Table-1: Some marketed Transdermal Products.

PRODUCT	DRUG	MANUFACTURER	INDICATION
Alora	Estradiol	TheraTech/proctol and Gamble	Postmenstrual syndrome
Androderm	Testosterone	Theratech/GalxosmithKline	Hypogonadism in males
Catapres-TTS	Clonidine	ALZA/Boehinger Ingelheim	Hypertension
Climaderm	Estradiol	EthicalHoldings/Wyeth-Ayerest	Postmenstrual syndrome
Climara	Estradiol	3M Pharmaceuticals/Berlex Labs	Postmenstrual syndrome
Deponit	Nitroglycerine	Schwarz pharma	Angina pectoris
Duragesic	Fentanyl	Alza/ Jansscn pharmaceutical	Moderate /severe pain
Estraderm	Estradiol	Alza/Novartis	Post menstrual syndrome
Fempatch	Estradiol	Parke-davis	Post menstrual syndrome
Habitraol	Nicotin	Novartis	Smoking cessation
Minitrann	Nitroglycerine	3M pharmaceuticals	Angina pectoris
Nicoderm	Nicotin	Alza/glaxo smithkline	Smoking cessation
Nitrodisc	Nitroglycerine	Roberts pharmaceuticals	Angina pectoris
Nitro-dur	Nitroglycerine	Key pharmaceuticals	Angina pectoris
Prostep	Nicotine	Elan Corp./Lederle Labs	Smoking cessation
Testoderm TTS	Testosterone	Alza	Hypogonadism in males
Transderm	Scopolamine	Alza/Novartis	Motion sickness
Transderm	Nitroglycerine	Alza/Novartis	Angina pectoris

Transdermal delivery systems of scopolamine is used for the prevention of motion sickness³. and nitroglycerine for the prevention of angina pectoris associated with coronary artery disease (Transderm Nitro). Transdermal drug delivery products give therapeuticbenefit to patients. Approximately 16 active ingredients and more than 35 Transdermal drug delivery products have been approved for use globally and for sale in the US respectively. In the year 2005 market of $ 12.7 billion and in 2015 market of $ 21.5 is found by statistics analysis that is expected to increase to $31.5 billion in the year 2015⁴. Patches applied to the skin eliminate the need for vascular access by syringe or the use of pumps and today there exist a number of patches for drugs such as clonidine, fentanyl, lidocaine, nicotine, nitroglycerin, oestradiol, oxybutinin, scopolamine, and testosterone. There are also combination patches for contraception, as well as hormone replacement. Depending on the drug, the patches generally last from one to seven days⁵. Transdermal drug delivery systems (TDDS) are the topically applied “patches” designed to deliver a therapeutically effective dose of a drug across the patient’s skin at a controlled rate for the systemic effect⁶. The major obstacle for the topical drug delivery is the low diffusion rate of drugs across the relatively impermeable, outermost skin layer, the stratum corneum⁷.Besides, the intercellular lipid region, the major pathway for lipophilic drugs, has a diffusion path length of about 500mm which is much longer than the thickness of stratum corneum 20mm⁴.

Despite the interests and the merits in this drug delivery system, only very few drug candidates have been approved for transdermal delivery. Besides skin toxicity of the drug or drug excipients, the major obstacle facing this route of delivery is the barrier nature of the skin which limits the number of molecules permeating it to only few that can meet certain criteria. Such molecules should possess appropriate physicochemical properties such as low melting point (<150ºC), low molecular weight (<500 D) and intermediate lipophilicity (log P= 1-3) as well as high potency (total daily dose < 10mg). Only few drugs meet these criteria. Consequently, several approaches have been established in an attempt to overcome the barrier properties and deliver most medicaments through the skin. They include both the chemical and physical enhancement strategies. The former strategy involving chemical methods include penetration enhancers, pro-drugs, colloidal formulations, and supersaturated systems. The latter strategy involves physical methods, including phonophoresis, electroporation etc. More researches in recent years have therefore been devoted towards investigating the effect of numerous chemical or physical or the combination of both enhancers on the skin permeability of most of the common drugs especially those drugs that already have problems at their present route of administration. Several percutaneous research strategies are available including in vivo and in vitro permeation studies⁸.

ADVANTAGES AND DISADVANTAGES OF TDDS:

1.1 Advantages:

First, there are biological advantages to delivering drugs through the skin:

· Transdermal delivery avoids the stomach environment where the drug can be degraded and rendered ineffective or where it can cause unpleasant gastrointestinal symptoms for the patient^9.

· Transdermal delivery avoids the first pass effect where active drug molecules can be converted to inactive molecules or even to molecules responsible for side effects^10.

· Transdermal drug delivery provides steady plasma levels. When a patch is applied that lasts for 24 hours, or even 7 days, once steady state is reached the plasma levels remain constant because the rate of drug delivered from the patch is constant. When a drug is given four times a day, or even once a day, the drug levels rise after administration and then gradually fall until the next administration producing peaks and troughs throughout the course of therapy^11.

· Unlike the limited controlled release from oral and intravenous routes, TDDS provides steady infusion of drug over an extended period of time, suitable for the drugs with short biological half life requiring frequent dosing, leading to increased patient compliance and decreased inter and intra patient variability^12.

· Therapeutic failure or adverse effects frequently associated with intermittent dosing for the chronic diseases can be avoided¹³.

· Self administration and removal when required.

· Pain, inconvenience of injections can be overcomed by this non- invasive and safe parenteral route of drug delivery¹⁴.

Other advantages to delivering drugs through the skin include the fact that:

· Transdermal drug delivery systems, especially simple patches, are easy to use and noninvasive and patients like noninvasive therapies.

· Because they are easy to use, patches can increase compliance and reduce medical costs.There are many studies that show a patient’s overall healthcare costs are reduced when pharmaceutical compliance is increased. In addition, there are specific studies that show that patient compliance increases and healthcare costs decrease when patches are prescribed.

· If a transdermal delivery system is used in place of a needle, then medical waste can also be decreased, again, decreasing healthcare costs^15.

1.2 Disadvantages:

No drug delivery system is without its disadvantages. Some of the challenges of transdermal drug delivery include: Only a narrow range of molecules can currently be delivered transdermally using available technologies. Only small, relatively lipophilic molecules can pass through the lipid bilayer “mortar” of the stratum corneum using traditional patch technology. As drug treatments become more and more complex, drug molecules are becoming larger and more complex as well and new technologies will be needed to deliver these drugs through the skin¹⁶. Figure-1 is representative of the types of molecules that can currently be delivered through the skin. All of these molecules are organic in nature and are considered lipid soluble. Even though these molecules contain a few polar atoms such as oxygen and nitrogen, they are made primarily of carbon and hydrogen atoms that render them nonpolar. Nicotine is the smallest molecule represented with a molecular weight of only 162.24g/mol. Although hormones or a molecule like fentanyl, with a molecular weight over 300 g/mol, are considered large organic molecules, they are still much smaller than even a small protein such as insulin.

Figure-1: Low molecular weight, lipophilic organic drug molecules.

· Currently, only small quantities of drug can be delivered through the stratum corneum. Therefore, drugs that are given transdermally must be relatively potent so that they can be effective at low doses.

· Patient trust issues can also be a barrier to effective transdermal drug therapy. The general public might have been willing to accept a 3-day scopolamine patch when it was introduced in 1979 but it was quite a challenge in 1984 to convince doctors and patients alike that a clonidine patch would control blood pressure for seven days continuously. In more recent years, there have been accidental overdose deaths from fentanyl patches and questions have been raised about the safety of transdermal contraception. As new transdermal technologies are introduced, there will certainly be questions from patients and healthcare professionals about the safety and effectiveness of these new delivery systems.

2. ADVERSE EFFECTS:

In 2005, the FDA announced that they were investigating reports of death and other serious adverse events related to narcotic overdose in patients using Duragesic, the fentanyl transdermal patch for pain control. The Duragesic product label was subsequently updated to add safety information in June 2005. In 2008, two manufacturers of the Fentanyl patch, Alza Pharmaceuticals (a division of major medical manufacturer Johnson & Johnson) and Sandoz, subsequently issued a recall of their versions of the patch due to a manufacturing defect that allowed the gel containing the medication to leak out of its pouch too quickly, which could result in overdose and death. As of 2010, Sandoz no longer uses gel in its transdermal fentanyl patch; instead, Sandoz-branded fentanyl patches use a matrix/adhesive suspension where the medication is blended with the adhesive instead of held in a separate pouch with a porous membrane), similar to other fentanyl patch manufacturers such as Mylan and Janssen. In 2007, Shire and Noven Pharmaceuticals, manufacturers of the Daytrana ADHD patch, announced a voluntary recall of several lots of the patch due to problems with separating the patch from its protective release liner. Since then, no further problems with either the patch or its protective packaging have been reported. In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from transdermal drug patches with metallic backings. Patients should be advised to remove any medicated patch prior to an MRI scan and replace it with a new patch after the scan is complete¹⁷. Skin burns have occurred with metal containing transdermal patches at the time of shock therapy from external as well as internal cardioverter defibrillators (ICD)¹⁸.

3. SKIN AND DRUG PERMEATION:

For understanding the concept of TDDS, it is important to review the structural and biochemical features of human skin and those characteristics which contribute to the barrier function and the rate of drug access into the body via skin.

3.1 Anatomically, the skin can be divided in to two layers:

Epidermis and Dermis or corium Some of the differences between epidermis and dermis layers of skin. The skin is one of the most extensive organs of the human body covering an area of about 2m² in an average human adult. This multilayered organ receives approximately one third of all blood circulating through the body¹⁹. Epidermis results from an active epithelial basal cell population and is approximately 150 micrometers thick. It is the outermost layer of the skin and the process of differentiation results in migration of cells from the basal layer towards skin surface²⁰. Below this layer are the other layers of the epidermis - the stratum lucidum, stratum granulosum, stratum spinosum and stratum germinativum.

Figure -2: Brick and Mortar Structure with Lipid Bilayer.

Together, these other layers constitute the viable epidermis. Dermis is foundation of firm connective tissue upon which epidermis is laid and is of mesoderm origin. The dermis or corium consists of a dense felt work of connective tissue in which bundles of collagenous fibres predominate, mingled with a certain proportion of elastic tissue in superficial levels. Dermis contains fine plexuses of blood vessels, lymphatics and nerves, hair follicles, sweat glands and sebaceous glands²⁰.

Figure-3: Schematic diagram of different layers of skin.

3.2.Drug penetration pathways:

There are critically three ways in which a drug molecule can cross the intact stratum corneum: via skin the appendages (shunt routes); through the intercellular the other layers of the epidermis the stratum lucilipiddomains; or by a transcellular route. A particular drug is likely to permeate by a combination of these routes, with the relative contributions of these pathways to the gross flux governed by the physicochemical properties of the molecule²¹.

3.3.The appendgeal route:

Skin appendages provide a continuous channel directly across the stratum corneum barrier. However, their influence on drug penetration is hindered by a number of factors. The surface area occupied by hair follicles and sweat ducts are small (typically 0.1% of skins surface area) therefore limiting the area available for direct contact of the applied drug formulation²².

3.4.Transcellular route:

Drugs entering the skin via the transcellular route pass through corneocytes. Corneocytes, containing highly hydrate keratin, provide an aqueous environment for which hydrophilic drugs can pass. The diffusion path- way for a drug via the transcellular route requires a number of partitioning and diffusion steps²³.

4. IDEAL REQUIREMENTS FOR TDDS:

· Shelf life up to 2 years

· Small size patch (i.e., less than 40 cm2)

· Convenient dose frequency (i.e., once a day to once a week)

· Cosmetically acceptable (i.e., clear, white colour)

· Simple packaging (i.e., minimum number of pouches and steps required to apply the system) Adequate skin adhesion (i.e., no fall off during the dosing interval and easy removal without skin trauma)

· No residue i.e., cold flow, around the edge of the patch in storage or after application to skin or beneath the patch after removal)

· No unacceptable dermal reactions (i.e., contact dermatitis, skin sensitization, photo toxicity, photosensitization, erythema, itching, stinging, burning, etc.)

· Consistent biopharmaceutical performance (i.e., precision of the required pharmacokinetic and pharmacodynamic response between individuals and in the same individuals over time²³.

5. CONCLUSION:

During the past decade, the number of drugs formulated in the patches has hardly increased, and there has been little change in the composition of the patch systems. Modifications have been mostly limited to refinements of the materials used. The reason is the only a limited number of drugs fit the molecular weight, and potency requirements for transdermal absorption. A rich area of research in recent years has been focused on developing transdermal technologies that utilize mechanical energy to increase the drug flux across the skin by either altering the skin barrier (primarily the stratum corneum) or increasing the energy of the drug molecules. These so-called “active” transdermal technologies include iontophoresis (which uses low voltage electrical current to drive charged drugs through the skin), electroporation (which uses short electrical pulses of high voltage to create transient aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum), and thermal energy (which uses heat to make the skin more permeable and to increase the energy of drug molecules). Even magnetic energy, coined magnetophoresis, has been investigated as a means to increase drug flux across the skin. However, subjective and objective analysis of these devices is required to make sure both scientific, regulatory and consumer needs are met. The devices in development are more costly and complicated compared to conventional transdermal patch therapies. In addition, effects of the device on the skin must be reversible, since any permanent damage to the SC will result in the loss of its barrier properties and hence its function as a protective organ. Regulatory bodies will also require data to substantiate the safety of the device on the skin for either short or long term use. Thus, for any of these novel drug delivery technologies to succeed and compete with those already on the market, their safety, efficacy, portability, user-friendliness, cost- effectiveness and potential market has to be addressed.

6. REFERENCE:

1. Aarti N, Louk ARMP, Russsel OP, Richard HG. Mechanism of oleic acid induced skin permeation enhancement in vivo in humans. Journal of Controlled Release, 1995; 37(3): 299- 306.

2. Aggarwal, G. Development, fabrication and evaluation of transdermal drug delivery system- A Review [Internet]. 2009 Available from: http://www.pharmainfo.net/reviews/development- fabrication-and-evaluation-transdermal-drug-delivery-system-review, excssed on 19 September, 2013.

3. Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Transdermal drug delivery.

4. Aqil M, Ali A, Sultana Y, Dubey K, Najmi AK, Pil-lai KK. In vivo characterization of monolithic matrix type transdermal drug delivery systems of pi-nacidil monohydrate: A technical note. AAPS Pharm Sci Tech, 2006; 7(1): 1-5.

5. Arunachalam A, Karthikeyan M, Kumar DV, Prathap M, Sethuraman S, Kumar SA et al. Transdermal Drug Delivery System: A review. Current Pharma Research 2010; 1(1):70-81.

6. Bagyalakshmi J, Vamsikrisna RP, Manavalan R, Ra-vi TK, Manna PK. Formulation development and in vitro and in vivo evaluation of membrane-moderated transdermal systems of ampicillin sodium in ethanol: pH 4.7 buffer solvent system. AAPS PharmSciTech, 2007; 8(1): 1-7.

7. Bhaskaran S, Harsha NS. Effect of permeation enhancer and iontophoresis on permeation of atenolol from transdermal gels. Indian Journal of Pharmaceutical Sciences, 2000; 62(6), 424- 426.

8. Bouwstra JA, Nguyen PL. Skin structure and mode of action of vesicles. Advanced Drug Delivery Reviews, 2002; 54(12): 41–55 .

9. Brown MB, Jones SA. Hyaluronic acid: a unique topical vehicle for localized drug delivery of drugs to the skin. Journal of the European Academy of Dermatology and Venereology, 2000; 19(3): 308-318.

10. Chakkapan S, Gandhi K, Thomas S, Katkam RR, Puri CP, Shrivastava R. Studies in transdermal drug delivery systems for estradiol. Indian Journal of Pharmaceutical Sciences, 1994; 56(4): 121-125.

11. Deshwal S, Verma N. Optimiation techniques in Transdermal Drug Delivery System. International Journal of Pharmaceutical Sciences and Research, 2012; 3(8): 2362-237.

12. Dey BK, Nath LK, Mohanti B, Bhowmik BB. Development and evaluation of propranolol hydrochloride patches by using hydrophilic and hydrophobic polymer.

13. Dimas DA, Dallas PP, Rekkas DM, Choulis NH. Effect of several factors on the mechanical properties of pressure sensitive adhesives used in transdermal therapeutic systems. AAPS PharmSciTech, 2000; 1(2): 80-87.

14. Dipen MP, Kavitha K. Formulation and Evaluation Aspects of Transdermal Drug Delivery System.

15. Divyesh P, Nirav P, Meghal P, Navpreet K. Transdermal Drug Delivery System: Review. International Journal of Biopharmaceutical & Toxicological Research, 2011; 1(1): 61-80.

16. Donnelly RF, Singh TR, Garland MJ, Migalska K, Majithiya R, McCrudden CM et al. Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery. Advanced Functional Materials, 2012; 22(23):4879-4890.

17. Dubey V, Mishra D, Nahar M, Jain V, Jain NK. Enhanced transdermal delivery of an anti- HIV agent via ethanolic liposomes. Nanomedicine: Nanotechnology, Biology and Medicine, 2010; 6(4): 590–596.

18. El-Laithy HM, Shoukry O, Mahran LG. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies. European Journal of Pharmaceutics and Biopharmaceutics, 2011; 77(1): 43–55.

19. Foco A, Hadziabdic J, Becic F. Transdermal drug delivery systems. Archives of Medicine, 2004; 58(1): 230-234.

20. Finnin BC, Morgan TM. Transdermal penetration enhancers: Applications, limitations, and potential. Journal of Pharmaceutical Sciences, 1999; 88(10): 955.

21. Flynn GL. Percutaneous absorption. In Bronaugh RL, Maibach HI, Editors. Choosing Candidates for Transdermal Development. Marcel Dekker, NY: CRC Press, 1985; pp 169- 185.

22. Gandhi K, Monika AD, Kalra T, Singh K. Transdermal drug delivery - A review. International Journal of Research in Pharmaceutical Sciences, 2012; 3(3): 379-388.

23. Gaur KP, Mishra S, Purohit S, Dave K. Transdermal delivery System: A review. Asian journal of Pharmaceutical and Clinical Research, 2009; 2(1):14-20.

Received on 15.12.2022 Modified on 08.02.2023

Asian J. Res. Pharm. Sci. 2023; 13(2):125-129.

DOI: 10.52711/2231-5659.2023.00023