Transdermal enhancer patent literature

Journal of Controlled Release, 25 ( 1993) l-20 0 1993 Elsevier Science Publishers B.V. All rights reserved 0168-3659/93/$06.00

COREL 00844

Review

Transdermal enhancer patent literature

G.C. Santusa and R.W. Bakerb “Recordati S.p.A., Milano, Italy and

bPharmetrix Corporation, 1330 O’Brien Drive, Menlo Park, CA, USA

(Received 28 December 1992; accepted in revised form 20 January 1993)

Patents are an under-utilized literature resource. This observation is particularly true in the area of transdermal drug permeation enhancement for which much of the most important research is being performed in industrial laboratories. This work is only reported in the patent literature. This review covers 203 patents on the general topic of skin permeation enhancement, issued prior to December 199 1. The patents are organized into four main categories: ( 1) broad general patents that cover any enhancer with any drug;; (2) patents with specific enhancers; (3) patents with many enhancers for a specific drug; and (4) patents on non chemical types of enhancement but excluding iontophoresis. The category covering specific enhancers is by far the largest. This has been further subdivided according to the chemical nature of the enhancer alcohols, amides, amino acids, Azone@ and Azone-like compounds, essential oils, fatty acids and fatty acid esters, macrocyclic compounds, phospholipids and phosphate derivatives, 2-pyrrolidone derivatives, so-called soft penetration enhancers, sulphoxides, and various miscellaneous enhancer compounds.

Key words: Transdermal patent; Transdermal enhancer; Percutaneous absorption enhancement; Transdermal drug delivery; Skin enhancer.

Introduction

Transdermal delivery of drugs has been a subject of increasing research since the introduction of the first transdermal product, Alza Corpora- tion’s Transderm Stop for delivery of scopola- mine, in 198 1. Since then, seven other drugs have been formulated into transdermal products: nitroglycerin, estradiol, clonidine, isosorbide dinitrate, fentanyl, nicotine, and norethisterone. Also, a number of drugs, including testosterone and buphrenorphine, are in late stages of devel- opment Excepting for estradiol and norethisterone, none of these drugs requires any chemical

Correspondence to: G.C. Santus, Recordati S.p.A., Via M. Civatali, 1, Milano, Italy.

enhancer to achieve skin penetration. As such, these drugs have been carefully selected, since it is now clear that relatively few drugs in the phar- macopeia are, by themselves, able to permeate the skin at a useful rate. Most drugs fall into the same category as estradiol, and require skin permeation enhancer to increase the skin’s permeability to the drug.

A tremendous amount of work has gone into developing these permeation enhancers in the last ten years. The bulk of this work was carried out by pharmaceutical companies, which regard the results of their work as proprietary. Therefore, these companies do not usually publish their results in the scientific literature, but do report the work in patents. This paper presents a review of permeation enhancer patent literature.

For the reasons described above, the patent literature is often a source of information that is unobtainable elsewhere. Nevertheless, patents are an under-used resource, partly because of the dense legal style in which they are written, and partly because it is often difficult to judge the re- liability of experimental data reported. Patents, for example, can contain both real and fictional (so-called prophetic) data. The level of experimental detail given in patents is also low. In addition, since patents are not subjected to inde- pendent referee checks, they are of variable quality. These caveats aside, a search of patents concerning transdermal skin permeation enhancers shows these patents to contain much useful information.

Patents are often filed in several countries. This analysis is based on a computer search of the worldwide Derwent patent index. When the same patent is listed as filed in the US and in other countries, only the US patent number is given. A World Patent Convention Treaty application number ( WO ), European Patent Office application (EP), or national patent number (such as JP for Japan) is given if no equivalent US patent has issued.

Each patent in this analysis has been desig- nated by a code number 83-1, 83-2, and so on. The first two numbers refer to the year the patents were issued ( 1983), and the last number re- fers to whether the patent was the first, second, third, etc, transdermal enhancer patent issued in that year.

The first work on penetration enhancers can be traced back to 1970, when Crown Zellerbach and Foster Milbum obtained patents on the use of dimethylsulfoxide (DMSO ) and dimethylacetamide (DMAC) for topical delivery of steroids and other drugs. Thereafter, the subject of enhancers was relatively quiet until 1985, when the first wave of modem enhancer patents ap- peared. Since then, patents covering transdermal enhancer formulations have been appearing at a rate of 20 to 30 applications per year. There is no sign of a drop in interest.

Figure 1 shows the issued patents and patent applications described in this report plotted

Enhancer ,50 paiWtS

Cumulative

100

50 LLI AIlllUZJl

0 0 El”82 83 84 85 86 87 88 89 SO 91 92

Before 1981

Y&WS

Fig. 1. The annual and total cumulative number of enhancer patents up to December 199 I.

against their year of publication. Our search pro- duced 203 patents and patent applications up to December 3 1, 199 1.

A detailed review of every patent would be te- dious to write and boring to read. We have, therefore, tried to give an overview of the information contained in these patents while group- ing them into four categories so that readers re- quiring more details on a specific enhancer or drug can find the source. (Another large category covering transdermal enhancement by elec- trical enhancement, that is, iontophoresis, was considered to be outside the scope of this study. ) We have also marked approximately 10% of the patents listed with an asterisk. We regard these patents as particular importance or informative and recommend them to the general reader of the transdermal literature.

The categories covered by our analysis are:

(I) broad general patents that cover any enhancer with any drug (three patents);

(II) patents that cover a specific enhancer or specific combination for many or at least one drug ( 168 patents). This category has been split into twelve groups according to the chemical structure of the enhancer.

3

(a) Alcohol enhancers; (b) amide enhancers; (c) amino acid enhancers; (d ) azone and azone-like enhancers; (e) essential oil enhancers; ( f) fatty acid and fatty acid ester enhancers; (g) Macro- cyclic enhancers; (h) phospholipid and phosphate enhancers; (i) 2-pyrrolidone derivatives; (j ) soft penetration enhancers; (k) sulphoxide enhancers; (1) miscellaneous enhancers.

(III) Patents covering a variety of enhancers for specific drugs or specific patch structures ( 14 patents).

(IV) Other forms of enhancement excluding iontophoresis ( 18 patents).

I. General enhancer patents

General patents are those that cover any enhancer with any drug. There are three patents in this category, all were, as to be expected, assigned to Alza.

Patents (83- 1) and (83-2) are related and the text is the same, with only the claims being different. These two important patents are the basis of Alza’s Estraderm@ patch, in which the delivery of estradiol is enhanced by ethanol. In the absence of ethanol, estradiol has a very low flux through the skin, of the order 0.01 pg/cm2-h. If a solution of estradiol in ethanol is applied to the skin, the estradiol flux increases lo- to 20-fold to 0.1-0.2 pg/cm2*h, but ethanol permeates the skin at a flux of more than 1 mg/cm2.h. The high ethanol flux means the patch must contain ex- cessive amounts of ethanol. The high ethanol flux can also provoke skin reactions. Alza’s solution

Table A General enhancer patents

Code # Patent # Assignee Comments

*83-l US 4,379,454 Alza

*83-2 US 4,460,372 Alza

*87-l US 4,698,062 Alza

Drug and enhancer in the reservoir

Drug and enhancer separated

Pulsatile delivery

to these problems was to create the device shown in Fig. 2.

Ethanol (or any other enhancer) is contained in the device reservoir and is metered to the skin at a controlled rate by the membrane, which is rate limiting for enhancer but freely permeable to drug. The enhancement in the skin’s permeability to estradiol is controlled by the rate of delivery of ethanol to the skin. Results taken from patent 83-l are shown in Fig. 3.

The 87- 1 patent describes a variant of the orig- inal 83-1 and 83-2 patents, in which the amount of ethanol contained in the drug reservoir is limited. As a result, there is a strong enhancement effect as long as the device contains ethanol. After

Membrane rate controlling ior ethanol

Adhesive

Fig. 2. Structure of the patch described in Alza Estraderm patent US 4,379,454. The rate controlling membrane is freely permeable to the drug (estradiol) but controls the rate of delivery of the enhancer (ethanol). Because skin permeability to estradiol is proportional to the delivery of the enhancer,

the rate of delivery of drug is indirectly controlled by the patch.

.30 7

Estradiol flux (pg/cmzhr)

_I

0 0.2 0.4 0.6 0.8 1.0 1.2

Ethanol flux (mg/cm*hr)

Fig. 3. In vitro skin penetration rate for estradiol as a func- tion of the rate of delivery of ethanol to the skin. Patches of the type shown in Fig. 2 were used. By controlling the permeation rate of ethanol through the membrane, the estradiol permeability of skin is controlled. (Data from US Patent

4,379,454.)

Average “IWO

plasma concentration (PGlmL-cmn)

looI 60

40

Device according to

US Patent 4,698,062

0 0 4 8 12 16 20 24

Time (hours)

Fig. 4. Nitroglycerin blood levels after application to the body of a patch made according to US Patent 4,698,062. The patch contains a limited amount of ethanol enhancer. After 12 h, the ethanol in the patch is depleted and the patches drug delivery rate falls to the value of a normal unenhanced patch.

12 h, however, the device is depleted of ethanol, and the drug delivery rate falls to its baseline unenhanced rate. This effect is potentially useful for delivery of drugs such as nitroglycerin, where tolerance to the drug occurs, and pulsatile delivery of drug is preferred. Some results taken from patent 87-1 are shown in Fig. 4.

II. Patents that cover specific enhancers

This is by far the largest group of enhancer patents. The patents have, therefore, been further divided into a number of subcategories, each covering a particular class of enhancer. Patents on specific enhancers are popular, because many companies have searched for a ‘magic’ enhancer that will work with all drugs. Despite the claims in these patents, no such all-powerful enhancer has been found and the search goes on.

A. Alcohol enhancers

The large number of patents describing alcohol-based enhancer formulations can be subdivided into patents describing the use of short chain C,-C, alcohols; patents on long chain fatty alcohols; and patents on polyalcohols, such as propylene glycol, and glycerin.

The enhancement effect of short-chain alcohols appears to be related to their ability to swell, and perhaps extract, stratum corneum lipids.

Short-chain alcohols are very readily absorbed by the skin; thus, rather large amounts of alcohol are required to obtain a prolonged enhancement effect. The high delivery rate of short-chain alcohol enhancers often produces skin irritation; a number of patents have issued covering the use of short-chain alcohols in combination with other components to minimize irritation. Patent 89-1, for example, describes the combination of ethanol and glycerin to reduce irritation. Some- times short-chain alcohols are used as dilute solutions to minimize irritation. The enhancement effect is then balanced against improved tolerance for the enhancer. Patents 85-1 and 86-1 describe the effect of dilute ethanol used to control the delivery of fentanyl and nitroglycerin. Some in vitro data showing the effect of alcohol concentration on delivery of fentanyl are shown in Table 1.

Patent 88-l describes the use of ethanol to enhance the delivery of 17gestradiol and norethisterone- 17-acetate from patches for the treatment of estrogen-deficiency conditions related to menopause. Patent 90-l describes enhanced delivery of these steroids using isopropyl and isobutyl alcohols. According to this patent, using this combination of alcohols results in a synergistic effect that increases the drugs permeability by a factor of two or more.

The use of long-chain alcohols is reported in several patents and patent applications for the delivery of nitroglycerin (patent 87-2); nonsteroidal anti-inflammatory agents (patent 88-2 ); estrogens and progestins (patents 88-3,90-2,90- 4, 90-5); beta-2 agonists such as clenbuterol (patent 90-3) and albuterol (patents 91-1, 91- 2 ); and glibenclamide (patent 9 l-3 ) . The role of the long-chain alcohol in these patents appears to be to plasticize the skin. The amount of long- chain alcohol required to produce enhancement is much less than when ethanol is used. The long- chain alcohol mentioned most frequently is n- dodecanol. Figure 5 shows data taken from patent 88-l describing the influence of a fatty alcohol’s chain length on the permeation of estradiol through cadaver skin. The figure shows that es-

5

Table B Alcohol enhancers


85-l US 4,588,580 85-2 US 4,948,588 85-3 GB 2158355 85-4 us 4590,190 86-1 US 4,615,699 87-2 EF 22498 1 87-3 JP 2215570 87-4 US 4,678,663 *88-l us 4,9 13,905 88-2 US 4,752,612 88-3 US 4,906,169 88-4 US 4,725,429 88-5 US 4,727,088 89-1 US 4,855,294 90-l US 4,942,158 ‘90-2 wo 9004397 90-3 DE 3843537 90-4 US 5,023,084 90-5 WO 9010425 90-6 EP 380989 91-1 EP 425268 91-2 EP431519 91-3 JP 3086828 91-26 WO9115210

91-27 WO9116930

Alza Kao Am. Home Prod. Nitto Alza Pace Res. Kao Neutrogena Ciba Geigy Nitto Rutgers Univ. Neutrogena Neutrogena Theratech Eastman Kodak Schering Plough Bejersdorf Rutgers Univ. Rutgers Univ. Knoll Searle Searle Toyama Alza

3M

Aqueous ethanol for delivery of fentanyl Glycerol or polyglycerol ether(s) Propylene glycol and glycerin Fatty alcohols and amide-type solvents for delivery of benzodiazepines Ethanol for delivery of nitroglycerin Fatty alcohols for delivery of nitroglycerin Glycerin derivatives Fatty alcohols and hydroquinone Ethanol for delivery of estradiol and a norethisterone n-Dodecanol and 2-methyl-2-pyrrolidone n-Dodecanol for delivery of estrogen and progestin Fatty alcohols and benzoyl peroxide Fatty alcohols and retinoic acid Ethanol and other solvents plus glycerin to reduce irritation Isopropyl and isobutyl alcohol(s) for delivery of steroids n-Dodecanol; I ,2 propandiol; etc. for delivery of steroids Alkyl alcohols plus other enhancers for delivery of clenbuterol n-Decyl alcohol for delivery of steroids n-Decyl alcohol for delivery of steroids Dexpanthenol for delivery for ex. of hydromorphone n-Dodecanol for delivery of albuterol n-Dodecanol for delivery of albuterol Fatty alcohol for delivery of glibenclamid 5-Fluorouracil and a mixture of alkanols, PG or PEG, and a third

penetration enhancer Lower and higher alcohols

TABLE 1

The effect of ethanol concentration on in vitro fentanyl skin permeation (from US Patent 4,588,580)

Ethanol concentration

(O/O)

Fentanyl flux through skin

(pg/cm**h)

47 8.7 30 4.5 20 4.8

O-10 3.7

tradiol flux increases with chain length to a max- imum at 10 carbon atoms, and then declines.

Long-chain alcohols are often used in combination with other enhancers, for example, in patent 88-2, in combination with 2-pyrrolidone derivatives to deliver nonsteroidal anti- inflammatory drugs. Patent 85-4 also reports the use of alcohols CIo_26 with amide-type solvents

0.6 1

Estradiol permeation o.4

rate @g/cm*. h)

’ IAl I I I I I 0 v 4

I

6 6 10 12 14 16

Carbon atoms in alcohol enhancer used

Fig. 5. Effect of alcohol molecular weight on the enhancement of estradiol (data from US Patent 4,9 13,905 ).

for the delivery of benzodiazepines, whereas patent 87-4 reports the use of alcohols (Z-,2 with hydroquinone (for the treatment of acne) with

6

Table C Amide enhancers


70-l US 3,472,931 88-6 us 4,999,379 88-7 US 4,902,676 88-8 US 4,808,4 14 91-4 EP436217

Foster Milburn Ciba Nelson Nelson Lederle

Dimethyl acetamide Long chain amide(s) for delivery of diclofenac N, N-Di-propyldodecanamide, for delivery of triamcinolone N,n-butyl-N,n-dodecyl-acetamide Crotamiton with nonsteroidal anti-inflammatory drug

Dimethylacetamide

CH,-_(CH,), 0

‘N-:-CH, CH3-w-Q, 1’

n-butyi-n-dodecylacetamide

n,n-di-n-propyldodecanamide

0

CH,--CH,-y-!-CH=CH-CH,

\ CH3 0 /

Crotamiton Table D Amino acids enhancers


86-2 JP 1225120 87-5 US 4,695,465 ‘88-9 US 4,732,892

Nitto N-Acyl-amino acids Takeda Water soluble proteins Am. Home Products L( cu)-amino acids for steroidal drugs

benzoyl peroxide, in patent 88-4, or with retinoic acid, in patent 88-5.

The third group of alcohol-based enhancers are multifunctional alcohols: The most commonly mentioned members of this group are propylene glycol and glycerol. These two enhancers are frequently used to lower the irritation effect of other enhancers. Glycerol and polyglycerol ethers, for example, are used alone and in combination with propylene glycol, in patents 85-2, 85-3 and 89-1, to increase skin absorption, and to decrease the irritating effect of C2 and C3 alcohols, AzoneB, and other compounds. A combination of lower alcohols, propylene glycol or polyethylene glycol, and a third enhancer, such as sucrose mon-

olaurate, is described for delivery of the cyto- toxic drugs 5-fluorouracil in patent 91-26. Permeation enhancement, using saturated aqueous solutions of lower alcohols (such as ethanol) with higher alcohols (such as octanol ) for delivery of calcium channel blocking agents and sympathomimetic drugs, is reported in patent 91-27. In many of these examples, glycerol and propylene glycol are used as enhancers. Dex- panthenol is another multifunctional alcohol that is reported to have enhancer properties, and to improve patch tolerance when used with other enhancers, such as isopropyl myristate and ethanol.

TABLE 2

Effect of amino acids dissolved in 40% ethanol on the steady state penetration of levonorgestrel through hairless mouse skin (data from US Patent 4,732,892

Amino acid Amino acid cont.

Final pH Skin Flux

(pg/cm3/h)

Lag time (h)

L- ( + )-Alanine L-( + )-Arginine L-(-)-proline L-(-)serine L- ( + ) -Aspartic AC. L-( + )-Cysteine L-Glutamic Acid Glycine L-( + )-Valine t_-Leucine L-Leucine L-Leucine L-(-)-Isoleucine L-(-)-Isoleucine L-(-)-Isoleucine Control (40% Ethanol)

0.2 m 4.8 0.2 m 4.2 0.2 m 4.6 0.2 m 4.7 0.2 m 4.4 0.2 m 4.9 0.03 m 4.6 0.2 m 4.7 0.2 m 4.1 0.1 m 2.4 0.1 m 6.0 0.1 m 9.1 0.1 m 2.4 0.1 m 6.0 0.1 m 9.7

0.9?0.1 2.7 l.Of0.3 3.4 1.1 kO.2 3.2 1.1 io.l 2.3 1.2kO.2 2.9 1.2kO.l 2.9 1.2TO.2 3.4 1.3f0.3 3.4 1.8kO.5 3.2 1.6kO.l 4.2 1.1+0.1 2.6 1.5fO.l 2.8 1.0*0.1 3.2 3.2kO.3 3.3 0.8+0.1 2.9 0.3kO.l 1.5

Table E Azone and azone-like enhancers

Code # Patent #

*76-l US 3989816 82-l US 43 16893 83-3 US 44056 16 85-5 us 4557934 86-3 US 4562075 87-6 US 487308 1 87-l US 4699777 87-8 us 4755535 87-9 US 4992422 87-10 WO 8704593 87-11 US 5034386 87-12 JP 2129274 88-10 EP 27 1983

Assignee Code #

Nelson 88-l 1 Nelson 88-12 Nelson 88-13 Procter & Gamble 88-14 Nelson 88-15 Nelson 88-16 Schering 89-2 Nelson 89-3 Nelson 89-4 Nelson 89-5 Nelson 89-6 Hisamitsu 89-7 Pfizer 91-22

Patent #

WO 882626 US 4801586 US 4886783 EP 268219 US 4917896 W0881131 EP 306 192 EP 331382 US 4920101 US 4879275 WO 8909800 US 4996199 us 504344 1

Assignee

Nelson Nelson Nelson Nelson Nelson Nelson Eli Lilly Pfizer Nelson Nelson Nelson Nelson Whitby Res.

B. Amide enhancers

Dimethylacetamide was the first compound in this class of enhancers to be used. This amide, along with other aprotic solvents, has been shown to enhance skin permeation by interacting with skin lipids. Unfortunately, dimethylacetamide, although a powerful enhancer, is generally thought to be too irritating to be used as an enhancer. Amides with longer aliphatic chains are

preferred, either alone or in combination with other enhancers. For example, patents 88-6, 88- 7, and 88-8 discuss amide compounds having alkyl or cycloalkyl groups. In patent 88-7, in vitro experiments, using hairless mouse skin and the drug triamcinolone, showed that NJ-di-n-propyl dodecanamide and N-butyl-N-dodecyl acetamide were more effective than the known penetration enhancer, Azone. Patent 9 l-4 describes the use of crotamiton as an enhancer for the de-

8

Table F Essential oil enhancers


85-6 US 4931283 *85-7 US 4560553 89-8 US 4888360 89-9 JP 1268648 89-10 US 4873266 89-l 1 US 4888362 90-7 US 5032403 90-8 US 4910205 90-9 US 4933184 90-10 EP 380047 90-l 1 WO 9008553 91-28 WO9115241

Amer. Home Prod. Merck Amer. Home Prod. Kuraray Amer. Home Prod. Amer. Home Prod. Ciba Geigy Schering Amer. Home Prod. Freund Ind. Abbott Lab. Morimoto

Menthol for delivery of propranolol etc. Eucalyptol for delivery of antimicrobials etc. I-Carvone for delivery of albuterol Terpene alcohol deriv. for many drugs I-Menthone for delivery of albuterol Eugenol for delivery of albuterol Mixture of 1,8-cineole and N-methyl-2-pyrrolidone Essential oil and fatty acid ester (IPM) Menthol for delivery of propranolol I-Carvone for delivery of many drugs Essential oil for delivery of leuprolide Terpene and narcotic analgesics

Table G Fatty acids enhancers


‘86-4 US 4626539 87-13 US 4983396 88-17 US 4731241 88-18 EP267617 88-19 EP 255485 88-20 US 4789547 88-2 1 US 4879297 88-22 EP 26705 1 89-12 JP 1265035 89-13 US4814173 *89-14 US 4863970 90-l 2 EP 376534 90-13 EP 351897 90-14 US 50081 IO 90-15 EP 368409 91-5 EP 43049 I 91-6 EP 428352 91-29 WO 9116077

DuPont de Nemours Key Pharm. Takeda Theratech Warner Lambert Warner Lambert Warner Lambert Moleculon Kuraray Warner Lambert Theratech Riker Labs Procter & Gamble Procter & Gamble Norwich (P&G) Lab. Beta Lab. Beta Medtronic

Saturated/unsaturated fatty acid or alcohol Oleic acid and 2 ethyl- 1,3-hexanediol Aliphatic monocarboxylic acid for delivery of molsidomine Oleic acid and alkanol Linoleic acid and glycol alcohol as solvent Linoleic acid and propylene glycol for delivery of procaterol Saturated/unsaturated fatty acid for delivery of synthetic opioid Salt of an amine drug with isostearic acid 5,9,13-Trimethyl-2,4,8,12-tetradecane-tetraene carboxylic acid Saturated/unsaturated fatty acid plus solvents (EtOH, etc.) Oleic acid and alcohols Fatty acid: oleic and/or isostearic acid Unsaturated fatty acids and diols Fatty acids and polar solvents for delivery of buprenorphine Fatty acids and solvent for delivery of buprenorphine Unsaturated fatty acid and glycerin for delivery of estradiol Oleic acid or isopropylmyristate Fatty acid and electrotransport

livery of the anti-inflammatory drug 4-bipheny- lylacetic acid, the active metabolite of fenbufen.

C. Amino acids enhancers

Amino acids and water soluble proteins can enhance the absorption of drugs. In particular, it is thought that N-alkyl-amino acids improve drug absorption by loosening the skin’s keratin layer. Patent 88-9, which describes how L(o)-amino acids can enhance the penetration of steroidal

contraceptives, particularly levonorgestrel and

estradiol is particularly interesting Table 2 presents some selected data from this patent on fluxes of a levonorgestrel system enhanced with amino acids in 40% ethanol. In some cases, the improvement in flux was quite substantial, more than ten-fold. All twelve amino acids tested enhanced the absorption of levonorgestrel compared to a water-ethanol control. The enhancer effect is pH dependent; the best results were obtained with r_-isoleucine at pH 6.

9

TABLE 3

Effect of various enhancers on naloxone penetration through human skin in vitro (Data from US Patent 4,626,539)

Vehicle

Silicone oil Mineral oil Sesame oil Olive oil Polyethylene Glyc01400 Isopropanol Propylene Glycol Ethanol Oleic Acid A’-Methylpyrrolidone Tris buffer, pH 8

Naloxone Skin concentration permeation (% of (pg/cm- saturation) hr)

100 0.3 100 0.2 100 2.1 100 3.5

34 3.4

65 9.8 100 12.1

42 25.2 100 70.0 15 200.0 33 0.4

D. Azone and azone-like enhancers

Azone was developed and patented by Nelson Research in 1976. It was first described in patent 76-1 and several other related patents, all assigned to Nelson. Nelson discovered that Azone had a significant enhancement effect on a number of drugs and, over the next 15 years, vigor- ously promoted its use. There can be few transdermal research groups that do not have a sample bottle of Azone on the shelf. As a result of this interest, a large number of patents have been ob-

TABLE 4

tained by Nelson and other companies in the use of this enhancer. Azone has the following structure:

c rj-Wz), ,-CH3

c\\ 0

1 -dodecylazacycloheptan-2-one (Azone@))

The mechanism by which Azone and similar substances enhance skin permeation is still un- known. One hypothesis suggests that they use an ion-pairing mechanism, whereas another postu- lates that Azone affects the fluidity of structured lipids in the skin’s intercellular channels. Patents 87-6 and 85-9 describe the use of Azone for enhanced delivery of anti-inflammatory or analge- sic compounds. Patent 87-7 describes the use of Azone with urea for the delivery of albuterol. Azone is also used in combination with ethanol (patent 88-10) and ethanol plus propylene gly- co1 (patent 89-2), especially for the delivery of dihydropyridine derivatives. A combination of Azone and cis-olelin (oleic acid) is reported in patent 89-3 for the delivery of many drugs, particularly amlodipine.

The Nelson Research patents describe Azone and several derivatives, among them compounds having the following structures:

The effect of fatty acidderivatives on the transdermal penetration of the base form of amine-functional drug compounds (the penetration enhancement factor is the ratio of the fatty acid enhanced skin flux to the flux in the absence of fatty acid enhancer (data from EP Patent 35 1897)

Drug compound Dial

Phenylpropanolamine base 1,2-Propanediol Pseudoephedrine base 1,2-Propanediol Chlorpheniramine base I ,2-Propanediol Doxylamine base 1,2-Propanediol Phenylephrinehydrochloride 1,2-Propanediol Chlorpheniramine maleate 1,2_Propanediol

Fatty compound

Oleic Acid Oleic Acid Oleic Acid Oleic Acid Oleyl Alcohol Methyl Oleate

Fatty compound: Penetration diol ratio enhancement factor

5:95 1.3 5:95 3.4 5:95 0.9 5195 1.0 5:95 0.8 5:95 1.7

IO

I: In these patents, compositions and methods are

CH,-_(CH2),,-N”C

i>

claimed for enhancing delivery of physiologi-

\ tally active agents to the skin or other mem- branes; enhancing delivery of plant nutrients,

- growth regulants, and pesticides to plants; and

OA FI enhancing dye penetration into fibers. Examples

N-C-(CH,),,-Ct-l, of active agents include haloperidol, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, propranolol, indomethacin, nifedipine, nicardipine,

R/-/8 diclofenac, and metoprolol.

CH,-(CH,),,---C-N N-C-(CH,),,-CH, Azacycloalkanes with the following structures

are reported in patents 87-12 and 91-22 to have enhancement properties:

TABLE 5 ?

Effect of various fatty acid derivatives on in vitro skin pene- /c

tration of nilvadipine CH,-(CH,),-0-(CH,),-N

\

Vehicle composition Penetration i> -

enhancement factor

l-(3-~tyloxy-propyl)-aza~ycl~~eptan-Z~ne

Control 30% PEG 400 in water Dioctyl adipate Benzyl alcohol Isopropyl myristate Diisopropyl adipate

1 8 0

16 30 72

c

N-_(CH,),,-CH,

The enhancement factor is the ratio of the drugs permeation rate to the control vehicle, which was 30% PEG 400 in water.

0

(Date from US 5001139). 1 dodecyl-~acyclo-heptan-2,7-dione

Table H Fatty acid esters enhancers


85-8 US 4555524 87-14 us 47 IO497 88-23 US 5001139 89-15 US 4906475 90-16 EP 399432 90-17 us 4954487 90-l 8 US 4892737 91-7 EP 435200 91-8 DE 3943385 91-9 EP 436203 91-10 EP 431942 91-l I us 5019395 91-12 US 4992445 91-30 WO9115176

Dolorgiet Nitto American Cyanamid Pace Takeda Procter & Gamble Univ. of Florida Nitto Schering Nitto Sansho Warner Lambert American Cyanamid Pharmetrix

Triglycerides for delivery of ibuprofen IPM and N-methyl-2-pyrrolidone for delivery of diazepam Fatty acid esters for delivery of I,4 dihydropyridine Polyethylene glycol fatty acid esters IPM and super water absorption resin Methyl myristate and ethanol Choline esters (laurate, oleate) IPM in acrylate polymer for delivery of estrogen IPM for delivery of rolipram IPM for delivery of ISDN Lactic acid esters for delivery of dopamine derivatives P.G. diester of caprylic acid and ethanol Diisopropyladipate for delivery of I ,4-dihydropyridine IPM and physostigmine

11

E. Essential oil enhancers

Terpenoid compounds have been widely used in perfumes, flavorings, and drugs; therefore, their toxicities are well documented. As percutaneous enhancers, they are believed to act by disrupting the ordered lipid structure of the stratum comeum and by increasing partitioning of the drug from its aqueous vehicle into the stratum comeum. Use of naturally occurring ter- penes is reported to avoid the side-effects asso- ciated with the more traditional enhancers, such as DMSO and Azone.

y-43

7OOCH,

OH

Wintergreen Oil

OH OCH3

/ 0 0

CH ‘+3-i 3 2

1- Carvone

Eugenol

Menthol

CH3

k /

0

CH li,H 3 3

Eucalyptol

This enhancer category includes essential oils such as rosemary, eucalyptus, spearmint, cedar wood, wintergreen, and peppermint oil. Other compounds mentioned specifically in these patents include menthol (patent 8 5-6 ), 1 -carvone (patent 89-8),1-menthone (patent 89-lo), eugenol (patent 89- 11) , eucalyptol (patent 85-7 ) , as well as terpene alcohol derivatives (patent 89- 9). Essential oils are also used in combination with fatty acid esters, such as isopropyl myristate (patent 90-g), and in combination with N- methyl-2-pyrrolidone (90-7 ).

F. Fatty acid and fatty acid ester enhancers

This group of enhancers has attracted a great deal of interest; it constitutes the largest group described in the patent literature. The group includes fatty acids and fatty acid esters. The most important of these enhancers are oleic acid, the methyl and ethyl esters of oleic and lauric acid, and the isopropyl ester of myristic acid.

F COOH

r/ CH y 3 Laurie acid

CH,(CH,),,COOH

10 9 3% LHdog - *@ l%H,/ Ol~~~~cid k-1 COOH

CH,(CH,),CH=CH(CH,),COOH

12

cHJ--clL:oocHIrH3~z 3

CH3(CH,), ,COOYCH&

(i) Fatty acids Fatty acids have a potent enhancement effect

that appears to involve disruption of lipids lill- ing the extracellular spaces of the stratum corneum. Unsaturated fatty acids are quite similar to the lipids in the stratum corneum. This simi- larity in structure may explain why infrared and differential-scanning calorimetry analyses have shown that unsaturated fatty acids affect the fluidity of lipids in the intercellular layers of the stratum corneum.

The power of fatty acid enhancers can be judged from some data reported in patent 86-4 for the penetration of naloxone through skin, using a variety of enhancers. The data is shown in Table 3.

Table I Esters of lauric acid and oleic acid


Oleic acid increased the permeability of the drug more than 1 OO-fold over the simple aqueous buffer-control. The enhancing effect of oleic acid was only exceeded by the solvent N-methylpyrrolidone, which of course has a very drastic dis- ruptive effect on skin.

Fatty acids, and particularly oleic acid, are often used alone or in combination with solvent enhancers such as alcohols and glycols. The use of fatty acids in combination with alcohols or glycols is described in patents 88-18, 87-l 3, 88- 17, 88-20, 90-13, 89-13, 89-14, 90-14, 91-5, 88- 2 1 and 91-6. In these patents, oleic acid with propylene glycol, ethyl alcohol, and propanediol are often cited as preferred enhancer combina- tions. Patent 90- 13, for example, shows the enhancement properties of oleic acid, oleyl alcohol, and methyl oleate with the free base form of various amine-functional drugs. The data is shown in Table 4. The table lists a “penetration enhancement factor”, that is, the ratio of the flux enhanced by addition of the fatty acid derivative to the unenhanced flux for each drug.

16-2 US 3952099 85-9 US 4537776 85-10 US 4552872 86-5 US 4568343 86-6 us 4573995 *86-7 US4751087 88-24 US4746515 88-25 US 4816258 88-26 US 4764319 88-27 EP 272981

Procter & Gamble Procter & Gamble Procter & Gamble Alza Alza Riker Alza Alza Alza Cygnus

88-28 US 4788062 *88-29 us 4900555 89-16 US 4820720 89-17 wo 890795 1 89-18 US 4906463 89-19 US 4863738 89-20 WO 8911872 *90-19 US4911916 ‘90-20 US 4940586 90-2 1 US 4956171 90-31 us 5049387 91-34 US 5069909

Alza Alza Alza Riker Cygnus Alza Alza Cygnus Alza Pace Alza Cygnus

Sucrose monooleate and decyl methyl sulfoxide Methyl laurate and N-2-hydroxyl ethyl pyrrolidone Methyl laurate and dials Polyethylene glycol monolaurate (PEGML) PEGML for delivery of naloxone or nalbuphine Glyceryl monolaurate (GML) for delivery of nitroglycerin GML for delivery of progesterone GML for delivery of ethynyl estradiol and levonorgestrel GML and ethanol for delivery of nilvadipine Propylene glycol monolaurate (PGML) for delivery of fentanyl and other drugs Sucrose monolaurate for delivery progesterone and estradiol Sucrose monolaurate for delivery of many drugs GML and ethanol GML and IPM PGML for delivery of fentanyl Glycerol monooleate (GMO) for delivery of steroids GM0 and ethanol PGML for delivery of many drugs Sucrose monolaurate Sucrose cocoate and methyl laurate Sucrose monolaurate and corticosteroids to induce immune tolerance PGML and oleic acid for delivery of buprenorphine

13

(ii) Fatty acid esters Isopropyl myristate is the fatty acid ester most

commonly used as an enhancer, partly due to its already established use in many pharmaceutical and skin preparations, and also because it is well tolerated by the skin.

Fatty acid esters, particularly isopropyl myristate, are widely used for the delivery of estrogen (patent 9 l-7 ) , 1 ,bdihydropyridine derivatives (patent 88-23), the antidepressant rolipram (patent 9 l-8 ) , isosorbide dinitrate (patent 9 l- 9), and physostigmine (patent 91-30). Some typical results from patent 88-23 are shown in Table 5.

(iii) Esters of iauric acid and oleic acid Many of the esters of lauric and oleic acid are

surfactants, characterized by the presence of both polar and nonpolar groups on the same molecule. It is believed that a Cl2 lipophilic molecule is the most effective enhancer, probably because it is lipophilic enough to affect the lipids of the stratum corneum, but hydrophilic enough to affect the protein structure. Different companies appear to have their favorite lauric acid ester. Procter and Gamble, for example, are attached to methyl laurate, whereas Alza favors polyethylene glycol monolaurate (PEGML) ; Cygnus, polypropylene glycol monolaurate (PGML); and Riker, glyceryl monolaurate (GML).

Two patents assigned to Alza describe the use of polyethylene glycol monolaurate (PEGML) for the delivery of a variety of drugs. Patent 86- 5 covers the delivery of 17/3-estradiol, nitroglycerin, and isosorbide dinitrate, patent 86-6 covers the delivery of naloxone, naltrexone and nalbuphine. In an example given in the patent, a transdermal system with a surface area of 1 cm2 containing naloxone was applied to the human forearm. As determined from the residual drug in the depleted system, the apparent drug flux through the skin averaged 30 pg/cm2-h for 2 days, significantly more than could be obtained without the enhancer.

Alza, in patent 88-24, describes the use of the related enhancer glyceryl monolaurate (GML) for the delivery of ethinyl estradiol and levonorgestrel in a contraceptive device. GML is used in combination with a 16-24 carbon ester of a fatty

acid, for the delivery of nitroglycerin (patent 86- 7); with IPM, for the delivery of estradiol (patent 89-17); with ethanol for the delivery of nilvadipine (patent 88-26); and with ethanol, for the delivery of several drugs, including estradiol and its esters, ergotalkaloids, and narcotic analgesics (patent 89- 16).

Procter & Gamble has two patents that use a combination of so-called ‘cell envelope disorder- ing compounds’ as enhancers. Patent 85-9 describes the use of methyl laurate and oleic acid with N-2-hydroxy-ethyl-pyrrolidone for the delivery of nonsteroidal anti-inflammatory drugs, and patent 85-10 describes the use of methyl laurate and oleic acid with propane/butane diols for the delivery of corticosteroids.

Cygnus has patents for the use of propylene glycol monolaurate (PGML) for the delivery of fentanyl (patents 89-18 and 88-27)) buprenorphine (patent 91-34), and many other drugs (patent 90- 19 ) . Some skin flux data for patches delivering fentanyl, with and without PGML as an enhancer, are shown in Fig. 6. This figure il- lustrates one of the attractive features of these enhancers; namely, small amounts of enhancer are required to produce the required result.

0’ ’ I I I I I

0 10 20 30 40 50 60

Tllm (hours,

Fig. 6. In vitro fentanyl permeation data obtained with patches using low loadings of propylene glycol monolaurate as an en-

hancer (data from US 4,906,463).

CH,COOC,,H,,

g--J~“yH20H

I 6H OH 1

Sucrose monolaurate

14

Table J Macrocyclic enhancers

Code # Patent #

*87-15 WO 8703473 89-2 1 EP 308181 90-22 US 4918532 91-13 US 5023252

Assignee

Conrex Novo Industry Pharmedic Conrex

Comments

Lactone and cyclic ketone Cyclodextrins Hydroxypropyl-P-cyclodextrins Cyclopentadecanolide

In recent years, Alza has obtained a number of patents centered on the use of sucrose monolaurate. These patents assert that sucrose esters have many advantages as permeation enhancers, including their low toxicity, their lack of color and odor, and no sensitization of the skin. Alza also states that these enhancers are not irritating to the skin, even when used in an occluded patch and after repeated applications at the same skin site.

G. Macrocyclic enhancers

Macrocyclic compounds are reported to enhance skin absorption by temporarily increasing the solubility of the drug in the skin. When the enhancer is removed, the skin returns to its normal state.

Patents 87-15 and 91-l 3 describe the use of macrocyclic compounds such as cyclopentade- canone and cyclopentadecanolide as enhancers.

(CH2)l 4

These macrocyclic compounds are intended not only for enhancing transdermal drug delivery, but also delivery through the nasal and va- ginal routes, and others. Fig. 7, taken from patent 87-15, shows the relative efficiency of macrocyclic ketones as an enhancers for delivery of hydrocortisone through hairless mouse skin.

Use of cyclodextrins is also reported in patents 89-21 and 90-22. The latter patent particularly describes the use’of hydroxypropyl-fi-cyclodex-

Fig. 7. Relative eff%ziency of various macrocyclic derivatives as enhancers for the transdermal delivery of hydrocortisone through hairless mouse skin in vitro (data from WO 87/

03473 ).

trin (HPBCD ) for increasing skin permeation of dehydroepiandrosterone, a drug designed to lower cholesterol blood levels.

H. Phospholipids and phosphate enhancers

The enhancement action of lecithin, phospholipids, and other phosphate derivatives is similar to the lauric acid esters and is believed to be related to the enhancer’s surfactant properties.

Patents 89-22 and 88-30 describe the use of phospholipids and phosphate derivatives as skin penetration enhancers. Patent 88-30 reports that lecithin substantially increases the flux of several drugs through hairless mouse skin. The specific lecithins chosen as examples were Epikuron 135F and Capcithin 50-R, used in concentrations of from 2 to 40%. The patent reports skin fluxes with and without enhancement for procaterol, dextrometorphan, oxymorphone, and diphenhydramine.

15

Table K Phospholipids and phosphate enhancers


86-8 US 4686211 *88-30 US 4783450 89-22 JO 1242521 91-14 EP 439042 91-15 JO 3123787

Kao Dialkylphosphate Warner Lambert Lecithin Nikko Chemicals Phospholipids for delivery of anti-inflammatory drugs Hoffmann LaRoche Lecithin Sagami Chem. Phosphate group containing unsaturated compounds

YH2--OCOR YH-OCOR -

9 +YH3 CH2-0-;-CH,CH,- r-CH3

0 CH3

R=Fatty acid(oleic,palmitic acid)

The enhancement properties of dialkyl phos- phates, particularly ditetradecyl phosphate, are reported in patent 86-8.

c H3- (CH,), 3-+0

CH,-(CH,),,--0’ ‘O-Arginine

The patent does not specifically mention the use of these substances in transdermal systems. It does, however, present data from rabbit tests that illustrate increased skin fluxes of methyl sal- icylate ointments containing these enhancers, compared to unenhanced ointments. Patent 9 l- 15 reports the use of acyclic ester derivatives containing phosphate groups as enhancers in concentration ranges of l-20% by weight.

I. 2-Pyrrolidone enhancers

N-Methyl-2-pyrrolidone and its derivatives are versatile solvent enhancers used in many topical preparations.

cl N '0

;H3

Although the specific mechanism of permeation enhancement for the pyrrolidones is not well understood, it is likely that their humectant properties play a role.

OH

AH,

Table L 2-Pyrrolidone enhancers


86-9 US 4863952 87-16 US 476285 I 89-23 US 4847250 90-23 US 4973708 91-16 US 5032402 ‘91-32 US 5066648

Nitto Merck Merck Univ. Kentucky Univ. Kentucky Merck

Alkyl pyrrolidones-5 carboxylate Alkyl pyrrolidones-5carboxylate Alkyl pyrrolidones-5-carboxylate 3-hydroxy-N-methyl-2-pyrrolidone 3-hydroxy-N-methyl-2-pyrrolidone Pyroglutamic acid esters

16

The 3-hydroxy derivative of N-methyl-2-pyrrolidone described in patents 90-23 and 9 I- 16 is reported to have enhancement properties. In a study reported in the patent, the 3-hydroxy derivative was compared to N-methyl-2-pyrrolidone for effectiveness in enhancing the flux of the drug clioquinol in Franz cells. Drug absorption using the 3-hydroxy derivative was greater than in the controls by a factor of 1.8, and greater than N-methyl-2-pyrrolidone by a factor of 1.3. The patent also asserts, that since 3-hydroxy-N- methyl-2-pyrrolidone is a major metabolite of N- methyl-2-pyrrolidone, the 3-hydroxy derivative should be less toxic.

Patents 86-9,87-l 6,89-23, and 9 l-32 describe the use of alkyl pyrrolidone-5-carboxylate esters with the following structures:

I \ R=decyl,dodecyl,oleyl

TABLE 6

Enalapril and clonidine fluxes in presence of alkyl pyrrolidone-5-carboxylate esters (data from US Patent 4,847,250)

Enhancer Enalapril Clonidine

Flux % delivered Flux % delivered (/lg.cm2.h) in 24 h) (&cm**h) in

24h

None - 0.9 - 1.1 Decyl 0.15 4.3 0.31 8.1 Dodecyl 0.5 1 9.9 0.63 13.2 Oleyl 0.92 18.7 0.26 4.4

Table M Soft penetration enhancers

Data illustrating the effectiveness of these alkyl pyrrolidone-5-carboxylate esters in enhancing the permeation of enalapril and clonidine across shed snake skin are presented in Table 6.

J. Soft penetration enhancers

The compounds in this category of enhancer are designed to degrade into nontoxic compounds after absorption. Typical examples of these so-called soft enhancers are the cyclic derivatives of dioxane and dioxolane, patented by Macrochem in 88-31. The structures are shown below. The enhancement properties of structure I has been tested on rat skin and penetration en- hancements of 2- to g-fold were obtained with drugs such as indomethacin. Related compounds are described in 89-24 assigned to IPRX.

W,-(” 0 1

2,rrnonyl-1,3-dioxane

CH3’C=CH-(CH$,-~~~H(o) CHj 0

2-(2’,6’,-dimethyl-l’,S-heptadienyl)l,3-dioxolane (I)

K. Sulphoxide enhancers

The sulphoxides, particularly dimethyl sulphoxides (DMSO), were very widely used as enhancers in the 1970s and early 80s. In fact, DMSO continues to be widely used in various snake oil preparations, either by itself, or in combination with various drugs. More orthodox studies on the use of DMSO as an enhancer are


88-31 US 486 1764 89-24 US 4845233 90-24 US 4980378

Macrochem IPRX Odontotex

Dioxolane derivatives Biodegradable compounds, dixoxolane, dioxane Biodegradable long chain alkylesters

17

Table N Sulphoxide enhancers


IO-2 us 3551554 70-3 us 3549770 72-l US 3711602 72-2 US 3711606 72-3 US 3740420 12-4 US 3143721 83-4 US4369190 85-11 us 4575515 91-33 US 5059603

Crown Zellerbach Crown Zellerbach Crown Zellerbach Crown Zellerbach Crown Zellerbach Crown Zellerbach None Clark Pharmaceutical Centuries Lab

DMSO DMSO DMSO for delivery of anti-inflammatory DMSO for delivery of glucocorticosteroids DMSO DMSO for delivery of antimicrobials DMSO for delivery of biphenamine DMSO for delivery of nonsteroidal anti-inflammatories DMSO papaverine and caffeine

given in a series of patents assigned to Crown Zellerbach. These patents discuss delivery of anti- inflammatories, steroids, benzodiazepine derivatives, and other drugs. Patent 83-4 describes the use of DMSO for the delivery of biphenamine. Patent 85-11, issued to Clark Pharmaceutical, describes its use for the delivery of nonsteroidal anti-inflammatory drugs. Patent 9 l-22 describes the use of DMSO with papaverine and caffeine to treat impotence. Despite its popularity, DMSO is poorly tolerated and potentially toxic, which imposes serious limitations on its use in transdermal systems. A particular problem with DMSO preparations is the presence of small quantities of the dimethysulphide derivative, which has a remarkably strong garlic taste. This problem is reduced when alkyl derivatives of DMSO are used; decylmethyl sulphoxide has been approved by the FDA in a topical tetracyc- line preparation for the treatment of acne.

CH3,

CH3’ s=o

Dimethyl sulphoxide(DMS0)

CH,- (C&J,,

CH3’ s=o

Decylmethyl sulphoxide

L. Miscellaneous enhancers

The substances described in the patents listed below cannot be conveniently categorized with the other enhancer groups and are, therefore, described together here.

(a) Oxazoline and imidazoline derivatives (patent 88-32), such as 2-dodecyl-oxazoline

Table 0 Miscellaneous enhancers


85-12 US 4743588 87-17 US 4677131 87-18 US 4837026 88-32 US 4876249 88-33 WO 88064 1 89-25 EP 309624 89-26 EP 299758 90-25 EP 349763 90-26 US 496077 1 91-23 US 505 1260 91-24 us 5045317

Allergan Merck Rajadhyaksha Rajadhyaksha Shiseido Nitto Univ. of California Bristol Meyers Rajadhyaksha Univ. of California Univ. of California

N-Alkanyl cyclic amine Imidazolinones Iv’-Alkanoyl cyclic amine Oxazoline and imidazoline derivatives Surfactants Proline esters Urethane compounds Imidazole derivatives Oxazolidinones derivatives Urethane compounds Urethane compounds

18

N 0 \N C

These derivatives may be used to enhance transdermal penetration of a wide variety of drugs, and also to enhance penetration into seeds of substances that enhance plant growth, such as micronutrients and chemical hybridization agents.

(b ) Imidazole derivatives (patent 90-25 ), such as 1,2-dimethyl imidazole

743

N

c‘r \ i CH3

N This group of enhancers is preferred for use

with antihistamines, sympathomimetic amines, metaproterenol, diuretics such as hydrochloro- thiazide, antitussives such as dextramethor- pham HBN, anti-inflammatories, and analgesics.

(c) ~xazolidinones (patent 90-26), such as 4- decyl oxazolidin-Zone

CH3-W2+-\

0, f

/NH

0

As described in this patent, 4-decyl oxazolidin-2-one is a superior enhancer when compared to Azone and a control.

(d)m Proline esters (patent 89-25), such as proline n-dodecyl ester

(“)-_ COO(CH,), ,-CH3

These esters are used in combination with polar compounds such as ethanol, glycols, and methyl pyrrolidone for delivery of propranolol.

(e) 2-Imidazolinone and 4-imidazolin-2-one (patent 87-l 7)) such as 1 -decyl-3-methyl-2- imidazolinone

0 I!

CH3-(CH,)g-N/b~N-CH, \

These compounds are useful as skin penetration enhancers, especially for beta lactam anti- biotics, aminoglycosides, antineoplastics, and antiviral agents.

(f) AMlkanoyl cyclic amines (patents 87- 18 and 85-12), such as 1 -dodecanoyl-2- carboxypyrrolidine

O=y-(CH,), ,-CH,

(“I- COOH \

(g ) Urethane compounds (patent 89-25), formed from reactions with diisocyanates and glycols or polyethers and hydroxy-terminated urethane (patents 9 l-23 and 9 f -24 ).

(h) Surfactants (patent 88-33)

The absorption of steroids, anti-inflammatories, and antihistamines is enhanced by the use of anionic, nonionic, and amphoteric surfactants. Patent 88-33 describes the use of surfactants in skin preparations such as creams.

III. Patents covering a variety of enhancers for specific drugs or specific patch structures

The patents described in Section II all centered around the use of specific enhancer com-

19

Table P Patents covering a variety of enhancers


“86-10 US 4645502 86-l 1 EP 196769 87-19 US 4883669 87-20 US 4690683 88-34 US 480634 1 88-35 US4818540 90-21 DE 3823070 90-28 EP 371496 90-29 us 4904415 90-30 US 5028435 91-17 WO 9102553 91-18 JP 3031217 91-19 EP 429039 91-25 us 5045319

Alza Delivery of highly ionized drugs Rutgers Univ. Polymer matrix plus enhancer Rutgers Univ. Many enhancers for delivery of estrogens Rutgers Univ. Many enhancers for delivery of verapamil Rutgers Univ. Many enhancers for delivery of narcotic analgesics Rutgers Univ. Many enhancers for delivery of estrogen and progestins Kettelhack Riker Water soluble polymer in a matrix Schering Solvent-like enhancers for estradiol Alza Delivery of highly ionized drugs Adv. Polymer SystemParticles in a matrix Schering Many enhancers for delivery of nitroglycerin Yamanouchi Enhancers for delivery of skeletal muscle relaxants Alko Enhancers for delivery of opiate antagonists Rutgers Univ. Many enhancers for delivery of propranolol

TABLE 7

In vitro estradiol fluxes with different enhancers from US Patent 4,883,669. The enhancers are applied at a level of 8.2 mg/cm’

Enhancers Normalized permeation rate

(pglcmah)

Enhancement factors

No enhancers 1.2? 1.0 1 Propyl myristate 11.423.4 9 Propyl oleate 17.8k8.2 15 1 -Dodecylazacycloheptan-2-one (Azone) 24.6 + 8.9 20 Decyl methyl sulphoxide 15.4kO.5 13

Table Q Other forms of enhancement


‘85-13 US4685911 86-12 WO 8602272 86-l 3 US 4649075 87-21 JP 1282313 81-22 US 4738848 *88-36 EP 273004 *88-37 US 4767402 89-27 US 4824676 89-28 US 4860058 89-29 US 4834978 ‘89-30 US 4879 119 89-3 1 US 4845081 90-3 1 WO 9009809 90-32 EP 384266 90-33 EP 384267 90-34 US 4963360 91-20 JP 3170172 91-21 WO 9112772

Yamanouchi Key Pharm. JOST Nitto Nitto Ciba Geigy MIT Schering Ben-Amoz Biotek Yamanouchi Univ. Florida Univ. Utah Lohmann Therap. Lohmann Therap. Argaud Sumitomo Cygnus

Microparticles in a fatty base that melts Pretreatment of skin with anticholinergic drugs Bernoulli effect Pretreatment of skin with enzymes Use of acids to increase solubility of diclofenac Conversion to more permeable form (nicotine) Ultrasound Pretreatment of skin with anticholinergic drugs Ultrasound Ultrasound

Prodrugs Pretreatment of skin with enzymes Conversion to more permeable form (nicotine) Conversion to more permeable form (nicotine) Exothermic effect Ultrasound Ultrasound

20

pounds to increase the skin penetration of a variety of drugs. The patents listed in this section describe a variety of enhancers to effect the penetration of a specific drug or class of drugs.

The enhancement factors claimed in some of the patents are often spectacular. Some typical examples taken from patent 87- 19 are shown in Table 7.

IV. Other forms of enhancement

This final category of patent covers devices in which drug enhancement is achieved by some form of physical treatment, rather than by application of a chemical enhancer. For example, patents 90-3 1 and 87-2 1 describe pretreatment of the skin with a joint patch containing an enzyme such as papain, after which a second patch containing the drug is applied. There are also a number of patents issued to Cygnus, MIT, Biotech, Ben Amoz, and Sumitomo describing the use of ultrasound to increase skin permeability. The practicality of this technology is unclear.

We conclude our discussion of these patents by describing a personal favorite issued to Yaman- ouchi Pharmaceutical: US patent 85-13. The patent, illustrated in Fig. 8, describes a patch for dispensing vasodilators. The drug is contained in a low-melting-point wax. Lest the wax not soften

Heating element seal

/

SIXI

/

Peel strip Liner adhesive

Fig. 8. A self-heating transdermal patch from US patent 4,685,911.

sufficiently at body temperature for adequate drug delivery, the patch may be made self-heating by including a compartment containing iron powder. When this is exposed to air and water, the resulting exothermic reaction softens the wax.

Conclusions

Many researchers rarely, if ever, read or cite the patent literature both because some of the data contained in patents is of questionable quality, and because patents are hard to read. This is a pity, since patents contain a good deal of valuable information that is unavailable elsewhere. In this review, we have tried to provide a guide to this literature.

Transdermal enhancer patent literature

Documents