdate.com/brand/brand_name/DUROGESIC

34. FDA Approved TDDS Products Drug Name Generic Name Approval Date CATAPRES TTS CLONIDINE October 10, 1984 VIVELLE ESTRADIOL October 28, 1994 CLIMARA ESTRADIOL December 22, 1984 ESTRADERM ESTRADIOL September 10, 1986 CLIMARA PRO ESTRADIOL/LEVONORGESTREL November 21, 2003 ORTHO EVRA NORELGESTROMIN/ETHINYL ESTRADIOL November 20, 2001 DURAGESIC FENTANYL August 7, 1990

35. Drug Name Generic Name Approval Date LIDOCAINE LIDOCAINE May 21, 1996 NITRO-DUR NITROGLYCERIN April 4, 1995 MINITRAN NITROGLYCERIN August 30, 1996 OXYTROL OXYBUTYNIN February 26, 2003 EXELON PATCH RIVASTIGMINE July 6, 2007 TRANSDERM-SCOP SCOPOLAMINE Approved prior to January 1, 1982 ANDRODERM TESTOSTERONE September 29, 1995

36. Drug Name Generic Name Approval Date NICODERM NICOTINE August 2, 1996 HABITROL NICOTINE November 12, 1999 NICOTROL NICOTINE July 3, 1996 TRANSDERM-NITRO NITROGLYCERIN February 27, 1996 TESTODERM-AT TESTOSTERONE December 18, 1997 Sadrieh Nakissa . Challenges in the Development of Transdermal Drug Delivery Systems. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 2009. (www.fda.gov)

37. Recent Research Reports From Pubmed Drug Polymer or Major Excipients Type of Patch and Preparation Method Remarks Reference IQP-0410 (HIV Inhibitor) EC, HPMC, PG, DnBP (Di-n-butyl phthalate) EC/HPMC-based transdermal films & solvent casting technique Successful in vitro reduction of HIV-1 activity from the delivered drug over a 3 day application suggests the potential of IQP-0410 to be administered via transdermal patches. Ham et al, 2013 Donepezil Sodium alginate (matrix-forming agent), Propylene glycol and dl-limonene Matrix type transdermal films Alternative Delivery Approach in Alzheimer’s Disease Treatment Galipoglu et al, 2014

38. Drug Polymer or Major Excipients Type of Patch and Preparation Method Remarks Reference Buprenorphine Lauryl alcohol, Tween 80, Levulinic acid ( Chemical penetration enhancers ) Drug In Adhesive Patch & Using Box- Behnken Experimental Design Chemical penetration enhancers could enhance permeation flux of buprenorphine through the skin Taghizadeh et al, 2015 Zolmitriptan Oleic acid and Span 80, Isopropyl myristate (IPM) , Triethylamine , Azone Drug in Adhesive Patch & Solvent evaporation technique Pharmacokinetic parameters were determined via i.v . and transdermal administrations using animal model of rabbit. Chao Liu and Liang Fang, 2015

39. Drug Polymer or Major Excipients Type of Patch and Preparation Method Remarks Reference Khardal ( Brassica nigra ), Zanjabeel ( Zingiber officinale ), Podina ( Mentha arvensis ) Chitosan , PEG-400, tween 80 Drug in Adhesive Patch & solvent evaporation technique Design and development of an antiemetic transdermal Unani formulation in a novel dosage form for a common clinical condition, namely, vomiting/emesis. The patch was found to be stable & showed no signs of skin irritation. Saleem M N & Idris M, 2016 Galipoglu et al. Biopolymer - Based Transdermal Films of Donepezil in Alzheimer’s . AAPS Pharm Sci Tech 2014; 16(2): 284-292. Taghizadeh et al. Influence of skin penetration enhancers on buprenorphine patch release system. Journal of Advanced Research . 2015; 6: 155–162. Chao Liu and Liang Fang. Transdermal Patch of Zolmitriptan and Pharmacokinetic Study. AAPS Pharm SciTech. 2015; 16 (6): 1245-1253. Ham et al. IQP-0410 HIV Inhibitor Transdermal Film. PLOS ONE. 2013; 8(9): e 75306 . Saleem MN, Idris M. Formulation Design and Development of a Unani Transdermal Patch for Antiemetic Therapy and Its Pharmaceutical Evaluation. [P.G. Unani Thesis ]. Ayurvedic & Unani Tibbia College, Karol Bagh , New Delhi, India, 2016.