Journalof Controlled Release, 29 ( 1994) 1 V-185 0 1994 Elsevier Science B.V. All rights reserved 0168-3659/94/$07.00

COREL 00933

Polymers for transdermal drug delivery systems

Kenji Sugibayashi and Yasunori Morimoto Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan

(Received 15 April 1993; accepted in revised form 23 July 1993)

177

Advances in transdermal delivery systems (TDS ) and the technology involved have been rapid be- cause of the sophistication of polymer science which now allows incorporation of polymeric additives in TDS in adequate quantity. Polymer selection and design are of prime importance in formulating various criteria of new TDS. In this review paper, typical polymers in topical drug formulations are introduced by category, and their usefulness is discussed. Several methods for regulation of release and skin permeation of drug by polymers are also introduced and evaluated.

Key words: Polymer; Transdermal drug delivery system; Topical formulation; Skin

Introduction

The skin is the most expansive and readily ac- cessible organ of the human body. It has been used as an administration site of pharmaceutical drugs with local action on it and on muscle be- neath, and it is now recognized that other drugs with systemic action can also be introduced through the skin. Topical formulations contain- ing drugs showing systemic action are called transdermal delivery systems (TDS ) or trans- dermal therapeutic systems (TTS ). Transder- ma1 delivery may be defined as the delivery of a drug through intact skin so that it reaches the systemic circulation in sufficient quantity to be beneficial after administration of a therapeutic dose. TDS provides a variety of advantages in- herent in the transdermal route, including elim- ination of gastrointestinal absorption problems and hepatic first pass effect, reduction of dosage

Correspondence to: K. Sugibayashi, Faculty of Pharmaceuti- cal Sciences, Josai University, l-l Keyakidai, Sakado, Sai- tama 350-02, Japan.

XSDI0168-3659(93)E0118-Y

and dose interval, predictable and extended du- ration of activity, improved patient compliance, quick termination by simple removal of the sys- tem from the skin surface, and possible self- administration. The successful introduction of several TDS has greatly expanded the search for drugs suitable for delivery via the transdermal route. Drugs with which transdermal therapy was pioneered include scopolamine, nitroglycerine, isosorbide dinitrate, clonidine, estradiol, nico- tine and testosterone.

The major parts of TDS are a controlled re- lease device composed of polymers, the drug, ex- cipients and enhancers, a fastening system, usu- ally a pressure-sensitive adhesive (PSA), to fix the device to the skin, and a hermetically sealed package composed of impervious film. Ad- vances in transdermal drug delivery technology have been rapid because of the.sophistication of polymer science which now allows incorporation of polymers in TDS in adequate quantity. The importance of polymer selection can be appreci- ated more if one considers the different design criteria which must be fulfilled. In this review

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TABLE 1

Polymers possibly useful for transdermal devices

Role

Natural polymers Gelatin Na-alginate Gum arabic Starch Gum tragacanth Shellac Paraffin waxes Proteins Casein Natural rubber

Semi-synthetic polymers Carmellose Cellulose acetate phthalate Methyl- & ethylcellulose Nitrocellulose Hydroxypropylcellulose (HPC)

Synthetic elastomers Polybutadiene Polyisoprene Polysiloxane Styrene-butadiene rubber Silicone rubber

Synthetic polymers Polyvinyl alcohol Polyethylene Polypropylene (PP) Polystyrene Polyurethane Polyvinylpyrrolidone Polymethylmethacrylate Polyvinylacetate Polyhydroxyethyl methacrylate (PHMA) Polyvinyl chloride (PVC) Polyacrylate Polyacrylamide Polyethyleneglycol (PEG ) Polyester Polyamide & polyurea

Epoxy Ethylene vinyl acetate

copolymer (EVA) Polybutene Polyisobutylene (PIB)

Adapted from Ref. 1.

base, adhesive base, adhesive base with adhesive base, adhesive adhesive

adhesive base with adhesive

base, adhesive

base, adhesive

base, adhesive

base with adhesive

base with adhesive base with adhesive

aq. base, adhesive linear, backing membrane, linear co-adhesive foam, backing aq. base, adhesive

base

liner, backing

base, adhesive base, adhesive base linear, backing foam foam

membrane viscosity modifier viscosity modifier

TABLE 2

Categorization of polymeric systems for controlled release

Physical systems Reservoir systems with rate-control Membrane systems Adhesive membrane systems Microreservoir systems (Microencapsulation or Macroencapsulation)

Reservoir systems without rate-control Hollow fibers Porous film

Monolithic systems Physically dissolved in nonporous, polymeric, or elastomeric matrix (Nonerodible, erodible, environmental agent, or degradable) Physically dispersed in nonporous, polymeric, or elastomeric matrix Laminated structure Other physical methods (Osmotic pumps, Adsorption onto ionexchange resins)

Chemical Systems Chemical erosion ofpolymer matrix Heterogeneous, Homogeneous

Biological erosion ofpolymer matrix Heterogeneous, Homogeneous

Adapted from Ref. 1.

paper, typical polymers in topical drug formula- tion are introduced (Tables 1 and 2 [ 1 ] ), and their usefulness is discussed.

Polymeric additives in ointments and other topical formulations

Dermatological additives can be divided into three categories: aqueous, powder and oil [ 21. The permutation and combinations of the ingre- dients of the three classes along with other ingre- dients lead to a great number of topical formu- lations. Many polymers such as natural products (carbohydrates, tragacanth, alginate, gelatin), cellulosics (methylcellulose, carmellose ) and synthetics (carboxyvinyl copolymer) are used as additives in the aqueous phase. Starch and syn- thetic polypropylene and silicones are represent- ative polymers of the powder and oil phase, re-

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spectively. These combinations make soak, lotion, powder, paste, ointment, gel and cream with the aid of emulsifiers. We recently devel- oped a film-forming transdermal liquid using polyvinylacetate [ 3 1, which may prove beneti- cial on flexible parts (i.e., elbow) and complex parts (the base of fingers and toes) of the body. Although such formulations containing a drug with systemic action (i.e., nitroglycerin) have been developed, these are expected to be re- placed by a dermal patch which offers much bet- ter control of dosage and more easily gains pa- tient compliance.

It was recently reported that release of lido- Caine from ointment bases containing carboxy- vinyl polymers was lower than from those con- taining methylcellulose [ 41. Most polymers generally decrease the drug released from for- mulations probably due to their greater viscosity and polymer-drug interaction [ 51. Studies on drug-polymer interaction should be continued from pharmaceutical and technological points of view. Much experience with the polymeric addi- tives used in ointments and other topical dosage forms is making possible the enhanced fabrica- tion of new topical TDS formulations.

Polymers for pressure-sensitive adhesive (PSA) matrix devices

The fastening of all transdermal devices to the skin is now done using a PSA. The PSA can be positioned on the face or the back of the device and extended peripherally. Either way, it must fulfill the following requirements: cause no irri- tation and no sensitization during its period of contact with the skin, provide sufficient adhe- sion to skin during the dosing interval, and be easily removed without leaving an unwashable residue. Face adhesion is physically and chemi- cally compatible with the active agent as well as with excipients and other compounds such as en- hancers and solubilizers. Peripheral adhesion is perhaps less elegant and certainly involves a sub- stantially greater area. The most typical PSAs are acrylic, rubber or silicone adhesive [ 61. New

isosorbide dinitrate tapes, FrandolR tape-S (Ya- manouchi Pharmaceutical Co. ) and Antup (Ti- jin) (Table 3) have been developed which de- crease the skin irritation by adding isopropyl myristate as a softening agent and hollow fibers as water vaporization-enhancing material into PSA. Such attempts to reduce the biological side effects of PSA are continuing toward the goal of obtaining one which is non-irritating. The low volume of PSA is somtimes a shortcoming be- cause the amount of active drug and chemical enhancer which can be loaded is limited. Plister [ 71 was responsible for a new, improved sili- cone-type PSA with higher maximum loading capacity.

One of the simplest TDS is a PSA matrix de- vice; Fig. 1 a shows a common type. The drug res- ervoir itself is the adhesive. The rate of drug re- lease is defined by the equation of either W.I. Higuchi [ 8 ] or T. Higuchi [ 9 1, which can be used for drug-in-solution or suspension formulation, respectively, like a matrix device [ lo]. Mono- lithic PSAs, for example, are: FrandolR tape-S available in the Japanese market and Nitro-Dup II (Key Pharmaceuticals, Inc.) used as a medi- cation for angina pectoris. These and other rep- resentative systems on the market are shown in Table 3.

Polymers to regulate skin permeation

Membrane system

Rate-control is best done by membrane sys- tems, but they can be used as reservoir devices both with and without utilizing this function. The drug reservoir is totally encapsulated in a com- partment molded from a drug-impermeable me- tallic plastic laminate and the polymeric mem- brane. Figure 1 b shows a cross-section of a typical device. Several TDS have been successfully de- veloped from this technology [ 11,12 ] and are best exemplified by Transderm-ScopR, Trans- derm-NitroR, EstradermR (Ciba Pharmaceutical Co. ), and CatapresR-TTS (Boehringer-Ingel- heim). Drug molecules are released across the membrane simply by diffusion through the pores

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TABLE 3

Representative commercial transdermal products

Acdve agenr (indication) Product name

Scoparumine (motion sickness) Transderm-Stop Kimete Patch

Nitroglycerin (angina) Transderm-Nitro (Nitriderm TTS, Nitroderm TTS) Nitro-Dur II (Diafusor) Nitrodisc Deponit

Minitran NTS Patch (Nitrocine) Nitrol Herzer (Myrisrol )

Zsosorbide dinitrate (angina) Frandol Tape-S

Apatya Tape Antup Tape Isopit Tape Sawadol Tape Nitrous Tape Penety ISDN Tape Rifatac

Clonidine (hypertension) Catapres TTS

Estrodiol (hormone treatment) Estradiol

Nicotin (aid to smoking cessation) Nicotine11 TTS Niconil (ProStep, Nicolan, Nicotrans) Nicoderm’ Habitrol Nicotrol

Fen&nil (opioid analgesic) Duragesic

Mepindodol (Hypertension) Pharmed’

Company

AlzaJCiba Myun Moon

Alza/Ciba

Key/Schering

G.D. Searle Lohman/Schwarz /Wyeth 3M Riker Hercon/Bolar

Paco/Adria Nichiban/Taiho /Nihon Kayaku

Toaeiyo /Yamanouchi Teikoku Tisan/Teijin Toko/Mitsui Sawai Taikyo Sekisui Meiji

Alza/Boehringer Ingelheim

Ciba

Lohman/Ciba Elan

Alza Ciba Cygnus

Alza/Ivers Lee Reservoir /Janssen

Type of device

Reservoir Reservoir

Reservoir

Matrix

Microsealed PSA adhesive

PSA Matrix

Matrix PSA

PSA

PSA PSA PSA PSA PSA PSA PSA

Reservoir

Reservoir

Woven pad

Bio-TSD

Polymer

PIB, EVA

EVA, Silicone

Acrylic type PSA

Silicone, PEG

PVC

Acrylic type PSA

Acrylic type PSA

Acrylic type PSA Hollow fiber Rubber type PSA Acrylic type PSA

Acrylic type PSA Acrylic type PSA

PIB, PP

HPC, EVA, PIB

*FDA or related organization approved. For abbreviations. refer to Table 1.

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ImDermeabie

reservoir conlainlng drug

Drug-impermeable metallic plastic laminate

Ratecontroiiing +--.poiymeric membrane

x

+ t t ‘Adhesive layer

, Drug-impermeable metallic lastic laminate

-Adhesive layer

2 DVug reservoir layer

Rate-controlling adheslve membrane

Occlusive baseplate (aluminum foil disc)

Adhesive foam pad /(flexible polyurethane)

-- Adhesive rim

Microscopic drug reservoirs

Absorbent pad Drug-impermeable

I / plastic backing

t t t ’ Drug reservoir

Fig. 1 Cross-sectional view of several TDS: (a) PSA matrix device; (b) membrane-moderated TDS; (c) adhesive-controlled TDS; (d) microreservoir-type TDS; (e) matrix dispersion-type TDS

among the polymers filled with solvent in a mi- sive polymer may be used to achieve intimate croporous membrane such as Millipore filters or contact of the device with the skin. The release CelgardR porous polypropylene, and through rate from this type of TDS can be tailored by polymer itself in a solution-diffusion membrane varying the polymer composition, permeability

like one of silicone. On the external surface of coefficient, and thickness of the membrane and

the polymeric membrane, a thin layer of adhe- adhesive. Selection of polymeric membrane is

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very important in designing a variety of mem- brane permeation-controlled TDS.

Since the release and skin permeation of a drug from the former system are influenced by the in- gredients in the drug reservoir, their release and permeation kinetics should be controlled so that the drug is permeated at a constant rate. We have reported the benefits of styrene-butadiene-sty- rene copolymer as a membrane maintaining a constant reservoir of flurbiprofen and various ratios of water-ethanol mixed solvent as model drug and vehicle [ 13 ] ; further advantages are anticipated employing such membrane and the osmo-regulatory principle [ 141. These systems are applicable to several others containing sol- vent type penetration enhancers such as ethanol.

Adhesive membrane system

An adhesive layer can be used instead of poly- meric membrane for rate-control in reservoir de- vices. Figure lc shows a typical type of adhesive diffusion-controlled system [ 15 1. The drug res- ervoir is formulated by directly dispersing the drug in an adhesive polymer and then spreading the medicated adhesive by solvent casting or heating molding onto a flat sheet of drug-im- permeable backing to form a thin drug reservoir layer. On top of this, a layer of nonmedicated, rate-controlling adhesive polymer of constant thickness is spread to produce an adhesive dif- fusion-controlled drug delivery system. The rate of drug release generally obeys Fick’s law. Drug release from the DeponitR system (Pharma- Schwarz GmbH) composed of several PSA lay- ers is controlled by different diffusivities of the layers.

Microreservoir system

Microcapsules and macrocapsules prepared by polymers and polymeric membranes can be used in types of reservoir devices, such as hollow li- bers, porous polymer sheet or filter, and foam as the wall of a capsule. Microcapsulation agents are

one of the most important components in this system, and several hydrophilic and hydropho- bic polymers are available for this purpose. Hy- drophilic polyether gels, cross-linked polyvinyl alcohol, and acrylates are some examples of hy- drophilic polymers, while silicone rubber, soft nylon and plasticized polyvinyl chloride are hy- drophobic polymers.

Strictly speaking, such microreservoir systems may be considered monolithic matrix systems. A microreservoir type TDS is actually a hybrid of reservoir and matrix dispersion-type DDS. In this approach, the drug reservoir is formed by sus- pending the drug solids in an aqueous solution of water-soluble liquid polymer. The drug sus- pension is then dispersed homogeneously in a li- pophilic polymer by high-shear mechanical force, to form thousands of unleachable, microscopic spheres of drug reservoirs. A cross-section of this type TDS is shown in Fig. Id. This technology has been utilized in the development of NitrodiscR [ 161 (Searle Pharmaceuticals, Inc. ) . Release of a drug from a microreservoir-type DDS can follow either a partition-control or a matrix diffusion-control depending upon the rel- ative magnitude of solubility of the drug in the liquid compartment and in the polymer matrix

1171.

Polymeric matrices

Probably the simplest and least expensive way to control the release of a drug is to disperse it through an inert polymeric matrix. In mono- lithic systems, the drug is physically blended with polymeric powder (either hydrophilic or lipo- philic), and the medicated polymer is then molded into a medicated disc with a defined sur- face area and controlled thickness. This drug res- ervoir containing the polymer disc is then glued onto an occlusive baseplate in a compartment fabricated with a drug-impermeable plastic backing. This type of TDS is exemplified by the Nitro-DurR system [ 18 ] (Key Pharmaceuticals, Inc. ), a cross-section of which is shown in Fig. le. The adhesive polymer is usually applied

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around the circumference to form an adhesive rim around the medicated disc; the active agent then dissolves in the polymeric or elastomeric matrix until saturation is reached. The agent is released from this device by diffusing through the matrix at a rate defined by either W.I. Higuchi’s [ 8 ] or T. Higuchi’s [ 91 equation.

An interesting monolithic device which pro- vides the versatility of either zero order or bi- modal release has been reported [ 191. Called a heterogeneous interpenetrating polymer net- work and consisting of two chemically indepen- dent cross-linked polymers, it may be useful in preventing tolerance in nitroglycerin patches.

Polymers to enhance skin permeation

Penetration enhancers

Enhancers which promote skin permeation of an active ingredient must be considered a key part of most transdermal formulations because of the strong barrier properties of the stratum corneum, the uppermost layer of the skin. Some of the lipophilic solvents and surface active agents evaluated have been found to be effective, but their irritation and sensitization limit their application. The potential for systemic toxicity due to their low molecular weight is of particular concern.

Aoyagi et al. recently reported that a novel type of polymeric enhancer [ 20,2 11, which itself per- meated through the skin only with difficulty, was synthesized by radical polymerization of a cati- onic surfactant monomer, pvinylbenzyldime- thylalkylammonium chloride containing a long alkyl group (Fig. 2a). The enhancing activity of the polymer, which was evaluated by measure- ment of rabbit skin permeation of Mluorouracil in vitro, was found to be high. These researchers also reported another type of polymeric enhan- cer composed of polydimethylsiloxane with methylpyridium group (Fig. 2b) [ 221. In a se- ries of experiments with this polymer, the skin permeation of indomethacin was increased with increase in degree of polymerization. A mecha-

Cd33

b) I-

+’ \ Ye

Me.N 3 CH,CH, (SjO),$iMe, -

Me

Fig. 2 Structures of polymeric enhancers

nism of skin penetration enhancement differing from that by low molecular enhancers was sug- gested: polymeric enhancers did not increase the diffusion coefficient of the drug in the skin bar- rier, so that they may have less systemic and skin toxicity.

Release enhancers

At a recent pharmaceutical meeting we re- ported that some hydrophilic polymers, such as hydroxypropylcellulose and polyethyleneglycol, increased the release of clonidine hydrochloride, a model hydrophilic compound, from lipophilic PSA matrix devices [ 23 1. Although the release- enhancing mechanism is still not clear, this is a useful technique to retain high thermodynamic activity of the drug in the vehicle. Research to maintain a high release rate and activity of drugs is important for the fabrication of even more so- phisticated TDS.

Pulsed delivery

Stimuli-sensitive polymers are potentially use- ful in a pulsed drug delivery even in the TDS area; they can help to overcome the tolerance that oc- curs with a constant delivery rate. Environmen- tal stimuli include temperature [ 24 1, pH [ 25 1, electric field [ 26 ] and certain chemicals [ 27 1. Nozawa et al. presented a prototype of antife-

184

brile TDS which worked only under a high fever condition using temperature-sensitive material- embedded polymer membrane [ 24 1.

Iontophoresis

Iontophoresis can be defined as a process or method in which the permeation rate of ionic species into the body is enhanced by applying an electric current between viable tissues. This sys- tem has been used to enhance transdermal per- meation rate of a drug. Several polymers can be employed in the iontophoretic system such as polyelectrolytes, ion exchange polymeric mem- branes and polymer batteries, in addition to polymers in the drug reservoir and counter elec- trode phase.

Polymer selection and design are of great im- portance in meeting the various criteria of new TDS to be fabricated. The function of a polymer together with the physicochemical properties of the pharmacologically active drug should be well considered, and the polymer’s biocompatibility, especially with the skin is significant.

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