MXPA99006959A - Composition for the transdermal administration of steroid drugs - Google Patents

Abstract

A composition for the transdermal administration of a steroid drug containing a therapeutically effective amount of the drug;an absorption promoter consisting essentially of a diethylene glycol ether and a sorbitan ester;and a pharmaceutically acceptable adhesive matrix.

Description

"COMPOSITION FOR THE TRANSDERMAL ADMINISTRATION OF STEROID DRUGS" FIELD OF THE INVENTION The present invention relates to a composition for the transdermal administration of spheroidal drugs, wherein a mixture of a diethylene glycol ether and a sorbitan ester is used as an absorption promoter; and with a transdermal formulation that contains the same.

BACKGROUND OF THE INVENTION The supply of a drug through the skin offers advantages in relation to conventional oral administration which is prevented by problems such as unpredictable drug absorption regimes, metabolic degradation of the drug and other detrimental effects eg, gastrointestinal irritation caused by the drug itself or metabolites thereof. Namely, the administration of the transdermal drug alleviates the aforementioned problems and supplies a drug to a controlled regimen for a prolonged period of pre-established time due to the increased bioavailability of the drug that degrades in the digestive tract. When a drug is transported through the skin, the horny layer of the skin acts as a barrier against the penetration of the drug into the systemic circulation. Accordingly, various absorption promoters, or penetration enhancers that facilitate penetration of the drug through the stratum corneum, have been used in transdermal drug compositions. For example, U.S. Patent Nos. 4,006,218; 3,551,554; 4,568,343; 4,746,515; 4,379,454; 4,906,463; 4,440,777; 4,783,450 and 5,212,199 disclose, as these absorption promoters, dimethyl sulfoxide (DMSO), dimethylformamide, polyethylene glycol monolaurate, glycerol monolaurate, ethanol, propylene glycol monolaurate, eucalyptol, lecithin and sorbitan esters. The diethylene glycol monoethyl ether, which has been used as a solubilizer in the formulation of naproxen, nitroglycerin, phenylbutazone and prazepam, was also disclosed as being effective as an absorption promoter in the transdermal administration of theophylline and prostaglandin E2 (Touitou and others, International Journal of P armaceutics, 70, 159-166 (1991), and Watkinson, A. and others, ibid, 74, 229-236 (1991)).

Other absorption promoters disclosed in the prior art include: a mixture of linoleic acid and propylene glycol (European Patent Publication Number 261429); and mixtures of N- (hydroxyethyl) pyrrolidone and methyl laurate, ethanol and glycerol monolaurate, diethylene glycol monoethyl ether and propylene glycol monolaurate (U.S. Patent Nos. 4,537,776, 4,764,379, and 4,973,468). Conventional transdermal formulations can be divided into three types: a reservoir type, a simple matrix type and a multi-layer lamination type. The simple matrix type formulation as disclosed in U.S. Patent Nos. 4,314,577; 4,438,139; and 4,839,174, comprises a drug dispersed in an elaborated layer of a matrix of the pressure sensitive adhesive. This formulation can be produced at a low cost through a simple process. However, he has the problem that the drug release regime is high in the initial stage and graduates abruptly later. In addition there are needs to supply a large dose of the drug over a prolonged period using a simple matrix type formulation. For this purpose, attempts have been made to raise the content of the drug in the matrix to a level beyond the drug's solubility in the matrix, that is, to supersaturate the matrix with the drug. However, supersaturation represents a thermodynamically unstable state and the drug in this formulation tends to form crystals. To alleviate this problem, inhibitors of crystal formation, e.g., polyvinyl pyrrolidone and polyvinyl pyrrolidone-vinyl acetate copolymer have been used, but the efficacy of these was found to be marginal (Ma, X. et al., ibid, 142, 115-119 (1996)). Accordingly, there is a need for a transdermal drug formulation of the improved matrix type which has a constant and high rate of drug release over a prolonged period and also a high level of non-crystallized drug content. The present inventors have sought to develop an improved composition for the transdermal administration of spheroidal drugs, the composition having a new absorption promoter which is capable of fulfilling the aforementioned needs. It has been unexpectedly found that a diethylene glycol monoalkyl ether and a sorbitan ester, each of which has been individually known as an absorption promoter having limited efficacy, provide a synergistic effect when combined, i.e. a mixture of a diethylene glycol ether and a sorbitan ester has been found to be a remarkably efficient absorption promoter for the transdermal transport of steroidal drugs.

COMPENDIUM OF THE INVENTION Therefore, an object of the present invention is to provide an improved composition for the transdermal administration of a steroidal drug. Another object of the present invention is to provide a transdermal formulation comprising the composition. In accordance with one aspect of the present invention, there is provided a composition for the transdermal administration of a steroidal drug, comprising: a therapeutically effective amount of the drug; an absorption promoter consisting essentially of a diethylene glycol ether and a sorbitan ester; and a pharmaceutically acceptable adhesive matrix.

BRIEF DESCRIPTION OF THE DRAWINGS The foregoing objects and features and others of the present invention will be apparent from the following description of the invention taken in conjunction with the following accompanying drawings, wherein: Figure 1 shows a schematic cross-sectional view of one embodiment of the invention; pharmaceutical formulation of the invention for the transdermal delivery of a steroidal drug; Figure 2 presents the time-dependent changes in the cumulative amount of estradiol that is transported through the skin of a bald mouse as a function of the absorption promoter used; Figure 3 illustrates the time-dependent changes in the cumulative amount of norethisterone acetate transported through the skin of a bald mouse as a function of the absorption promoter used; Figure 4 illustrates the time-dependent changes in the cumulative amount of norethisterone acetate transported through the skin of the human cadaver as a function of the absorption promoter used; and Figure 5 shows the time-dependent changes in the cumulative amount of norethisterone acetate transported through the skin of the human corpse as a function of the content of sorbitan monolaurate and diethylene glycol monoethyl ether.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a composition for the transdermal administration of steroidal drug, comprising: the steroidal drug; a mixture of diethylene glycol ether and sorbitan ester which is used as an absorption promoter; and a pharmaceutically acceptable adhesive matrix. Exemplary steroidal drugs for use in the composition of the present invention include estrogens, e.g., estradiol, ethynyl estradiol and estradiol ester; progestogens, e.g., noretiesterone, noretiesterone acetate, medroxyprogesterone acetate, desogestrel, gestaten and levonorgestrel; androgens, e.g., testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone and dihydroepiandrosterone; and a mixture of them. The total amount of the steroidal drug used in the composition of the invention can vary from 0.05 percent to 30 percent by weight, preferably from 0.1 percent to 10 percent by weight based on the total weight of the composition. The absorption promoter of the present invention is composed of a monoalkylether of diethylene glycol and a sorbitan ester mixed in a weight ratio ranging from 1: 4 to 4: 1, preferably from 1: 2 to 2: 1. The diethylene glycol monoalkyl ethers that can be used appropriately in the present invention include diethylene glycol monoethyl ether and diethylene glycol monomethyl ether, and appropriate sorbitan esters include sorbitan monolaurate and sorbitan monooleate. The total amount of the mixture of the diethylene glycol ether and sorbitan ester used in the composition of the invention may vary from 5 percent to 30 percent, preferably from 5 percent to 25 percent based on the total weight of the composition , wherein the weight ratio of the two components is maintained within the aforementioned scale. The pharmaceutically acceptable adhesive matrix used in the present invention can be any of those known in the art., e.g., polyacrylate adhesives such as ethyl acrylate, butyl and 2-ethylhexyl, polyisobutylene and silicone rubber. The composition of the present invention may further comprise flavoring agents, preservatives, antioxidants, stabilizers and pigments. The transdermal formulation of the steroidal drug according to another aspect of the present invention can be constructed using: a protective backing layer that is impermeable to the steroidal drug; a drug reservoir layer containing the aforementioned composition of the present invention, one side of which is laminated to the protective backing layer; and a release layer attached to the other side of the drug reservoir layer, the release layer being able to protect the composition from the environment until it is removed to place the drug reservoir layer in contact with the skin. The formulation of the present invention may further comprise a supplementary adhesive layer that is selected from those known in the art, eg, a ring-shaped adhesive layer sealable to the periphery of the drug reservoir layer and the backing layer protective Figure 1 shows a schematic cross-sectional view of an embodiment of the transdermal formulation of the present invention comprising the release layer (1), the drug reservoir layer (2), the protective backing layer (3) and the supplementary adhesive layer (4). The composition of the invention for the transdermal delivery of a steroidal drug has advantages since: it is of a simple type of matrix that can be prepared at low cost; the use of the improved absorption promoter disclosed above makes it possible to maintain a high flow of the drug over a prolonged period, the apparent drug penetration rate follows zero-order kinetics; and the crystal formation of the drug is still inhibited at a high drug loading level due to the use of the improved absorption promoter. The dosage administered to a patient using the composition of the present invention can be controlled by adjusting the content of the drug and the absorption promoter. The following Examples are intended to further illustrate the present invention without limiting its scope.

Determination of Skin Penetration Regimen through Skin The flow, or skin penetration rate (SPR), of a drug through a skin sample was determined by the following procedure. A sample of skin, either from human cadaver skin or a piece of cut skin from a 6-week-old bald female mouse, was installed in the Valia-Chien diffusion cell (Crown Glass, USA) in such a way that the The stratum cornea of the skin was oriented outward from the cell, and then a transdermal formulation containing one or more steroidal drugs was fixed on the skin. 3.4 milliliters of the physiological saline solution containing 40 percent of the polyethylene glycol 400 (Sigma Scientific Co.) was added to this cell, and stirred throughout the period of the experiment. Then, 100 microliter samples of the physiological saline solution were taken periodically and subjected to a high performance liquid chromatography to determine the cumulative amount of the drug transported through the skin. The skin penetration rate (SPR) of the drug through the skin was calculated by regression analysis of the cumulative amounts that depend on the drug time (microgram / centimeter square / hour). The process described above was repeated 3 times and averaged to define the SPR of the drug.

Reference Example 1: Preparation and Test of Transdermal Administration Compositions Containing Conventional Absorption Promoters (bald mouse skin) 0.6 weight percent estradiol (DE), 3.0 weight percent norethyesterone acetate was added (NETA) and an absorption promoter that is listed in the Table 1 to a polyacrylate adhesive (Durotac 87-2074, National Starch Chem. Co.), and then the mixture was stirred sufficiently to dissolve the drugs in the adhesive.

- The mixture obtained in this way was emptied into a waterproof protective backing layer (Scotchpak 1109, 3M Co.) to coat a matrix layer having a thickness of 1000 micrometers. The resulting material consisting of the protective backing layer coated with the matrix layer was dried in an oven raising the temperature stepwise from 60 ° C to 120 ° C. The resulting material was cured in the open air for 1 hour and laminated thereon in the release layer (Scotchpak 1012, 3M Co.) The resulting transdermal formulation was stored at room temperature. The penetration rates of the drugs through the skin and the bald mouse were determined and the results are shown in Table 1 and Figures 2 and 3.

- Table 1. Penetration Regimens of ED and NETA through the skin of the mouse in the presence of the conventional absorption promoter Example DE NETA Promoter SPR * SPR * of (% in (% en de (ED) (NETA) Reference weight) weight) Absorption (% by weight) 1-1 0.6 3.0 - 0.12 0.43 +0.02 +0.09 1-2 0.6 3.0 azona 0.10 0.64 (10) +0.01 +0.08 1-3 0.6 3.0 tricaprylin 0.16 0.49 (10) +0.05 +0.10 1-4 0.6 3.0 monolaurate 1.02 1.87 of +0.05 +0.17 sorbitan (10) 1-5 0.6 3.0 tritertíano 0.19 1.98 (10) +0.03 +0.48 1-6 0.6 3.0 decanol 0.11 0.45 (10) +0.01 +0.05 * SPR: Skin penetration rate through the skin (edio + SD (microgram / square centimeter / hour)) Figures 2 and 3 show the cumulative amounts that depend on the time of estradiol and norethisterone acetate transported through the skin as a function of the absorption promoter used. As can be seen from Table 1 and Figures 2 and 3, the compositions containing sorbitan monolaurate (Reference Examples 1-4) and triterpene (Reference Examples 1-5) as the absorption promoter exhibited high rates of penetration. However, crystals of the drugs were observed in each of the aforementioned Reference Examples.

Reference Example 2: Preparation and Test of Transdermal Administration Compositions Containing Conventional Absorption Promoters (human cadaver skin) Four transdermal delivery compositions were prepared and tested by the procedure of Reference Example 1, with the exception that human cadaver skin was used instead of mouse skin, and 4 weight percent norethisterone acetate was used (NETA) together with the absorption promoter listed in Table 2. The results are shown in Table 2 and Figure 4.

Table 2. NETA Penetration Regimes Through Human Corpse Skin When Conventional Absorption Promoters are Used Example NETA Promoter of SPR of (% in Absorption Reference weight) (% by weight) 2-1 4.0 - 0.18 + 0.03 2-2 4.0 sorbitan monolaurate 0.72 + 0.09 (15) 2-3 4.0 triterteno (15) 0.43 + 0.03 2-4 4.0 monoethyl ether of 0.52 + 0.04 diethylene glycol (15) As can be seen from Table 2 and Figure 4, compositions containing sorbitan monolaurate (Reference Example 2-2), triterpene (Reference Example 2-3) and diethylene glycol monoethyl ether (Reference Example 2-4) as the absorption promoter improved the penetration rate of NETA through the skin of the human corpse to a degree that is - significantly lower than that determined for the skin of the bald mouse. In addition, crystal formation was observed in the drug in all but Reference Example 2-4 where diethylene glycol monoethyl ether was used as the absorption promoter.

Example 1 to 3 and Comparison Examples 1 to 6: Nine transdermal delivery compositions were prepared and tested by the procedure of Reference Example 1, with the exception that the skin of the human cadaver as well as 0.4 weight percent estradiol and 2.7 weight percent noretiesterone acetate were used together with the absorption promoters listed in Table 3. As a positive control, a commercially available deposit type formulation was used, ie, Estragest (R> (EG, Ciba Geigy, Switzerland) in Example 6 of Comparison. The results are shown in Table 3 and Figure 5.

Table 3. Penetration regimes of ED and NETA through the skin of the human corpse NET NUMBER SML C SPR SPR (% in (% in (% in (% in (ED) (NETA) weight) weight) weight) weight) Ex. 1 of 0.4 2.7 0.08 0.17 Comparison +0.02 +0.01 Ex. 2 of 0.4 2.7 0.19 0.41 Comparison +0.01 +0.05 Ex. 3 of 0.4 2.7 10 0.22 0.46 Comparison +0.02 +0.03 Ex. 4 of 0.4 2.7 15 0.27 0.51 Comparison +0.06 +0.02 Example 1 0.4 2.7 10 10 0.23 0.72 +0.01 +0.06 Example 2 0.4 2.7 10 0.23 0.75 +0.03 +0.06 Example 3 0.4 2.7 10 0.26 0.62 +0.03 +0.03 Ex. 5 of 0.4 2.7 10 0.17 0.35 Comparison +0.04 +0.02 Ex. 6 of 0.15 0.45 Comparison +0.04 +0.09 SML: sorbitan monolaurate, TC: diethylene glycol monoethyl ether As can be seen from Table 3 and Figure 5, the compositions of the invention containing a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) which have a weight ratio of TC to SML within the scale of 0.5 to 2 (Examples 1, 2 and 3) as the absorption promoter, exhibited remarkably improved penetration rates of the drugs through the skin of the human cadaver in comparison with those observed from Comparison Examples 1 to 6. Penetration regimes follow apparent zero-order kinetics. In addition, no drug crystals were observed in Examples 1, 2 and 3.

Example 4 and Comparative Examples 7 to 10: Five transdermal delivery compositions were prepared and tested by the procedure of Example 1, reference with the exception that human cadaver skin and 3.5 weight percent testosterone were used together with the absorption promoters listed in Table 4. .

- - Table 4. Regimes of penetration of testosterone through the skin of the human cadaver Number Testosterone Prompt Absorption SPR (% by weight) (by weight) Example 7 3.5 0.70 of Com- +0.32 paración Example 8 3.5 SML (20] 3.07 of Com- +1.22 paración Example 9 3.5 2.21 Buyiraglycol monolaurate (20) +0.04 paration Example 10 3.5 TC (20) 2.03 of Com + 0.25 paración Example 4 3.5 TC (10) and SML (10) 3.57 +0.77 As the results in Table 4 show, the composition of the invention containing a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 4) as the absorption promoter exhibited a remarkably higher penetration rate. elevated than those observed when single TC and SML were used (Comparison Examples 8 and 9). Examples 5 to 7 and Comparison Examples 11 to 12: Five transdermal delivery compositions were prepared and tested by the procedure of Reference Example 1 with the exception that the human cadaver skin and 0.8 weight percent estradiol were used together with the absorption promoters listed in Table 5.

Table 5. Regimes of penetration of estradiol through the human cadaver skin as a function of the absorption promoter used. Number ED Promoter of SPR. { % in Absorption weight) (% by weight) Example of 0.8 0.15 + 0.01 Comparison 11 Example of 0.8 SML (10) 0.31 + 0.02 Comparison 12 Example 5 0.8 TC (10) and SML (2.5) 0.54 + 0.06 Example 6 0.8 TC (10) and SML (5) 0.58 + 0.01 Example 7 0.8 TC (10) and SML (10) 0.42 + 0.03 As the results in Table 5 show, the compositions of the invention contain a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML). ) having a ratio of TC to SML ranging from 1 to 4 (Examples Nos. 5, 6 and 7) exhibited improved rates of penetration of estradiol through the skin of the human cadaver.

Claims (16)

CLAIMS:

1. A composition for the transdermal administration of a steroidal drug comprising: a therapeutically effective amount of the drug; an absorption promoter consisting essentially of a diethylene glycol ether and a sorbitan ester; and a pharmaceutically acceptable adhesive matrix.

The composition of claim 1, wherein the weight ratio of the diethylene glycol ether and the sorbitan ester varies from 1: 4 to 4: 1.

3. The composition of claim 2, wherein the weight ratio of diethylene glycol ether to sorbitan ester ranges from 1: 2 to 2: 1.

4. The composition of claim 1, wherein the diethylene glycol ether is diethylene glycol monoethyl ether, diethylene glycol monomethyl ether or a mixture thereof.

The composition of claim 1, wherein the sorbitan ester is sorbitan monolaurate, sorbitan monooleate or a mixture thereof.

The composition of claim 1, wherein the steroidal drug is an estrogen, progestogen, androgen, or a mixture thereof.

7. The composition of claim 6, wherein the estrogen is estradiol, ethynyl estradiol or estradiol ester.

The composition of claim 6, wherein the progestogen is noretiesterone, noretiesterone acetate, medroxyprogesterone acetate, desogestrel, gestaten or levonorgestrel.

The composition of claim 6, wherein the androgen is testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone or dehydroepiandrosterone.

The composition of claim 1, wherein the amount of the steroidal drug ranges from 0.05 percent to 30 percent by weight based on the total weight of the composition.

The composition of claim 10, wherein the amount of the steroidal drug ranges from 0.1 percent to 10 percent by weight based on the total weight of the composition.

The composition of claim 1, wherein the amount of the absorption promoter ranges from 5 percent to 30 percent by weight based on the total weight of the composition.

The composition of claim 12, wherein the amount of the absorption promoter ranges from 5 percent to 25 percent based on the total weight of the composition.

The composition of claim 1, wherein the adhesive matrix is a polyacrylate, polyisobutylene or silicon rubber adhesive.

15. A transdermal formulation for the transdermal administration of a steroidal drug comprising: a protective backing layer; a drug reservoir layer containing the composition of claim 1, which is placed on the protective backing layer, one side of which is laminated to the backing protective layer; and a removable release layer attached to the other of the drug reservoir layer.

16. The formulation of claim 15, further comprising a supplementary adhesive layer.