Pressure sensitive adhesives for transdermal drug delivery system

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PSTT Vol. 2, No. 2 February 1999

Pressure-sensitive adhesives for transdermal drug delivery systems Hock S. Tan and William R. Pfister Adhesives are a critical component in transdermal drug delivery (TDD) devices. In addition to the usual requirements of functional adhesive properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug, various components of the formulation, and provide consistent, effective delivery of the drug. This review discusses the three most commonly used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD devices, and provides an update on recently introduced TDD products and recent developments of new adhesives.

Hock S. Tan* and William R. Pfister Lavipharm Laboratories Inc. 131 Ethel Road West Suite 6 Piscataway New Jersey 08854 USA *tel: 11 732 572 9660 fax: 11 732 572 1306

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▼ Transdermal drug delivery (TDD) systems are

drug-loaded adhesive patches which, when applied to the skin, deliver the therapeutic agent, at a controlled rate, through the skin to the systemic circulation and to the target organs. The first commercial TDD system, Transderm-Scop®, a controlled delivery system for scopolamine, was developed by Alza Corporation (Palo Alto, CA, USA) and in 1980 it was introduced to the US market for the treatment of motion sickness. Since then, seven drugs and more than 25 different TDD products in multiple dosages and strengths for the systemic treatment of various diseases have been marketed in the USA1. These include nitroglycerin for the treatment of angina pectoris, clonidine for hypertension treatment, fentanyl for pain management, estradiol – alone or in combination with norethindrone acetate – for the relief of postmenopausal symptoms and treatment of osteoporosis, nicotine as an aid in smoking cessation, and testosterone for the treatment of hypogonadism.The TDD product market and dosage form designs have recently been reviewed1. A summary of the TDD products marketed in the USA is given in Table 1. Transdermal drug delivery products that were introduced in 1998 included FemPatch® (Cygnus, Inc.,

Redwood City, CA, USA) and CombiPatch® (Noven Pharmaceuticals, Miami, FL, USA) for hormone replacement therapy. Transdermal drug delivery systems, as compared to their corresponding classical oral or injectable dosage form counterparts, offer many advantages1–3.The most important advantages are improved systemic bioavailability of the pharmaceutical active ingredients (PAI), because the first-pass metabolism by the liver and digestive system are avoided; and the controlled, constant drug delivery profile (that is, controlled zeroorder absorption). Also of importance is the reduced dose frequency compared to the conventional oral dosage forms (that is, once-a-day, twice-a-week or once-a-week). Other benefits include longer duration of therapeutic action from a single application, and reversible action. For example, patches can be removed to reverse any adverse effects that may be caused by overdosing. In TDD applications, adhesives are used to maintain intimate contact between the patch and the skin surface. Many classes of adhesives are available that might be considered for use with TDD patches, although in practice pressuresensitive adhesives (PSAs) are preferred. Pressuresensitive adhesives are generally defined as materials that adhere to a substrate with light pressure and which leave no residual adhesive upon their removal4.They offer the advantages of convenience of use (PSAs do not require water/solvents or heat in order to achieve adhesion), good stability (PSAs are generally not sensitive to environmental humidity or temperature degradation), simplicity of manufacture, and good appearance5. In addition to the usual requirements of functional pressure-sensitive adhesive properties, such as adequate tack, skin-adhesion and cohesive strength, there are other factors to be considered in the selection and use of PSAs for TDD systems.These include biocompatibility, formulation

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00119-4

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PSTT Vol. 2, No. 2 February 1999

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Table. 1. Transdermal drug delivery (TDD) products marketed in the United States Drug

Product

Developer/marketer

TDD system designa

Pressure-sensitive adhesive typeb

Clonidine Estradiol Estradiol Estradiol Estradiol Estradiol/ Norethindrone Acetate Fentanyl Nicotine Nicotine Nicotine Nicotine Nitroglycerin Nitroglycerin Nitroglycerin Nitroglycerin Nitroglycerin Scopolamine Testosterone Testosterone

Catapres-TTS® Climara® Estraderm® Vivelle® FemPatch® CombiPatch®

Alza/Boehringer Ingelheim 3M Pharmaceuticals/Berlex/Schering AG Alza/Novartis Noven/Novartis Cygnus/Parke-Davis Noven/Rhone-Poulenc Rorer

DIA-multi-laminate DIA-monolithic Reservoir DIA-monolithic DIA-monolithic DIA-monolithic

PIB Acrylate PIB Acrylate Silicone Acrylate

Duragesic® Nicoderm® Harbitrol® Nicotrol® Prostep® Transderm-Nitro® Minitran™ Nitro-Dur® Nitrodisc® Deponit® Transdermal-Scop® Androderm® Testoderm®

Alza/Janssen Pharmaceutical Alza/SmithKline Beecham Lohmann/Novartis Cygnus/McNeil Consumer Products Elan/Lederle Alza/Novartis 3M Pharmaceuticals Key Pharmaceuticals/Schering Plough G.D. Searle/Roberts Lohmann/Schwarz Pharma Alza/Novartis TheraTech/SmithKline Beecham Alza

Reservoir DIA-multi-laminate Polymer matrix DIA-monolithic Polymer matrix Reservoir DIA-monolithic DIA-monolithic Polymer matrix DIA-multi-laminate DIA-multi-laminate Reservoir DIA-monolithic

Silicone PIB Acrylate PIB Acrylate Silicone Acrylate Acrylate Acrylate PIB PIB Acrylate EVA

aTDD

system designs: drug-in-adhesive (DIA), liquid reservoir (reservoir), multi-laminate drug-in-adhesive (DIA)/control membrane composite (multi-laminate)

bPSA

Types: polyisobutylene (PIB), polyacrylate copolymer (acrylate), polysiloxane-based (silicone), ethylene-vinyl acetate copolymer (EVA).

compatibility, delivery system compatibility, and acceptable regulatory status (that is, the availability of drug master files or equivalent supporting documentation). Biocompatibility requires that the PSAs are biologically inert, non-irritating and non-sensitizing to skin, and have no systemic toxicity. Formulation compatibility requires that the PSAs do not induce drug or excipient degradation, do not react with the drug and other formulation components, maintain stability and functional properties when formulated, and offer the desired solubility. Delivery system compatibility requires that the PSAs provide adequate diffusivity and permeability to the drug and/or permeation enhancers6,7. Pressure-sensitive adhesives are therefore regarded as one of the critical components in TDD devices1. Thus, making a change in the PSA component of a TDD system might be considered to be a major change that would require the demonstration of bioequivalence and necessitate a regulatory amendment. This review discusses TDD products, transdermal system designs and components, and focuses on the PSAs that are currently used in TDD devices. In addition, this review highlights some recent advances, including new TDD products and inno-

vative developments in PSA technology. Earlier reviews on the subject of PSAs, along with other components, used in commercial TTD products may be found in the References 6–9. Transdermal drug delivery system designs Transdermal drug delivery can be achieved via active or passive systems, depending on whether external energy is used to assist the transport of the drug through the skin10.The active systems use heat, electric current (iontophoresis), sound waves (sonophoresis), or transient high-voltage electrical pulses (electroporation) to enhance the delivery of drugs into the systemic circulation10–12. Ionophoretic drug delivery devices have been used for more than a decade for local delivery of PAI in the treatment and diagnosis of disease (that is, skin inflammation, psoriasis, local anesthesia, muscle ache and pain). The ionophoretic devices are now in the clinical development stage for systemic drug delivery, and commercial applications can be expected within three to five years10. In passive TDD systems, the drug diffuses through the skin into the systemic circulation by passive means.The concentration gradient of the drug across the skin and the difference in solubility 61

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(a) Drug-in-adhesive: monolithic

PSTT Vol. 2, No. 2 February 1999

(b) Drug-in-adhesive: multilaminate Impermeable backing Drug-adhesive matrix Rate-controlling membrane Adhesive Release liner

(c) Liquid reservoir

(d) Polymer matrix Impermeable backing Drug–polymer matrix Drug reservoir Rate-controlling membrane Adhesive Release liner

Figure 1. Typical designs of transdermal drug delivery (TDD) systems.

between the adhesive and skin are the driving force for delivery to the surface of the skin. In general, chemical permeation enhancers (pharmaceutical excipients) are required for passive delivery to achieve the required delivery of the drug from a patch of a reasonable size (that is, a surface area of