Indian Journal of Pharmacology 1997; 29: 140-156

EDUCATIONAL FORUM

TRANSDERMAL DELIVERY OF DRUGS#

RAMESH PANCHAGNULA
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar Punjab - 160 062. Manuscript Received: 20.8.1996 Revised: 17.12.1996 Accepted: 1 SUMMARY

.1 .1997

Delivery of drugs into systemic circulation via skin has generated lot of interest during the last decade. Transdermal drug delivery systems (TDDS) offer many advantages over the conventional dosage forms or controlled release peroral delivery systems. TDDS provides; constant blood levels (l-7 days), avoids first-pass metabolism, increased patient compliance, and dose dumping never occurs. The choice of drugs delivered transdermally, clinical needs, and drug pharmacokinetics are some of the important considerations in the development of TDDS. In addition to methods to enhance transdermal absorption of drugs such as sorption promoters and prodrugs, the physicochemical and biological factors affecting transdermal permeation of drugs are discussed. Although, novel approaches like iontophoresis and ultrasound are gaining importance as a means to increase drug permeation into systemic circulation, clinical products based on these approaches are still far away. The importance of appropriate animal model selection in the development and evaluation of TDDS cannot be ignored. The cost per milligram of drug delivered transdermally is more expensive than peroral route. The added cost could be justified, if TDDS improve patient compliance and reduces toxic/side effects. controlled release penetration and permeation

KEY WORDS Transdermal delivery

1. INTRODUCTION Conventional systems of medication which require multi-dose therapy are not without problems. The newer approach to drug delivery is to deliver drug into systemic circulation at a pre-determined rate, known as controlled release drug delivery system. The impetus for the development of newer/novel drug delivery systems, apart from therapeutic efficacy is cost. The developmental cost of a new drug may be about $ 250 million (Rs. 900 crores) and takes about 12 years to reach the market place. Whereas an existing drug molecule can get a second life with newer drug delivery systems that can be developed in half of the time with 20% cost of the new drug discovery. Skin is the most extensive and readily accessible organ in the body. Its chief functions are concerned with protection, temperature regulation, control of water output, and sensation. In an average adult it covers an area of about 1.73 m2 and receives one third of circulating blood through the body at any given time. The potential of using intact skin as the site of administration for dermatological preparations to elicit pharmacological action in the skin tissue has been recognized for several years. Until the turn of the century, the skin was thought to

be impermeable. However, this view has changed and the progress achieved in this area clearly demonstrates that the skin is a complex organ and allows the passage of chemicals into and across the skin. The permeation of chemicals, toxicants, and drugs are much slower across the skin when compared to other biological membranes in the body. The understanding of this complex phenomena has lead to the development of transdermal drug delivery systems, in which the skin serves as the site for the administration of systemically active drugs. Following skin permeation, the drugs first reach the systemic circulation. The drug molecules are then transported to the target site, which could be relatively remote from the site of administration, to produce their therapeutic action2. In addition to relationship between rate of drug delivery to the skin and maximum achievable drug permeation across the skin, the choice of drugs to be delivered transdermally, clinical needs, and drug pharmacokinetics are some of the important considerations in the development of transdermal drug delivery systems (TDDS)ss4. Schematic representation of drug levels in blood from P.O. and transdermal routes of administration are shown in Figure 1. As can be seen from Figure 1, a TDDS is designed to release drugs at a predetermined

# Presented at XXVIII Conference of Indian Pharmacological Society, Patiala, November 1995. NIPER Communication No.002

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RAMESH PANCHAGNULA

Figure 1. Hypothetical blood level pattern from a conventional multiple dosing schedule, and an ideal pattern from a transdermal delivery system. --

Figure 2.

Possible macro routes for drug penetration across human skin via intact horny layer or hair follicles or eccrine sweat glands (with permission, Ref.59).

- - Rapid release 0000 Transdermal delivery n Stratum corneum Viable epidermis

Sebaceous

Subtherapeutic
Hair follicle

Time

Dermal paplila

rate and continuously, avoiding unnecessarily high peaks and subtherapeutic troughs in plasma drug levels. The following are the advantages of TDDS; 1. Avoids hepatic first-pass metabolism 2. Maintains constant blood levels for longer period of time 3. Improves bioavailability 4. Decreases the dose to be administered 5. Decreases side or unwanted effects 6. Decreases gastrointestinal side effects 7. Easy to discontinue in case of toxic effects 8. Increased patient compliance 2. PERCUTANEOUS ABSORPTION Percutaneous absorption is defined as penetration of substances into various layers of skin and permeation across the skin into systemic circulations. The percutaneous absorption is a step-wise process and can be divided into three parts: Penetration, is the entry of a substance into a particular layer. Permeation, is the penetration from one layer into another, and is different both functionally and structurally from the first layer. Absorption, is the uptake of a substance into systemic circulation. The stratum corneum is a wall-like structure with protein bricks and lipid mortar5. The lipid matrix6 (keratin-phospholipid complex) of the stratum corneum plays a significant role in determining the permeability of substances across the skin7vs. This is supported by the evidence from controlled stripping experiments, electron microscopy studiesgllO, and also from the analysis of penetration and permeation data 1 r1 2. 2.1. Routes of Skin Permeation Figure 2 illustrates the possible macro routes of drug permeation across intact skin. The transappendageal route, transports substances via the sweat glands and the hair follicles with their as sociated sebaceous glands. The transepidermal route across the continuous stratum corneum comprises transport via intracellular and intercellular spaces. Both polar and non-polar substances diffuse via transcellular and intercellular routes by different mechanismss. The polar molecules mainly diffuse through the polar pathway consisting of boundwater within the hydrated stratum corneum, whereas the non-polar molecules dissolve and diffuse through the non-aqueous lipid matrix of the stratum corneum. Figure 3 describes possible micro routes of drug permeation 14. The transappendageal route is considered to be of minor importance because of their relatively small area (less than 0.1% of total surface). However, this route may be of some importance for large polar compounds15. Several mathematical models to describe the permeability across stratum corneum have been reported16. These models can be broadly classified into homogeneous and heterogeneous models17.

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Figure 3. Possible micro routes for drug penetration across human skin intercellular or transcellular (with permission, Ref.59). Intercellular route Transcellular route

Plasma I Cell membrane 1 cytoplasma

Aqueous

Intercellular space i

Lipid

Aqueous

Cholesterol Triglyceride sulphate

Minimallipid

3. FACTORS AFFECTING PENETRATION AND PERMEATION The factors which influence transdermal absorption (TA) are very complex in nature and act in a mutually dependent manner. The clinical response after TDDS application is a step-wise process: 1. Release of drug from formulation 2. Penetration into and permeation across the skin 3. Activation of pharmacological response The factors influencing the TA include, biological characteristics of skin, physicochemical characteristics of drug and vehicle, and the dosing conditions. 3.1. Biological factors The biological factors viz thickness of the skin18-lg, regional site20, age3, blood flow rate21 and skin conditioning22-23 can influence the penetration and permeation. Skin permeability can be altered by physical (ultraviolet, infrared or ionizing radiation), chemical (solvents, detergent, acids, and alkalis), and pathological conditions, such as mechanical damage and skin diseases3s24. Mixtures of polar and non-polar solvents can delipidize the skin,

forming artificial shunts in the skin. Depending on the solvent system used, this can result in a substantial reduction of the barrier function of the skin. The importance of metabolism of drugs in the skin was not recognized in the past25-27. However, recent reports suggest that the skin metabolism is worth investigating with respect to drugs in general, and to the design and activation of prodrugs in particulati~28. 3.2. Physicochemical factors

In addition to the structure of the Stratum comeum through which TA occurs, the physicochemical properties of both the drug and the vehicle play an important role in determining the percutaneous absorption13s2g. These factors include the molecular properties of the drug and the vehicle3!13. TA is also dependent on the molecular weight, size, structure, partition coefficient, pH of the drug solution in the vehicle, and the concentration of the drug on the surface of the skin in addition to the nature and effect of the vehicle, and other chemicals present in the vehicle which may act as sorption promoters11.30. Role of individual factors and their interplay on penetration and permeation is an important area in the field of dermal/TDDS.

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Table 1. Commercially available transdermal therapeutic systems. Drug/ Manufacturer Scopolamine Alza/Ciba Nitroglycerin Alza/Ciba Hercom Searle Key Wyeth lsosorbide dinitrate Nitro electric industrial Clonidine Boehringer/lngelheim Estradiol Ciba-Geigy Nicotine* Alza Ciba-Geigy Parke-Davis Fentanyl Janssens Duragesi? 3 days Relief from moderate / severe pain 54-55 Nicoderm@ Habitrol@ Prostep@ 1 day Reservoir Matrix Matrix Aid in smoking cessation 51-53 Estraderm@ 3 days Reservoir Relief of post-menopausal symptoms 48-50 Catapres-TX@ 7 days Reservoir Treatment of hypertension 45-47 Frandol Tape@ 1 day Matrix Transderm@-Nitro NTS Nitrodis? Nitro-dur@ Deponite@ 1 day Reservoir Matrix Matrix Matrix Sandwich Treatment and prevention of angina 40-44 Transderm@-Stop 2 days Reservoir Alleviate motion sickness 36-39 Trade Name Duration Type of System Therapeutic use References

- do -

Information not available. IThis product is available in India [Transderm-TTS; CIBA-GEIGY; Top-nitro; FULFORD (India)] 2This product is very recently launched in India.

4. TRANSDERMAL DRUG DELIVERY SYSTEMS (TDDS) The main objective of TDDS is to delivery of drugs into systemic circulation at a predetermined rate with no or minimal (statistically insignificant) interor intra-patient variation in TA31. Therefore the rate limiting step in TA is provided by TDDS rather than skin. Many TDDS systems have been described and mainly can be classified into3117r32-33: a. Membrane controlled, where drug is encapsulated in a polymeric membrane and drug release from TDDS is controlled by its permeation across the polymer wall. b. Matrix controlled, where drug is homogeneously mixed with rate controlling polymer, and rate of drug release from TDDS is controlled by its diffusion through polymer matrix.

c. Sandwich type, where a combination of above are seen, the matrix system is coated with ratecontrolling polymeric membrane. Several TDDS have been developed and introduced into the market place since introduction of scopolamine in 1981 (Table 1). The early thinking of TDDS providing optimum therapy with no and/or minimal side effects has changed during the last 15 years. One of the main reasons for reasonable success of TDDS is due to patient convenience and compliance34-35. 4.1. Limitations of TDDS The first TDDS was developed for scopolamine for motion sickness in 1981. Since then many TDDS have appeared in market with great success. In spite of the therapeutic success achieved in last 15 years by using TDDS, the number of TDDS

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available in the market place are very few. This is mainly due to inherent limitations of the TDDS listed below: 1. TDDS cannot deliver ionic drugs
2.

TDDS cannot achieve high drug levels in blood/plasma

ultrasoundses57, are briefly discussed. However, clinical products based on these techniques are still far away. It appears from the literature, iontophoresis or sonophoresis could be the answer for protein drug delivery, especially for peptides and small proteins. 5.1. Sorption Promoters Skin sorption promoters (SP) are molecules which reversibly decrease the barrier nature of the Stratum corneum14~15~ss~64. SP allow the drugs to penetrate into skin and then permeate across skin more readily and thus increase the systemic availability3~70. SP should possess certain qualities and they include; 1. The chemical to be non-toxic 2. Pharmacologically inert, nonirritating and nonallergic 3. It should have an immediate effect in a predictable manner 4. SP activity should be reversible 5. SP should be pharmaceutically stable and suitable for TDDS 6. SP should be cosmetically acceptable SP act by interaction with intercellular lipids leading to disruption of their organization and increasing their fluidityss. Some of them also interact with intercellular protein, keratin denaturation (eg. azone and oleic acid)s6167, while others act by both mechanisms (eg. DMSO and propylene glycol)6* . Another possible mechanism is by altering the skin hydration22123. The mechanism of these SP to some extent is also related to octonal/water partition coeff icient30. Recently, lipid-protein-partition theory has been formulated to describe the potential mechanisms of action of sorption promoters14~68~6g. Different classes of sorption promoters are listed in Table 2. 5.2. Pro-drugs Approach Prodrugs are therapeutically inactive derivatives of therapeutically active drug. A prodrug undergoes metabolism (bioconversion) by hydrolysis or enzymatic degradation to produce therapeutically active drug in biological environment25q71. Based on the above concept the skin permeation of a drug can be altered by developing a prodrug which will have different physicochemical properties72. Different prodrugs were developed for estradiol (Figure 4) and based on the results Transdermal Bioactive

3. Cannot develop TDDS for drugs of large molecular size 4. TDDS cannot deliver drugs in a pulsatile fashion 5. Cannot develop TDDS, if drug or formulation causes irritation to skin The limitations of TDDS due to ionic drugs, large molecular weight drugs and delivery in a pulsatile fashion can be overcome to some extent by novel approaches such as iontophoresi@ v6*, electroporation63 and ultrasound56157. 5. METHODS TO INCREASE PERMEATION To achieve and maintain therapeutic concentration of drug in blood, the resistance of the skin (Stratum corneum) to diffusion of drugs has to be reduced in order to drug molecules to cross skin and to maintain therapeutic levels in blood. Many approaches are available to increase the drug permeation across the skin and can be divided into following4. Physical Approach: 1. lontophoresis 2. Sonophoresis 3. Thermal energy 4. Stripping of Stratum corneum 5. Hydration of Stratum corneum Chemical Approach: 1. Delipidization of Stratum corneum 2. Synthesis of lipophilic analogs 3. Use of sorption promoters Biological Approach: 1. Synthesis of bio-convertible prodrugs 2. Use of skin metabolism inhibitors Some of the above approaches are non-invasive in nature and has great potential to develop into viable techniques for TDDS 56-58. In this review the role of sorption promoters1sp*4v5g, and novel approaches such as bio-convertible products (prodrugs)4z60, iontophoresi@l ,s2, electroporationss and

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RAMESH PANCHAGNULA

Table 2.

Different classes of sorption promoters Examples References

A. Established sorption promotors 1. Sulfoxide and similar compounds 2. Pyrrolidones

Figure 4. Schematic representation of pro-drug approach to increase drug penetration across skin (Redrawn from Ref.4)
EPIDERMIS DERMIS SUBDERMAL

Dimethylsulfoxide Dimethyl acetamide Dimethylformamide N-methylformamide 2-Pyrrolidone 1 -methyl 2-pyrrolidone 5-methyl 2-pyrrolidone 1,5 dimethyl 2-pyrrolidone 1 -ethyl 2-pyrrolidone Oleic acid, Lauric acid Linolic acid, Myristic acid

59,70 75-79

59-70
Stratum corneum CAPILLARY NETWORK BLOOD CIRCUL ATION

Multilayered skin model showing increased skin permeation of drug forming prodrug on viable epidermis 59,70 65-67, 80 59,70

3. Fatty acids

4. Azone or laurocapram and its derivatives 5. Urea 6.

Surfactant

80-82, 88, a9 59,64,70

Estradiol -1 7-ester

anionic cationic nonionic 7. Alcohols

Sodium laurayl sulfate Trimethyl ammonium bromide Synperonic NP series Ethanol Lauryl alcohol Linolenyl alcohol Octanol Propylene glycol Polyethylene glycol 400

59,70
17p4maioi Estradiol 17-acetate Estradiol 3-17-diacetate Estradiol 17-valerate Estradiol 17-heptanoate Estradiol 17-cypionate RI -H COW, COCH. COGH2)+CH3 -COW,)rCH, -COCHzCH,C,H, 872 -H -H cow -H -H -H

59, 70,

a3

Estradiol

Chemical structures of estradiol and its prodrug esters 59,

a. Glycols

68,70, 80

Bioconversion of estradiol -3-17 diester by esterases in cutaneous tissue to produce biologically active estradiol

B. Under investigation
1. Terpenes and Terpenoids Menthol and Camphor 59, 69,

84, a5

2. n-Pentyl N-acetylprolinate 3. Lactam N-acetic acid esters

86 a7

Hormone Delivery (TBHD) devices were developed73t74. The release rate of estradiol from TBHD is dependent on the chain length of ester group at 17th position4. A major hindrance to the application of peptide/protein moieties as drugs is poor delivery characteristics. A possible approach to overcome this is by producing prodrugs which are more lipophilic than the parent peptide/protein. Derivatization may protect small peptides against degradation and

facilitate absorption because of its lipophilicity60. The potential utility of this approach includes prodrugs of pyroglutamyl group, the a-aminoamide moiety, and the peptide bond itself of several small peptide/protein drugs. Poor permeability of thyrotropinreleasing hormone (TRH) across the skin is not due to enzymatic degradation but ascribed to very low lipophilicity of TRH. TRH prodrug, N-octyloxycarbonyl- TRH, shown good skin permeation. The increased permeation is due to good water solubility and lipophilicity. Although the increase in permeation is very encouraging, the therapeutic plasma levels were not achieved. Hence, use of sorption promoters could be of help in this type of situation. Although the prodrug approach is a very feasible way to increase the skin permeation of peptide/protein drugs, achieving therapeutic plasma levels by itself is still questionable60.

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Table 3. Category Antibodies

Peptide/protein drugs currently approved for therapeutic, preventive and other applications by FDA, USA. Peptide/Protein 1. Anti-Rh globulin 2. Antivenins 3. General immune globulins 4. Specific immune globulins Vaccines 1. 2. 3. 4. 5. 6. 7. 8. 1. 2. 3. 4. 5. Asparaginase Chymopapain Collagenase Hyaluronidase Pancreatic enzymes Plasminogen activators Thrombin Trypsin Insulin Vasopressin Oxytocin Human GF Gonadotropins hCG, LH, FSH etc. Biomedical application Prevention of Rh iso-immunization Treatment of snakebite lmmunodeficiency Passive immunization to rabies, tetanus, hepatitis B and pertussis Active immunization against viral diseases eg. smallpox, mumps, poliomyelitis, hepatitis B Leukemia Herniated lumbar disc Topical debridement Enhancement of SQ absorption Digestive supplement Thrombolysis in Ml and other thromboses Topical hemostasis Digestive supplement, Topical debridement Diabetes mellitus Diabetes insipidus Maintenance of labor Hypopituitary dwarfism Induction of ovulation, spermatogenesis and cryptorchidism Anticancer, hair ceil leukemia, Antiviral Sugar supplement Dermal reconstruction Antibiotic Hemophilia Plasma extender Nutrient

Antigens Enzymes

Hormones

Immune factors Miscellaneous

Interferon - a 1. Aspartame 2. Collagen 3. Cyclosporin 4. Factor VIII & IX complex 5. Serum albumin 6. Protein hydrolysate

5.3. lontophoresis Transdermal iontophoresis, which delivers ions and charged molecules across the skin into systemic circulation at an increased rate in a controllable manner by the use of electric currentgo. Although many drugs were studied as suitable agents for transdermal iontophoresis, peptide/protein (PP) drugs are best suited for this technique for the following reasons. A large number of biologically active PP have been introduced as drug entities (Table 3). The recent advances in genetic engineering and recombinant technology has resulted in production of large quantities of PP drugs at low cost with relative ease. Thus providing impetus to research in the area of peptide/ protein drug delivery. Bio-active PP can only be administered by frequent injections. Patient non compliance is a

major hurdle in therapy except in life threatening situations. 5. Poor biomembrane permeation, rapid enzymatic degradation and clearance, and harsh GIT conditions are responsible for their low peroral bioavailability. The lack of peroral efficacy of PP has focused attention on alternate routes of administration (nonparenteral). Delivery by non-parenteral routes include nasal, buccal, rectal, vaginal, ocular, percutaneous and to some extent pulmonary. A number of drugs are metabolized by proteolytic enzymes in most of the routes of administration mentioned above. TRANSDERMAL route is most promising and has received lot of attention because the skin has minimal proteolytic enzyme activitygl. The other advantages are already mentioned in section 1, Inspite of the advantages, transdermal delivery of PP drugs has some difficulties because of its; a) hydrophilicity, b) large molecular weight, c) charged

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RAMESH PANCHAGNULA

Table 4. Peptide/ Protein drugs that have been iontophoresed. Drua Vasopressin Desmopressin acetate TRH, Leuprolide acetate, Leuproline Enkephalins LHRH lnsulln Angiotensin Model In vitro, hairless rat skin In vivo, rabbits In vivo, rats In vitro. human ln vitro, human hairless mouse In vivo, hairless guinea pig In vitro, In vivo rats, rabbits, humans In vitro, hairless mouse Remarks Increased drug transport Effective Effective increased drug transport Similar to S.C. administration Increased drug transport Effective, Similar to S.C. administration Effective, Similar to S.C. administration Increased drug transport References 91-94 95 61, 96-100 101-102 63, 103-110 58, 105, 111-119 121-122

molecules, and d) lipophilic nature of skin. Many reports indicate the feasibility of delivery of PP drugs into systemic circulation by iontophoresis61~g1~g4~120, and are listed in Table 4. The following are the major points of interests, which need further investigation so that the technique of iontophoresis results in the development and availability of the drug delivery devices for PP drugs which are acceptable by patients. If the technique is to be fully developed, the following are to be investigated in depth: 1. Formulation aspects for iontophoresis. 2. Standardization of iontophoresis technique. 3. Toxic/adverse effects of iontophoresis. Latest reports regarding use of reverse iontophoresisss~ti7 for monitor of blood glucose is certainly going to steer and focus the research interests towards the development of commercially viable and acceptable formulation for PP drugs in general, and for insulin in particular62~118. 5.3.1. Electroporation Therapeutic uses of compounds produced by biotechnology are presently limited by the lack of non-invasive methods for continuous administration of biologically-active macromolecules. One of the newer approaches to deliver very large molecules across the skin is by use of high-voltage treatment, known as electroporation, whereas in iontophoresis low-voltage is applied 12s. Electroporation creates new aqueous pathways (pores) across lipid con-

taining barriers, and forces the molecules through the pores in to systemic circulation 123,124. Although creation of transient aqueous pores is well explained in electroporation, the physical nature of structural changes of skin is not yet clear. Flux values of model compounds have increased exponentially from negligible values due to electroporation. Upon beginning a pulse protocol, the flux increases from negligible values, and exponentially approaches a quasi-steady state flux with a lag time constant, and depends on the pulse spacing, pulse time constant, rather than transdermal voltage magnitude. Stoppage pulsing has resulted in decreased flux125127. Few model compounds such as heparin126, calcein127 and LHRH12s drugs were studied for increased transdermal absorption by electroporation. 5.4. Sonophoresis Sonophoresis or phonophoresis - the application of ultrasound to enhance the percutaneous drug delivery has been used by physiotherapists for over 30 years, especially the combination of ultrasound plus steroids or analgesics in order to treat a variety of muscular and arthritic conditions. Most of these treatments have been conducted on a subjective and non-quantitative basis. Recently, sonophoresis has attracted lot of interest in transdermal delivery with a focus on peptide/protein delivery. Especially reports from Langers group from MIT are very encouraging in the area of ultrasound mediated transdermal protein delivery57. The above group has used insulin (MW, ~6000), interferon (-17,000) and erythropoeitin (-48,000) as model drugs.

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Table 5. Name

Transdermal nitroglycerin (GTN) patches. Strength available (mg/h) 0.1 0.2 0.4 0.6 0.1 0.2 0.3 0.4 0.6 0.2 0.4 0.2 0.4 Total GTN content 12.5 mg/ 5 cm2 25 mg/ 10 cm2 50 mg/ 20 cm2 75 mg/30 cm* 20 mg/ 5 cm2 40 mg/ 10 cm2 60 mg/ 15 cm2 80 mg/ 20 cm2 120 mg/ 30 cm2 16mg/8cm 32 mg/ 16 cm2 16mg/16cm2 32 mg/ 32 cm*

Figure 5. Plasma levels obtained after transdermal delivery of GTN from different patches (Redrawn from Ref.14).

Transderm-Nitro

Nitrodur

r----- Nitrodisc

Nitrodisk Deponite

Transdermal nitroglycerin (GTN) patches in India Transderm-TTS Top Nitro* 0.2 0.4 0.2 0.4 25 mg/ 10 cm2 50 mg/ 20 cm* 40 mg/ 10 cm2 80 mg/ 20 cm2

I I
I

Transderm-Nitro

* Deponit + Nitrodur

These patches are marketed by Hindustan Ciba-Geigy 2These patches are marketed by Fulford (India).

O.Olo_ 8 12 16 20 24 Time (hrs)

Mechanistic studies were also conducted by the above groups. Preliminary results indicate that generally skin permeability decreases with increase in molecular size and therapeutically effective plasma levels were achieved by using ultrasound. No adverse/side effects were observed in the preliminary studies at low frequency ultrasound12g. Long-term safety aspects of low frequency ultrasound need to be investigated. Physiological and immunological aspects of sonophoresisfurther need to be evaluated before proceeding with clinical trails56. SP alone as a means to increase PP drugs across skin is not very promising but the use of SP along with iontophoresis or sonophoresis has enormous potentiaV30. 6. NITROGLYCERIN TDDS Although many TDDS are available in the market (Table 1), treatment of angina by nitroglycerin TDDS are discussed in detail because these patches are already available in the Indian market (Table 5). Nitroglycerin (GTN) has been used for treatment of angina for over a century and in congestive heart failure for over a decade, and mainly given by sub-

lingual route. Even though topical nitroglycerin formulations131 have been available for over 25 ears, the use of dosage form is limited because of1 Y2-134: a. b. c. d. e. Non-uniformity in dose applied GTN release is faster than skin absorption Large variation in GTN blood levels GTN metabolism Patient non-compliance

The need to overcome the above limitations has resulted in the development and marketing TDDS of GTN. The physicochemical and pharmacokinetics properties of GTN, solubility and apparent partition coefficient, extensive first pass metabolism and very short biological half-life, make it very good for transdermal drug delivery132. The dose required to maintain required therapeutic blood levels (pg/ml) for 24 hours is about 10 mg and it is very easy to deliver it in less than 50 cm2 patch. TDDS of nitroglycerin for treatment of angina has been used over a decade and substantial progress has been achieved over the years. Therapeutic effect is usually seen with an hour of application of TDDS and persists for about 30 minutes after removal of patch. The fabrication of these patches and release

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Table 6.

Percutaneous absorption of several compounds using different animal skins. % of dose absorbed (through different animal skins)

Compounds Rat Testosterone Hydrocortisone Benzoic acid Haloprogin Cortisone Acetylcysteine Caffeine Butter yellow Testosterone DDT Lindane Parathion Malathion Resorcinol 2-nitro-PPD 4-amino-2-nitrophenol 95.8 24.7 3.5 53.1 48.2 95.8 47.4 Rabbit 69.6 Pig 29.4 _ Monkev 18.4 2.9 59.2 19.7 4.1 6.0 32.4 41.9 19.7 43.4 37.6 14.5 15.5 1.5 16.0 30.3 19.3 0.016 0.111 6.2 Guinea pig 34.9 _ 20.0 _ _ _ 0.065 0.508
0.694

Human 13.2 1.9 42.6 11 .o 3.4 2.4 47.6 21.6 13.2 10.4 9.3 9.7 8.2 0.071 0.127 0.236

References 149,155 149,150 150, 152 156 156 156 156 157 158 152 152 152 152 152 152 152

113.00 30.3 2.0 69.2 1000.0 113.0 46.3 51.2 97.5

64.6

mechanisms are different, the in vivo performance is remarkably similar135 (Figure 5). Although various TDDS of GTN employ different mechanisms of drug release, there is no clear cut advantage of one over the other. The most important factor in TDDS is the amount GTN absorbed into systemic circulation over 24 hours is regulated by delivery system, rather than the size of the patch or GTN content in the patch, or characteristics of the patients skin (Table 5 and Figure 5). The preference to a particular TDDS is based on comfort, aesthetics and adhesiveness136. TDDS are applied on hair free area and the site of administration should be in rotation. In one study using Nitro-Dur TDDS, the pharmacokinetics/ pharmacodynamics were studied in healthy volunteers137. The plasma levels were achieved in about an hour and showed significant haemodynamic effects. The effects include increase in heart rate and decrease in end diastolic dimension due to dilation of pe-

ripheral venous vessels. Prophylactic use of TDDS of GTN in angina has resulted in about 63% decrease in the frequency of angina attacks at rest138. Resting blood pressure was reduced, whereas there was no effect on exercise-induced increase in blood pressure, but exercise-induced angina pectoris was less severe and shorter in duration. Initially dosing is usually with 0.1 to 0.2 mg/hr TDDS, which is then titrated to 0.6 to 0.8 mg/hr based on frequency of angina, blood pressure response and exercise tolerance13g. All clinical studies indicated TDDS of GTN are effective in patients with angina and have shown significant increase in patient compliance32-33. The long term efficacy of GTN patches is now questionable because of the development of tolerance. Although the dosage regimen of GTN results in constant blood levels of GTN and its metabolites, one of the main problems of TDDS of GTN is development of tolerance140-142, which is manifested by headache. Tolerance is not

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Table 7. Compound Water Water Water Water

Percutaneous absorption of several compounds using different animal skins. Order Frog > Human Rabbit > Rat > Guinea pig > Cat > Monkey > Dog > Pig Guinea pig > Rabbit > Hairless mouse > Mouse > Nude rat > Hairless rat > Rat > Human Rat > Guinea pig > Swine > Human male abdomen > Human female thigh > Neonatal rat Mouse > Guinea pig > Goat > Horse > Cat > Dog > Monkey > Pig > Human > Chimpanzee Rabbit > Rat > Human Rabbit > Rat > Human Rat > Human Hairless mouse > Guinea pig > Mouse > Rabbit > Nude rat, Hairless rat > Rat > Human Rat > Human Nude mouse > Human References 158 159 160 152 161 162 163 164 158,164 152,158 165

Classified chemical warfare agent Scopolamine Naproxen Toluene Paraquat Paraquat Digoxin

important problem in patients with unstable angina or post-myocardial infarction patients because the drug is given intermittently. One way to overcome tolerance is by removing the patch during night so that the GTN blood levels fall below the therapeutic levels1s4 or nitrate free interval of about 8 to 10 hours dailyi4s-145. This could result in noncompliance and patient is prone to anginal attacks during the night. Another approach is the development of biphasic TDDS which do not produce constant blood levels of GTN over a period of 24 hours146.
an

7. ANIMAL MODELS TO STUDY TRANSDERMAL ABSORPTION Ex vivo penetration and permeation are routinely performed to study percutaneous absorption and transdermal permeation characteristics of drugs and other chemicals. These ex vivo studies allow the determination of drug concentration in the skin (penetration) and rate of transfer across the skin (permeation). Ex vivo experiments are easy to perform and the simplicity of methodology allows flexibility in adapting the model in addressing different aspects involved in preliminary or feasibility studies in the development of skin/transdermal drug delivery systems147. An animal skin membrane that is

sufficiently similar or close to human skin is needed to substitute human skin in ex vivo penetration and permeation, and topical bioavailability studies148. Human skin is difficult to obtain and uniformity is difficult to maintain, since most of human skin comes from cadavers whose sex, age and genetic history are uncontrolled. Whereas, animal skin is easier to obtain and is more uniform. Humans and animals have wide differences in the number of appendageal openings per unit area thickness of skin, structure and pilosity of skin, and these factors clearly effect the percutaneous absorption of drugs14g-151. Only the progress in in vitro methodology with an appropriate animal model can resolve these limitations. It would be a simple mathematical excercise to predict the skin permeability in humans from animal experiments. If there is constant ratio between skin permeability in human to animal, independent of the drug under study. If correlation can be established for drugs with different physicochemical properties, experiments using appropriate animal skin will be more reliable in the developmental stage of skin/transdermal drug delivery systems14g-150. It appears that hairless guinea pig and brattleboro rat are to be good animal models for skin/ transdermal drug delivery systems, where as snake appears not to be a good model to evaluate permeation

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of drugs across skin (unpublished data). Wester and Noonan suggest pig and monkey are most predictive of percutaneous absorption in man14gl 152. In reviewing the studies comparing transdermal absorption of drugs between animals and humans, care must be taken to ascertain the influences of methodology and model might have on the data, and utmost care must be taken to avoid any misinterpretation or wrong concIusions153,154. According to the literature available no consensus is available regarding animal models which truly reflects human skin14*. Tables 6 and 7 describes the summary of different studies, which clearly shows the wide variation in results. 8. CONCLUSION The cost per mg of drug delivered transdermally is more expensive than peroral administration and could only be justified, if TDDS improves therapeutic efficacy, patient compliance and reduce toxic/ side effects. TDDS has been recognized as a potential delivery system inspite of its limitations. Future TDDS may release drugs in pulsatile fashion to meet the requirements of chronopharmacology/pharmacokinetics. Although delivery of peptide/protein drugs via skin into systemic circulation has limitations, use of ultrasound or iontophoresis along with sorption promoters appears to be very promising and may include biphasic, feedback loops and user activated TDDS . The advances achieved in these areas certainly are encouraging and may result in the development of therapeutically and commercially acceptable TDDS of PP drugs. The other area seems to have bright future is Reverse iontophoresis which could develop into non-invasive tool in therapeutic drug monitoring. This, along with closed loop drug delivery system can form an important set up in intensive and cardiac care units.

4. Chein YW. Advances in transdermal systemic drug delivery. Drugs of Future 1988;13:343-62. 5. Williams ML, Elias PM. The extracellular matrix of stratum corneum: Role of lipids in normal and pathological function. Crit Rev Ther Drug Carr Sys 1989;3:95-122. 6. Moghimi HR, Williams AC, Barry BW. A lamellar matrix model for stratum corneum intercellular lipids. II. Effect of geometry of startum corneum on permeation of model drugs 5-fluorouracil and oestradiol. Int J Pharm 1996;131: 116-29. 7. Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 1983;80:44s-9s. 8. Golden GM, McKie JE, Potts RO. Role of stratum corenum lipid fluidity in transdermal flux. J Pharm, Sci 1987;76:25-8. 9. lmokawa G, Hattori M. A possible functions of structural lipids in water-holding properties of stratum corneum. J Invest Dermatol 1985;84:282-4. 10. Grayson S, Elias PM. Isolation and lipid biochemical characterization of stratum corneum membrane complexes: Impilications for cutaneous permeability. J Invest Dermatol 1982;78: 128-35. 11. Barry BW. Dermatological Formulations. Percutaneous Absorption. New York: Marcel Dekker, 1983:95-120,138139,144,128-233. 12. Moghimi HR, Williams AC, Barry BW. A lamellar matrix model for stratum corneum intercellular lipids, I. Characterization and comparison with startum coreneum intercellular structure. Int J Pharm 1996;131:103-15. 13. Blank IH, Scheuplien RJ, McFarlane DJ. Mechanism of percutaneous absorption Ill. The effect of temperature on transport of non electrolytes across skin. J Invest Dermatol 1967;49:582-9. 14. Barry BW. Lipid-protein-partition theory of skin penetration enhancement. J Cont Rel 1991:15:237-48. 15. Barry BW. Mode of action of penetration enhancers in human skin. J Cont Rel 1987;6:85-97. 16. Houk J, Guy RH. Membrane models for skin penetration studies. Chem Rev 1988;88:455-71. 17. Franz TJ, Tojo K. Shah KR, Kydonieus A. Transdermal delivery. In: A Kydonieus, ed. Treatise on Controlled Drug Delivery. New York: Marcel Dekker, 1992:341-421. 18. Feldmann RJ, Maibach HI. Regional variation in percutaneous penetration of C-cortisol in man. J Invest Dermatol 1967;48:181-3. 19. Elias PM. Lipids and the epidermal permeability barrier, Arch Dermatol Res 1981:270:95-l 17.

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