Transdermal Drug Delivery Technology Revisited : Recent Advances

By Shreeraj Shah - 10/14/2008

in Latest Reviews Vol. 6 Issue 5 2008

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The number of medications and the ways in which they can be administered have expanded dramatically over the years.One such advance has been the development of transdermal patch delivery systems. Transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. Transdermal Drug Delivery System is the system in which the delivery of the active ingredients of the drug occurs by the means of skin. Skin is an effective medium from which absorption of the drug takes place and enters the circulatory system. Various types of transdermal patches are used to incorporate the active ingredients into the circulatory system via skin. The patches have been proved effective because of its large advantages over other controlled drug delivery systems. This review article covers a brief outline of various components of transdermal patch, applications of transdermal patch, their advantages, disadvantages, when the transdermal patch are used and when their use should be avoid and some of the recent development in the field along with the latest patents in this field.

Introduction1,4,5,6Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side-effects with some of these formulations is indicative of absorption through

the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. Moreover, it over comes various side effects like painful delivery of the drugs and the first pass metabolism of the drug occurred by other means of drug delivery systems. So, this Transdermal Drug Delivery System has been a great field of interest in the recent time. Many drugs which can be injected directly into the blood stream via skin have been formulated. The main advantages of this system are that there is controlled release of the drug and the medication is painless. The drug is mainly delivered to the skin with the help of a transdermal patch which adheres to the skin. A Transdermal Patch has several components like liners, adherents, drug reservoirs, drug release membrane etc. which play a vital role in the release of the drug via skin. Various types of patches along with various methods of applications have been discovered to delivery the drug from the transdermal patch. Because of its great advantages, it has become one of the highly research field among the various drug delivery system. Here, a general view over the transdermal patch has been discussed along with its advantages, disadvantages, methods of applying, care taken while applying, types and applications of transdermal patch and recent advances along with recent patents and market products.

DefinitionA transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream.

The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979, which administered scopolamine for motion sickness.2, 3

Components of Transdermal Patch5(1)Liner - Protects the patch during storage. The liner is removed prior to use. (2) Drug - Drug solution in direct contact with release liner. (3) Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin. (4) Membrane - Controls the release of the drug from the reservoir and multi-layer patches. (5) Backing - Protects the patch from the outer environment.

Conditions in which Transdermal Patches are used 8Transdermal patch is used when: (1)When the patient has intolerable side effects (including constipation) and who is unable to take oral medication (dysphagia) and is requesting an alternative method of drug delivery. (2) Where the pain control might be improved by reliable administration. This might be useful in patients with cognitive impairment or those who for other reasons are not able to self-medicate with their analgesia. (3) It can be used in combination with other enhancement strategies to produce synergistic effects.

Conditions in which Transdermal Patches are not used 9The use of transdermal patch is not suitable when: (1)Cure for acute pain is required. (2) Where rapid dose titration is required. (3) Where requirement of dose is equal to or less then 30 mg/24 hrs.

Marketed Products of Transdermal Patches:10, 11, 12, 13, 14, 15Brand Name NicotinellR

Drug Nicotine

Manufacturer Novartis

Indications Pharmacological smoking cessation

Matrifen

R

Fentanyl Norelgostromin/ Ethinyl Estradiol

Nycomed ORTHO-McNEIL

Pain relief patch Postmenstrual syndrome

Ortho EvraTM

NuPatch 100

Diclofenac diethylamine

Zydus Cadila

Anti Inflammatory

Neupro

R

Rigotine

UCB and Schwarz Pharma early-stage idiopathic Parkinsons disease

Alora

Estradiol

TheraTech/Proctol and Gamble

Postmenstrual syndrome

Nicoderm

R

Nicotine

Alza/GlaxoSmithKline

Smoking cessation

Estraderm

Estradiol

Alza/Norvatis

Postmenstrual syndrome

Climara

Estradiol

3M Pharmaceuticals/Berlex Postmenstrual Labs syndrome

Androderm

Testosterone

TheraTech/GlaxoSmithKline Hypogonadism in males

Nitrodisc

Nitroglycerin

Roberts Pharmaceuticals

Angina pectoris

Transderm- Scop

R

Scopolamine

Alza/Norvatis

Motion sickness

Nuvelle TS

Estrogen/Proge sterone

Ethical Holdings/Schering

Hormone replacement therapy

Deponit

Nitroglycerin

Schwarz-Pharma

Angina pectoris

Nitro-dur

Nitroglycerin

Key Pharmaceuticals

Angina pectoris

Catapres TTS

R

Clonidine

Alza/Boehinger Ingelheim

Hypertension

FemPatch

Estradiol

Parke-Davis

Postmenstrual syndrome

Minitran

Nitroglycerin

3M Pharmaceuticals

Angina pectoris

Climaderm

Estradiol

Ethical Holdings/WyethAyerest

Postmenstrual syndrome

Duragesic

R

Fentanyl

Alza/Janssen Pharmaceutical

Moderate/severe pain

Estraderm

Estradiol

Alza/Norvatis

Postmenstrual syndrome

Fematrix

Estrogen

Ethical Holdings/Solvay Healthcare Ltd.

Postmenstrual syndrome

Transderm- Nitro

R

Nitroglycerin

Alza/Norvatis

Angina pectoris

Testoderm TTS

R

Testosterone

Alza

Hypogonadism in males

Oxytrol

R

oxybutynin Nicotine

Watson Pharma Elan Corp./Lederle Labs

Overactive bladder Smoking cessation

Prostep

Factors affecting transdermal bioavaibility4, 16Two major factors affect the bioavaibility of the drug via transdermal routes: (1)Physiological factors (2) Formulation factors

Physiological factors include4, 16(1)Stratum corneum layer of the skin (2) Anatomic site of application on the body (3) Skin condition and disease (4) Age of the patient (5) Skin metabolism (6) Desquamation (peeling or flaking of the surface of the skin) (7) Skin irritation and sensitization (7) Race Formulation factors include4, 16

(1)Physical chemistry of transport (2) Vehicles and membrane used (3) Penetration enhancers used (4) Method of application (5) Device used

Care taken while applying transdermal patch17(1)The part of the skin where the patch is to be applied should be properly cleaned. (2) Patch should not be cut because cutting the patch destroys the drug delivery system. (3) Before applying a new patch it should me made sure that the old patch is removed from the site. (4) Care should be taken while applying or removing the patch because anyone handling the patch can absorb the drug from the patch. (5) The patch should be applied accurately to the site of administration.

Mechanism of Action of Transdermal PatchThe application of the transdermal patch and the flow of the active drug constituent from the patch to the circulatory system via skin occur through various methods.

1. Iontophoresis

18, 19

Iontophoresis passes a few milliamperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier. Mainly used of pilocarpine delivery to induce sweating as part of cystic fibrosis diagnostic test. Iontophoretic delivery of lidocaine appears to be a promising approach for rapid onset of anesthesia. 2.Electroporation18, 20, 21, 22, 23

Electroporation is a method of application of short, high-voltage electrical pulses to the skin. After electroporation, the permeability of the skin for diffusion of drugs is increased by 4 orders of magnitude. The electrical pulses are believed to form transient aqueous pores in the stratum corneum, through which drug transport occurs. It is safe and the electrical pulses can be administered painlessly using closely spaced electrodes to constrain the electric field within the nerve-free stratum corneum. 3.Application by ultrasound18, 24

Application of ultrasound, particularly low frequency ultrasound, has been shown to enhance transdermal transport of various drugs including macromolecules. It is also known as sonophoresis. Katz et al. reported on the use of low-frequency sonophoresis for topical delivery of EMLA cream. 4.Use of microscopic projection18

Transdermal patches with microscopic projections called microneedles were used to facilitate transdermal drug transport. Needles ranging from approximately 10-100 m in length are arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are large enough to deliver macromolecules, but small enough that the patient does not feel the penetration or pain. The drug is surface coated on the microneedles to aid in rapid absorption. They are used in development of cutaneous vaccines for tetanus and influenza. Various other methods are also used for the application of the transdermal patches like thermal poration, magnetophoresis, and photomechanical waves. However, these methods are in their early stage of development and required further detail studying.

Types of Transdermal Patch251. Single-layer Drug-in-Adhesive The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. 2. Multi-layer Drug-in-Adhesive The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. The multi-layer system is different however that it adds

another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing. 3. Reservoir Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order. 4. Matrix The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it. 5. Vapour Patch In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapours patches release essential oils and are used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market.

Drugs used in the Transdermal Patch25(1) Nicotine: to quit tobacco smoking (2) Fentanyl: analgesic for severe pain (3) Estrogen: menopause and osteoporosis (4) Nitroglycerin: angina (5) Lidocaine: peripheral pain of shingles (herpes zoster). Recent developments expanded their use to the delivery of hormonal contraceptives, antidepressants and even pain killers and stimulants for Attention Deficit Hyperactivity Disorder/ADHD.

Recent research done in the field:Many research works have been and are few are going on in this field. Few of the latest research done in the field of transdermal patches are stated below:

Pain-free diabetic monitoring using transdermal patches26

The first prototype patch measures about 1cm2 and is made using polymers and thin metallic films. The 55 sampling array can be clearly seen, as well as their metallic interconnections. When the seal is compromised, the interstitial fluid, and the biomolecules contained therein, becomes accessible on the skin surface. Utilizing micro-heating elements integrated into the structural layer of the patch closest to the skin surface, a high-temperature heat pulse can be applied locally, breaching the stratum corneum. During this ablation process, the skin surface experiences temperatures of 130C for 30ms duration. The temperature diminishes rapidly from the skin surface and neither the living tissue nor the nerve endings are affected. This painless and bloodless process results in disruption of a 4050m diameter region of the dead skin layer, approximately the size of a hair follicle, allowing the interstitial fluid to interact with the patch's electrode sites.

Testosterone Transdermal Patch System in Young Women with Spontaneous Premature Ovarian Failure27In premenopausal women, the daily testosterone production is approximately 300 g, of which approximately half is derived from the ovaries and half from the adrenal glands. Young women with spontaneous premature ovarian failure (sPOF) may have lower androgen levels, compared with normal ovulatory women. Testosterone transdermal patch (TTP) was designed to deliver the normal ovarian production rate of testosterone. The addition of TTP to cyclic E2/MPA therapy in women with sPOF produced mean free testosterone levels that approximate the upper limit of normal.

Transdermal Patch of Oxybutynin used in overactive Bladder28, 29, 30The product is a transdermal patch containing Oxybutynin HCl and is approved in US under the brand name of Oxytrol and in Europe under the brand name of Kentera. OXYTROL is a thin, flexible and clear patch that is applied to the abdomen, hip or buttock twice weekly and provides continuous and consistent delivery of oxybutynin over a three to four day interval. OXYTROL offers OAB patients continuous effective bladder control with some of the side effects, such as dry mouth and constipation encountered with and oral formulation. In most patients these side effects however are not a troublesome.

Transdermal Patch (Ortho Evra) 31

The patch is 4.5 square centimeters in size and has three layers: the inner release liner which should be removed before application, a layer containing hormones, and an outer polyester protective layer. The patch contains 6 milligram of progestin, Norelgestromin 0.75 milligram of Ethinyle Estradiol. The patch is applied on the skin through which the hormones are absorbed in order to provide continuous flow of hormones during menstrual cycle. The patch is marketed by Ortho McNeil Pharmaceutical with the brand name Ortho Evra.

Rotigotine transdermal patch32The rotigotine transdermal patch is used for symptom control in Parkinsons disease. The patches are effective in reducing the symptoms of early Parkinsons disease, and in reducing off time in advanced Parkinsons disease. It is available in market under the brand name of NeuproR.

Most recent Patents:Below are listed some of the most recent patents made in the field of transdermal patch. Patent No. Date Title Information

US7415306

33

Aug. 19, Transdermal 2008 Delivery Emetic Medication

The present invention provides a transdermal delivery system for hydrophilic anti-emetic agents and methods hydrophilic adhesive composition of a hydrophilic polymer and hydrophilic anti-emetic agent, a patch containing at least one hydrophilic layer of the composition, and an apparatus that generates hydrophilic micro-channels in skin of a subject using the patch or composition

System for Anti- of using thereof. The system includes an anti-emetic

US7413748

34

Aug. 19, Transdermal 2008

A specific dosage regimen of buprenorphine achieves

Buprenorphine pain relief from painful episodes due to sickle cell to treat Pain in disease. The dosage regimen comprises administering Sickle Cell Crisis to a patient in need of pain relief from sickle cell disease at least one BTDS transdermal patch. The present invention provides a transdermal drug delivery system which comprises: a therapeutically effective amount of a non-steroidal anti-inflammatory drug; at least one dermal penetration enhancer, which is a safe skin-tolerant ester sunscreen ester; and at least one volatile liquid. The invention also provides a method for administering at least one systemic or locally acting non-steroidal anti-inflammatory drug to an animal

US7387789

35

Jul. 17, 2008

Transdermal Delivery of Non-Steroidal Anti Inflammatory Drugs

US7398121

36

Jul. 8, 2008

Iontophoresis Device

An iontophoresis device useful for administering an ionic drug by iontophoresis has an iontophoresis electrode section and a ground electrode section Both of which are to be connected to a power source. The iontophoresis device includes elements (members) of both of the electrode sections are all formed of membrane bodies, and includes ion exchange membranes different in ion selectivity, one being selective to ions of the same species as charged ions of the ionic drug and the other to ions different in species from the charged ions of the ionic drug that are

arranged in the iontophoresis electrode section, and at least an ion exchange membrane selective to ions opposite to the charged ions of the ionic drug is arranged in the ground electrode section. The iontophoresis device can administer the ionic drug stably over a long period of time at high transport efficiency.

US7395111

37

Jul. 1, 2008

Transdermal Delivery System for Drug

The present invention provides a system for transdermal delivery of water insoluble drugs and methods using the same. The system includes a and a carrier molecule that enhances the solubility of the drug in aqueous solution, a medical patch containing the same and an apparatus that generates hydrophilic micro-channels in an area of skin of a subject using the composition or patch.

Water Insoluble pharmaceutical composition of a water insoluble drug

Conclusion7A lot of progress has been done in the field of Transdermal Patches. Due to large advantages of the Transdermal Drug Delivery System, this system interests a lot of researchers. Many new researches are going on in the present day to incorporate newer drugs via this system. Various devices which help in increasing the rate of absorption and penetration of the drug are also being studied. However, in the present time due to certain disadvantages like large drug molecules cannot be delivered, large dose cannot be given, the rate of absorption of the drug is less, skin irritation, and etc. the use of the Transdermal Drug Delivery System has been limited. But, with the invention of the new devices and new drugs which can be incorporated via this system, it used is increasing rapidly in the present time.

References:1. Ranade, V, V.; Drug delivery systems. 6. Transdermal drug delivery, The Clinical Journal Of Pharmacology Available http://jcp.sagepub.com/cgi/content/abstract/31/5/401 2. Segal, Marian. "Patches, Pumps and Timed Release: New Ways to Deliver Drugs". Food and Drug Administration. Retrieved on 2007-02-24. 3. "FDA approves scopolamine patch to prevent peri-operative nausea". Food and Drug Administration (1997-11-10). Retrieved on 2007-02-12. 4. Jacoby, David B., Youngson, R. M., Marshall Cavendish Corporation; Encyclopedia Of Family Health, Published by Marshall Cavendish, 2004, Pg: 2259

5. Bayarski, Yury; Transdermal Drug Delivery, Transdermal Patches Available: http://ezinearticles.com/?Transdermal-Drug-Delivery,-Transdermal-Patches... 6. MANAGED CARE April 2004. MediMedia USA , Available : http://www.managedcaremag.com/archives/0404/0404.biotech.html 7. Hillery, Anya M, Lloyd, Andrew W., Swarbrick, James; Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists, Published by Taylor & Francis, 2001 Pg 216 8. Guy, Richard H., Hadgraft, Jonathan; Transdermal Drug Delivery Second Edition Published by Informa Health Care, 2002 Pg 322 9. Arcangelo , Virginia P., Peterson, Andrew M.; Pharmacotherapeutics for Advanced Practice, Published by Lippincott Williams & Wilkins, 2005 Pg 74 10. http://images.google.co.in/imgres?imgurl=http://www.chimei.org.tw/main/r... 11. http://images.google.co.in/imgres?imgurl=http://www.fda.gov/bbs/topics/n... 12. http://images.google.co.in/imgres?imgurl=http://lh4.ggpht.com/_m8Z9nkvXX... 13. http://images.google.co.in/imgres?imgurl=http://www.prescribingreference... 14. Kumar, Ritesh and Philip, Anil; Modified Transdermal Technologies: Breaking the Barriers of Drug Permeation via the Skin; Tropical Journal of Pharmaceutical Research, March 2007; 6 (1): 633-644 15. Jain N, Talegonkar S, Jain N K. New ways to enter the blood stream: Emerging strategies in transdermal drug delivery. The Pharma Review 2004; Oct.: 41- 59. 16. Williams, Adrian; Transdermal and Topical Drug Delivery Published by Pharmaceutical Press, 2003; Pg: 14-18 17. Elling, Bob, Elling, Kirsten M. Rothenberg, Mikel A.; Why-Driven EMS Enrichment Published by Thomson Delmar Learning, 2001 Pg 103 18. Medscape Today journal Available http://www.medscape.com/viewarticle/530060_4 19. The Indian Anaesthetists' Forum - On-Line Journal ( http://www.theiaforum.org/ ) available http://www.theiaforum.org/april2004.htm 20. Electroporation From Wikipedia, the free encyclopedia available http://en.wikipedia.org/wiki/Electroporation 21. Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH (1982). "Gene transfer into mouse lyoma cells by electroporation in high electric fields". EMBO J. 1 (7): 8415. PMID 6329708. 22. Sugar IP, Neumann E (1984). "Stochastic model for electric field-induced membrane pores. Electroporation". Biophys . Chem. 19 (3): 21125. doi : 10.1016/0301-4622(84)87003-9. PMID 6722274 . 23. ^ Sarah Yang ( 2007 - 02-12 ). " New medical technique punches holes in cells, could treat tumors". Retrieved on 2007 - 12-13 . 24. Sonophoresis From Wikipedia, the free encyclopedia available http://en.wikipedia.org/wiki/Sonophoresis 25. Transdermal patch From Wikipedia, the free encyclopedia available : http://en.wikipedia.org/wiki/Transdermal_patch April 2004

26. Paranjape, Makarand; Biomedical Optics & Medical Imaging, Pain-free diabetic monitoring using transdermal patches Available: http://spie.org/x27077.xml 27. Kalantaridou, Sophia N., Calis, Karim A., Mazer, Norman A., Godoy, Heidy, Nelson, Lawrence M.; A Pilot Study of an Investigational Testosterone Transdermal Patch System in Young Women with Spontaneous Premature Ovarian Failure The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6549-6552 Copyright 2005 by The Endocrine Society Available http://jcem.endojournals.org/cgi/content/abstract/90/12/6549 28. Anandi Krishnan, Pharmainfo.net Available http://www.pharmainfo.net/reviews/overactivebladder-disease-overview-re... 29. http://en.wikipedia.org/wiki/Kidney 30. Watson Pharmaceuticals' OXYTROL(R) Receives Positive Opinion for Approval in the European Union CORONA, Calif., Nov. 24 /PRNewswire-FirstCall; Web site: http://www.watsonpharm.com 31. Pill, Yasmin, Ring, Nuva, Ortho Evra Patch, Lunelle Injectable; Contraceptive Advances Available http://www.reproline.jhu.edu/english/1fp/1advances/1combined/patch.htm 32. Issue in Emerging Health Technology, Issue 112 February 2008 Available http://cadth.ca/media/pdf/E0056_Rotigotine-Patch-Parkinsons-Disease_ceta... 33. http://www.freepatentsonline.com/US7415306.html?query=PN/US7415306%20OR%... 34. http://www.freepatentsonline.com/US7413748.html?query=PN/US7413748%20OR%... 35. http://www.freepatentsonline.com/US7387789.html?query=PN/US7387789%20OR%... 36. http://www.freepatentsonline.com/US7398121.html?query=PN/US7398121%20OR%... 37. http://www.freepatentsonline.com/US7395111.html?query=PN/US7395111%20OR%...

Transdermal Delivery SystemsTransdermal drug delivery technology can provide advantages over conventional dosage forms, such as tablets, capsules and injections. Improved Absorption Reliable Blood Levels Avoid Hostile GI Environment Less Frequent Doses, Better Compliance Better Safety Profile Removing the TDS product from the skin can stop drug input and terminate the treatment if unexpected effects occur.

Convenient patch delivery systems can be designed that incorporate antiirritant ingredients and proprietary skin penetration enhancers. Weekly or twice weekly patch systems can provide sustained release and better compliance. A variety of thin, flexible, transparent and cosmetically aesthetic designs are available.

Xel has developed proprietary once-a-week drug-in-adhesive transdermal matrix patches to deliver Huperzine A for the treatment of Alzheimer's Disease (XEL 001HP) and to deliver Bulleyaconitine for pain management (XEL 002BP).

Samples of Transdermal Patch

Types of Formulation DesignSingle-Layer Drug-in-Adhesive

This system is characterized by the inclusion of the drug directly within the skin-contacting adhesive. The adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation containing the drug and the excipients. Multi-layer Drug-in-Adhesive

This system is also incorporated directly into the adhesive. However, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film.

Liquid Reservoir

This system has liquid compartment containing drug separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component responsible for skin adhesion can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Matrix

This system has a semisolid matrix containing a drug solution or suspension in direct contact with the release liner. The component for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.Trasdermal Delivery System The patch uses transdermal technology. Transdermal medical or patch delivery is the non-invasive delivery of medications that first began in the late 1970s. Its a process where medication delivery is carried out by a patch that is attached to the body. It was discovered that using the surface of the skin the largest and most accessible organ of the human body - through its layers, could get medications to the circulatory system quicker and more efficiently.

The DeBug patch works with the same technology. It uses a special membrane to control the all natural ingredients contained within the patch allowing them to quickly pass through the skin and stop insects from biting for you for up to 48 hours

Transdermal Patch Technology

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the

system to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.

Backing The outermost layer of a transdermal system which protects the formulation against the environment, prevents evaporation or loss of thiamines and other volatile excipients, provides anchorage as well as flexibility, comfort and printability Thiamine-in adhesive Serves as the foundation to contain the Thiamine formula and adhere to the skin Liner Serves to protect the formulation during the storage period. The release liner is removed prior to the patch application

3M's proprietary drug-in-adhesive technology platform builds upon 3Ms core technologies. With their long history of adhesive technology and manufacturing capabilities, combined with their pharmaceutical experience and formulation chemistry allows them to customize the adhesive for the DeBug vitamin formula compound.