JP2002516879A - Composition for transdermal administration of non-steroidal anti-inflammatory analgesic - Google Patents

Abstract

(57) Abstract: A non-steroidal composition comprising a therapeutically effective amount of a non-steroidal anti-inflammatory analgesic, an absorption enhancer comprising a mixture of diethylene glycol ether and sorbitan ester, and a pharmaceutically acceptable sticky base material A composition for transdermal administration of an antiphlogistic analgesic.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a composition for transdermal administration of a non-steroidal anti-inflammatory analgesic using a mixture of diethylene glycol ether and sorbitan ester as an absorption enhancer, and a preparation for transdermal administration containing the same.

[0002] transfer of the drug through the background skin invention, the absorption rate of the drug unpredictable, the usual oral administration with problems such as side effects such as gastrointestinal disorders due to deterioration and the drug itself or metabolites thereof by metabolism of the drug Providing advantages over. That is, transdermal administration of a drug alleviates the problem by increasing the bioavailability of the drug, which degrades in the digestive tract, and delivers the drug at a controlled rate during prolonged prescription.

[0003] When a drug is transmitted through the skin, the stratum corneum acts as a barrier to absorption of the drug into the body. Accordingly, various absorption enhancers or absorption enhancers that facilitate the absorption of drugs through the stratum corneum have been used in drug compositions for transdermal absorption. For example,
U.S. Pat. Nos. 4,006,218; 3,551,554; 4,568,343; 4,746,515; 4,379,454; 4,906,463; Four,
In 440,777, 4,783,450 and 5,212,199, dimethylsulfoxide (DMSO), dimethylformamide, polyethylene glycol monolaurate, glycerin monolaurate, respectively, are used as skin absorption enhancers.
Ethanol, propylene glycol monolaurate, eucalyptol, lecithin and sorbitan esters are disclosed.

Further, diethylene glycol monoethyl ether, which is used as a solubilizing agent in the dosage forms of naproxen, nitroglycerin, phenylbutazone and prazepam, is used as an absorption enhancer in the dosage form for transdermal administration of theophylline and prostaglandin E2. (Touitou, at al., International
Jounal of Pharmaceutics, 70 , 159-166 (1991) and Watkinson, A., et al., I.
bid , 74, 229-236 (1991)).

[0005] Other absorption enhancers disclosed in the prior art include a mixture of linoleic acid and propylene glycol (European Patent Publication No. 261429), a mixture of N- (hydroxyethyl) pyrrolidone and methyl laurate, ethanol and Mixtures of glycerol monolaurate and mixtures of diethylene glycol monoethyl ether and propylene glycol monolaurate (U.S. Pat. Nos. 4,537,776, 4,764,379 and 4,973,468).

[0006] Further, as a dosage form for transdermal administration of a nonsteroidal anti-inflammatory analgesic, US Pat.
No. 527,832 discloses a gel-type composition comprising Poloxamer ™ as a gelling agent, and US Pat. No. 5,505,956 has a multi-layered structure and an adhesive in contact with the skin. It discloses a patch dosage form in which the water content increases from the conductive resin layer toward the upper layer. Also, U.S. Patent No. 5,656,286 discloses a simple matrix patch using polyacrylate as an adhesive.

[0007] Conventional transdermal dosage forms are divided into three types: storage, simple matrix, and multilayer. In particular, the simple matrix dosage forms disclosed in U.S. Pat. Nos. 4,314,577, 4,438,139 and 4,839,174 are dispersed in a substrate layer of a pressure sensitive adhesive. Including drugs. Although this dosage form can be easily manufactured at low cost, there is a problem that the drug release rate is initially high and decreases rapidly with time.

Therefore, there is a need for an improved formulation for transdermal administration of a substrate-type drug, in which the drug is released stably and at a high rate for a long period of time, and has a high content of non-crystallized drug. The present inventors have intensively studied to develop an improved composition for transdermal administration of a drug containing a new absorption enhancer capable of satisfying this demand, and as a result, individually as an absorption enhancer having a limited effect. When the known diethylene glycol monoalkyl ether and sorbitan ester are used as a mixture, a synergistic effect is exhibited, that is, the mixture of diethylene glycol and sorbitan ester has a remarkably excellent absorption promoting effect for transdermal administration of a nonsteroidal anti-inflammatory analgesic. To show the unexpected effect.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide an improved transdermal composition of a nonsteroidal anti-inflammatory drug.

[0010] Another object of the present invention is to provide a formulation for transdermal administration containing the composition.

According to one embodiment of the present invention, a therapeutically effective amount of a non-steroidal anti-inflammatory analgesic,
Provided is a composition for transdermal administration of a non-steroidal anti-inflammatory analgesic, comprising an absorption enhancer comprising a mixture of diethylene glycol ether and sorbitan ester, and a pharmaceutically acceptable sticky base.

[0012] The above and other objects and features of the BRIEF DESCRIPTION OF THE DRAWINGS The present invention will become apparent from the detailed description of the invention with the following drawings. FIG. 1 is a cross-sectional view showing the structure of a pharmaceutical preparation for transdermal administration of the nonsteroidal anti-inflammatory drug of the present invention. FIG. 2 shows the change over time in the cumulative amount of skin absorption of ketoprofen transmitted through human cadaver skin according to the composition of the absorption enhancer. FIG. 3 shows the time course of the cumulative amount of ketoprofen transmitted through human cadaver skin in an experiment using the preparation of the present invention and a commercially available dosage form.

[0013] The invention relates to non-steroidal anti-inflammatory agent, a mixture of diethylene glycol ether and sorbitan ester used as an absorption promoting agent, and non-steroidal comprise a pharmaceutically acceptable adhesive substrate Provided is a composition for percutaneous absorption administration of an anti-inflammatory analgesic.

Examples of nonsteroidal anti-inflammatory analgesics used in the composition of the present invention include ketoprofen, flurbiprofen, methyl salicylate, salicylic acid, ibuprofen, indomethacin, diclofenac sodium, flufenamic acid, naproxen, mefenamic acid, phenoic acid Mention may be made of profen, fenclofenac and pirocicam and mixtures thereof.

[0015] The amount of the non-steroidal anti-inflammatory analgesic used in the composition of the present invention is about 0.1 to 50% by weight, preferably about 1 to 20% by weight based on the total amount of the composition.

The absorption enhancer of the present invention contains diethylene glycol monoalkyl ether and sorbitan ester in a weight ratio of 1: 4 to 4: 1, preferably 1: 2 to 2: 1. Suitable diethylene glycol monoalkyl ethers for use in the present invention include diethylene glycol monoethyl ether and diethylene glycol monomethyl ether, and suitably sorbitan esters include sorbitan monolaurate and sorbitan monooleate.

The amount of the mixture of diethylene glycol ether and sorbitan ester used in the composition of the present invention is from 5 to 30% by weight, preferably from 5 to 25% by weight, based on the total amount of the composition. The weight ratio is adjusted within the above range.

The pharmaceutically acceptable adhesive substrates used in the present invention include those in the art such as polyacrylate adhesives such as ethyl, butyl and 2-ethylhexyl esters of acrylic acid, polyisobutylene and silicone rubber. Any of the known ones can be used.

The composition of the present invention may further contain a fragrance, a preservative, an antioxidant, a stabilizer and a dye.

A formulation for transdermal administration of a non-steroidal anti-inflammatory drug according to another embodiment of the present invention can be configured as follows: a protective layer impermeable to the non-steroidal anti-inflammatory drug A drug storage layer comprising the aforementioned composition of the present invention, one side of which is laminated on the protective layer; and a release layer adhered on the other side of the drug storage layer, the release layer being peeled off. And protect the composition from the surrounding environment until the drug storage layer is adhered to the skin.

The formulations of the present invention may further include auxiliary adhesives known in the art, such as, for example, an annular adhesive layer that is hermetically attached to the edges of the drug storage layer and the protective layer.

FIG. 1 shows a cross-sectional view of one embodiment of the preparation for transdermal administration of the present invention, which includes a release layer 1, a drug storage layer 2, a protective layer 3 and an auxiliary adhesive layer 4.

The preparation for transdermal administration of the present invention comprises a patch, a plaster, a pasta, a poultice, a gel,
It can be formulated in the form of an ointment or the like and applied to the skin for a desired period of time to obtain the desired blood concentration of the nonsteroidal anti-inflammatory analgesic.

The composition for transdermal administration of the nonsteroidal anti-inflammatory drug of the present invention has the following advantages: it can be manufactured at a low cost because it is a simple matrix type. The use makes it possible to maintain a high zero-order permeation rate of the drug for a long period of time: and by using the improved absorption enhancer, it is possible to suppress the crystallization even when a large amount of the drug is added. The amount of drug administered to a patient using the composition of the present invention can be controlled by adjusting the amounts of drug and absorption enhancer.

The following examples serve to illustrate the invention in more detail and do not limit the scope of the invention.

Measurement of Drug Permeability Through Skin The flow of a drug through a skin sample, or skin permeability (SPR), is measured by the following procedure.

[0027] The skin sample was prepared by cutting human cadaver skin or a skin fragment cut out from a 6-week-old hairless female mouse using a Valia-Chien diffusion cell (Crown Glas diffusion cell).
(USA), the stratum corneum was attached to the outside of the cell, and a preparation for transdermal administration containing one or more drugs was fixed on the skin. 3.4 ml of saline containing 40% polyethylene glycol 400 (Sigma Scientific Co.) was added to the cell and stirred during the experiment. Next, 100 μl of a physiological saline sample was periodically collected and subjected to high performance liquid chromatography to determine the cumulative amount of drug transmitted through the skin. The skin permeability of the drug passing through the skin was determined by regression analysis of the cumulative value (μg / cm ² / hr) of the drug over time.

The above procedure was repeated three times to determine the average SPR value of the drug.

Reference Example 1: Preparation and test of a composition for transdermal administration containing a conventional absorption enhancer (human cadaver skin ) 3.0% by weight of ketoprofen (KF) and an absorption enhancer having the composition shown in Table 1 below Is a polyacrylate adhesive (Durotack 87-2074, National Starch Chem. Co.
), And the mixture was stirred thoroughly so that the drug dissolved in the adhesive.

The obtained mixture is applied to an impermeable protective layer (Scotchpak 1109, 3M
Co.) and dried in an oven at a temperature ranging from 60 to 120 ° C. while gradually increasing the temperature in a range of 60 to 120 ° C. Was. After the obtained substance was air-dried for 1 hour, a release layer (Scotchpak 1012, 3M Co.) was laminated thereon. The preparation for transdermal administration thus prepared was stored at room temperature.

The permeability of the drug through human cadaver skin was measured, and the results are shown in Table 1 and FIG.

[0032]

TABLE 1 Permeability of ketoprofen to human cadaver skin in the presence of conventional absorption enhancers Note) ^* SPR: Permeability through skin (mean ± standard deviation (μg / cm ² / hr))

FIG. 2 shows the change over time in the cumulative value of skin absorption of ketoprofen transmitted through human cadaver skin according to the composition of the absorption enhancer.

As can be seen from Table 1 and FIG. 2, propylene glycol and lauric acid (Reference Examples 1-3) and sorbitan monolaurate and propylene glycol and polyvinylpyrrolidone (Reference Examples 1-4) are included as absorption enhancers. Although the composition showed high permeability, crystals and bubbles of the drug were observed in Reference Examples 1-3 and 1-4, respectively.

Example 1 and Comparative Examples 1-2 A transdermal delivery composition was prepared in the same manner as in Reference Example 1, except that 3.0% by weight of ketoprofen was used together with the absorption enhancer shown in Table 2. And tested.

As comparative controls, commercially available ketoprofen plaster Ketotop (trademark) (Pacific Pharmaceutical Co., Korea) (Comparative Example 1) and Kepentech (trademark) (Daiichi Pharmaceutical Co., Korea) (Comparative Example 2) Was used for each. The results are shown in Table 2 below and FIG.

[0037]

Table 2: Permeability of ketoprofen through human cadaver skin

FIG. 3 shows the time course of the cumulative amount of ketoprofen transmitted through human cadaver skin in an experiment using the formulation of the present invention and a commercially available dosage form.

As can be seen from Table 2 and FIG. 3, the composition of the present invention comprising a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 1) as an absorption enhancer, It showed about 2 to 4 times higher penetration than Examples 1 and 2.

Example 2 and Comparative Example 3 Two transdermal delivery compositions were prepared in the same manner as in Reference Example 1, except that 3.0% by weight of ibuprofen was used together with the absorption enhancer shown in Table 3. And tested. Table 3 shows the results.

[0041]

TABLE 3 Permeability of ibuprofen through human cadaver skin

As can be seen from Table 3, the composition of the present invention comprising a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 2) as an absorption enhancer was compared to Comparative Example 3. It showed significantly better penetration rates.

Example 3 and Comparative Example 4 Two transdermal delivery compositions were prepared in the same manner as in Reference Example 1, except that 3.0% by weight of flurbiprofen was used together with the absorption enhancer shown in Table 4. Articles were manufactured and tested. Table 4 shows the results.

[0044]

TABLE 4 Permeability of flurbiprofen through human cadaver skin

As can be seen from Table 4, the composition of the present invention comprising a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 3) as an absorption enhancer was compared to Comparative Example 4. It showed significantly better penetration rates.

Example 4 and Comparative Example 5 Two transdermal delivery compositions were prepared in the same manner as in Reference Example 1 except that 3.0% by weight of diclofenac was used together with the absorption enhancer shown in Table 5. And tested. Table 5 shows the results.

[0047]

TABLE 5 Permeability of diclofenac through human cadaver skin

As can be seen from Table 5, the composition of the present invention comprising a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 4) as an absorption enhancer was compared to Comparative Example 5. It showed significantly better penetration rates.

Example 5 and Comparative Example 6 Two transdermal delivery compositions were prepared in the same manner as in Reference Example 1, except that 3.0% by weight of naproxen was used together with the absorption enhancer shown in Table 6. And tested. Table 6 shows the results.

[0050]

Table 6: Permeability of nafloxene through human cadaver skin

As can be seen from Table 6, the composition of the present invention comprising a mixture of diethylene glycol monoethyl ether (TC) and sorbitan monolaurate (SML) (Example 5) as an absorption enhancer was compared to Comparative Example 6. It showed significantly better penetration rates.

Although the present invention has been described in connection with the above specific embodiments, those skilled in the art will be able to make various modifications and variations within the scope of the invention as defined by the appended claims. Of course, it can be changed.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view showing the structure of a preparation for transdermal administration of the present invention.

FIG. 2 shows the time course of the cumulative amount of skin absorption of ketoprofen transmitted through human cadaver skin according to the composition of the absorption enhancer.

FIG. 3 shows the time course of the cumulative amount of ketoprofen transmitted through human cadaver skin in an experiment using the formulation of the present invention and a commercially available dosage form.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/60 A61K 31/60 45/00 45/00 47/08 47/08 47/14 47/14 A61P 29/00 A61P 29/00 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, H, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Choi Jong Khun 302-222 Daejeon South Korea Mon Chor Republic of Korea 305-340 Daejeon, U-song, Dong-dong 388-11, Lucky Yong-lip 3 F-term (reference) 4C076 AA72 BB31 CC05 DD39 DD46 EE04 EE09 EE27 FF34 FF68 4C084 AA17 MA05 MA63 NA10 NA11 ZA081 ZB111 4C AA01 BC13 BC89 MA05 NA10 NA11 ZA08 ZB11 4 C206 AA01 DB20 FA33 MA05 MA83 ZA08 ZB11

Claims (13)

[Claims] 1. A non-steroidal anti-inflammatory comprising a therapeutically effective amount of a non-steroidal anti-inflammatory analgesic, an absorption enhancer comprising a mixture of diethylene glycol ether and sorbitan ester, and a pharmaceutically acceptable sticky substrate. A composition for transdermal administration of an analgesic. 2. The composition according to claim 1, wherein the mixing ratio of the diethylene glycol ether and the sorbitan ester is 1: 4 to 4: 1 by weight. 3. The composition according to claim 2, wherein the mixing ratio of the diethylene glycol ether and the sorbitan ester is 1: 2 to 2: 1 by weight. 4. The composition according to claim 1, wherein the diethylene glycol ether is diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, or a mixture thereof. 5. The composition according to claim 1, wherein the sorbitan ester is sorbitan monolaurate, sorbitan monoaurate or a mixture thereof. 6. The non-steroidal anti-inflammatory analgesic, wherein ketoprofen, flurbiprofen, methyl salicylate, salicylic acid, ibuprofen, indomethacin, diclofenac sodium, flufenamic acid, naproxen, mefenamic acid, fenoprofen, fenclofenac, pirocicam 2. The composition according to claim 1, which is a mixture thereof. 7. The composition of claim 1, wherein the amount of said drug is 0.1 to 50% by weight based on the total amount of the composition. 8. The composition according to claim 7, wherein the amount of said drug is 1 to 20% by weight based on the total amount of the composition. 9. The composition of claim 1, wherein the amount of said absorption enhancer is 5 to 30% by weight based on the total weight of the composition. 10. The amount of said absorption enhancer is from 5 to 25 based on the total amount of the composition.
10. The composition of claim 9, wherein the composition is in weight percent. 11. The composition of claim 1, wherein said tacky substrate is a polyacrylate adhesive, polyisobutylene or silicone rubber. 12. A protective layer; a drug storage layer containing the composition of claim 1, one surface of which is laminated on the protective layer; and a release layer adhered on the other surface of the drug storage layer. A formulation for transdermal administration of a nonsteroidal anti-inflammatory analgesic, comprising: 13. The preparation according to claim 12, further comprising an auxiliary adhesive layer.