JPS596287B2 - pharmaceutical formulations - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a transdermal absorption type pharmaceutical preparation that causes little skin irritation due to the drug used (and that provides sufficient medicinal efficacy even when the product is stored for a long period of time).

Recently, skin-adhesive pharmaceutical preparations are being used for the treatment of skin diseases such as wet examination, atopic dermatitis, and psoriasis.

This is due to the accuracy of the dosage, the fact that it does not stick to clothing, etc., and the ease of use.

Typical drugs used in such preparations are corticosteroids such as fludroxycortide, fluocinolone acetonide, glednisolone, and triamcinolone acetonide.

However, it has been pointed out that these steroids are highly effective, and that repeated use causes various side effects and that the skin becomes susceptible to infection by bacteria in the affected area.

Non-steroidal anti-inflammatory drugs have recently attracted attention as drugs that solve this problem.

Pendazac, Bufexamac, indomethacin, and the like have been proposed to be used as ointments.

In addition, it has also been proposed to incorporate the drug into a water-containing patch based on a water-soluble polymer, and into an oil-based gel patch based on a block copolymer rubber.

In addition to the above, other nonsteroidal anti-inflammatory drugs that have been described as being usable in the proposed patch include mefenamic acid, flufenamic acid, ibuprofen, ketoprofen, alclofenac, diclofenac, and flurbiprofen. be.

However, these nonsteroidal anti-inflammatory drugs include
It is difficult to uniformly disperse in the plaster base material because it is solid at room temperature, it irritates the skin because it has a carboxyl group in the drug molecule, and it is necessary to incorporate the drug into the plaster base material. requires a solvent to liquefy, crystallizes when stored for a long time even if liquefied and incorporated into a plaster base, has insufficient transdermal absorption, and has a low acute toxicity value. Currently, it has not been put into practical use due to various problems such as:

In view of the state of the prior art, as a result of intensive research, the inventors modified non-steroidal anti-inflammatory drugs and
We have discovered that the various problems mentioned above can be solved by combining this with a specific pressure-sensitive adhesive composition,
This is what led to this invention.

That is, this invention provides that a nonsteroidal anti-inflammatory drug that has a carboxyl group in its molecule and is solid at room temperature has a C number of 1 to 1.
It is uniformly blended into an acrylic pressure-sensitive adhesive layer that is esterified with 8 alcohols and is non-irritating to the skin, and one side of the adhesive layer has an adhesive that follows the application surface. The present invention provides a pharmaceutical preparation that is provided with a flexible member that does the following.

According to this invention, various problems caused by the use of non-steroidal anti-inflammatory drugs have been solved, including less skin irritation caused by the drugs, excellent storage stability, and high acute toxicity values. In this respect, it has a totally unexpected effect on this type of drug.

The nonsteroidal anti-inflammatory drugs used in carrying out this invention are those that have a carboxyl group in their molecules and are solid at room temperature, such as indomethacin,
Examples include flufenamic acid, aspirin, mefenamic acid, niflumic acid, diclofenac, ibuprofen, ketoprofen, alclofenac, alrbiprofen, ibufenac, and the like.

The alcohols used to esterify these drugs have a carbon number of 1 to 8, and the esterification of the drugs can be carried out by conventional methods.

The esterified drug derivative is blended into an acrylic pressure-sensitive adhesive composition that is not irritating to the skin, has excellent compatibility with the derivative, and does not cause crystallization.

Acrylic pressure-sensitive adhesive compositions satisfying such characteristics include n-butyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate,
(meth)acrylic acid esters such as isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate; Copolymerizable (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, methylaminoethyl methacrylate, methoxyethyl (meth)acrylate, etc. Acrylic compositions that are copolymers with functional monomers and/or vinyl monomers such as acrylonitrile, vinyl acetate, vinyl propionate are used.

Other examples include pressure-sensitive adhesive hydrogels made by blending water-soluble acrylic polymers such as polyacrylates and carboxyvinyl polymers with alcohols such as glycerin, crosslinking agents such as triglycidyl isocyanate, and water. Can be done.

The compounding amount of the drug derivative is about 10 to 2 per unit area.
000 μg is incorporated into the composition.

A penetration aid may further be added to the combination system of the drug derivative and the composition.

Penetration aids used in the practice of this invention refer to all substances that contribute to promoting the absorption of active drugs by the body surfaces to which they are applied, including As for its functions, it has a water retention function of the stratum corneum (skin), a function of promoting swelling or softening of the stratum corneum, a function of improving wettability of the stratum corneum, a function of opening pores, etc.

These multiple functions can often be obtained from a single substance.

Substances used as penetration aids include dimethyl sulfoxide, dodecyl sulfoxide, methyl octyl sulfoxide, dimethyl decyl phosphooxide, mono- or diethylacetamide, N-hydroxyethyl lactamide, dimethylacetamide, -N-dimethyldodecamide, dimethylformamide, toluic acid diethylamide, tetrahydrofurfuryl alcohol, tetrahydrofuran, sorbitol, dodecylpyrrolidone, methylpyrrolidone, urea, glycerin, diethyl adipate, squalene, squalane, acetylated lanolin, cetyl lactate, olive oil, Castor oil, dioctyl sebacate, ethoxylated stearyl alcohol, lanolic acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, liquid paraffin, petrolatum, amino acids, protease, benzyl nicotinate, ■-menthol, camphor,
Methyl salicylate, salokol, lauryl soda sulfate,
Sodium lauric acid, stearylglycerin stearate, higher fatty acid triglyceride, polyoxyl alkylene glycol, fatty acid mono (or di) ethanolamide,
Examples include, but are not limited to, ethylene glycol monoethyl ether, holoxypropylene alkyl ether, and higher alkyl sulfones.

It is preferred that the auxiliary agent is added to the formulation system in an amount of at most 50% by weight.

The paste containing the drug in this manner is formed to a predetermined thickness on a flexible member that follows the application surface.

Specific examples of the member include a film with a thickness of about 500 μm or less made of cellophane, cellulose acetate, polyester, flexible polyvinyl chloride, polyethylene, polypropylene, polyamide, polyvinylidene chloride, polyurethane, polyacrylic, etc. (with metal vapor deposited on the film surface) non-woven fabrics, woven fabrics, foams, etc., or laminated films or sheets thereof, preferably in a form that does not allow penetration aids to pass through or cause skin irritation or whitening. A material with a designed moisture permeability is used.

The features of this invention are specifically guaranteed by the examples shown below, and the notable facts include less irritation to the skin, good storage stability, and high acute toxicity value of the drug.

Example 1 Indomethacin is esterified using methyl alcohol to obtain liquid indomethacin methyl ester.

The acute toxicity value of the ester is 50 μ/22 ° of the raw material.
It is highly safe (tested using male mice).

On the other hand, 2-ethylhexyl acrylate: benzoyl peroxide (BPO): ethyl acetate = 95:5
:0.5 :25 (weight ratio) is polymerized by a conventional method to prepare a copolymer solution.

200% of the indomethacin methyl ester was added to the solution.
tt ft/ca, thickness 100μm
The pharmaceutical formulation of the present invention is obtained by applying the mixture onto a polyethylene film and drying it.

Example 2 Diclofenac is esterified using butyl alcohol to obtain liquid diclofenac butyl ester.

The acute toxicity value of the ester is 2.
It was as high as 20~/yu.

On the other hand, sodium polyacrylate (average degree of polymerization of about 200
00) A water-containing gel base material is obtained by heating and mixing nitriglycerin:water nitriglycidyl isocyanate-5:15:69:1.

200% of the diclofenac butyl ester was added to the base material.
μtlcrl polyoxyethylene (20)
Emulsify using sorbitan monolaurate 5% solution,
This is applied to a rayon nonwoven fabric and dried to gel the base material to obtain the pharmaceutical preparation of the present invention.

Table 1 shows the test results of Examples 1 and 2, and the comparative samples in the table are those in which the drug was blended in its original form in each Example.

Test method in Table 1 Skin irritation: Paste the sample on 8 rabbits for 24 hours.
After leaving the sample for a while, the sample was peeled off and the condition of the skin was observed after 1 hour and evaluated using the following scoring system.

The total score is divided by 8 to obtain the measured value.

1 point: No reaction, 2 points: 2 Slight erythema, 3 points: Very clear erythema, 4 points: Severe erythema, 5 points: Either blisters, edema, or necrosis.

Storage: Samples are stored alternately at 0°C and 50°C for one day at a time, and the crystallization state of the drug is observed after 30 days.

Carrageenin paw edema inhibition rate: After measuring the volume of the right hind paw of the rat, a sample piece (1×2 crIL) was attached to the right hind paw.

After 2 hours, the sample piece was removed, and 0.05rrLl of 1% carrageenan saline was subcutaneously injected into the same site.

The right hind paw volume was measured 3 hours after the carrageenin injection, and the difference from the right hind paw volume before the sample piece was attached was taken as the paw edema volume.

e −Vt Foot edema suppression rate (%) == X 100 c However, Vc and Vt indicate the average foot edema volume of the control group and the test sample group, respectively.

Adhesiveness: A sample was attached to the side of the upper arm of 10 panelists, and 24 hours later it was determined by self-view.

Treatment Examples 3 to 9 Esterified drugs as shown in Table 2 were treated with ethoxyethyl acrylate: 2-ethylhexyl acrylate:
Acrylic acid diBPO:ethyl acetate=20nia 7:3:0
．． 5:25 (weight ratio) was added to a copolymer solution polymerized by a conventional method so that the drug amount was 250 μf/cwt,
This is applied to a polyurethane foam film having a thickness of 1 mm and dried to obtain a pharmaceutical preparation of the present invention.

The acute toxicity values in Table 2 were tested on mice.

The symbols and measurement methods for test items in Table 2 are the same as in Table 1.

Claims (1)

[Claims] 1 Acrylic pressure-sensitive adhesive that is non-irritating to the skin and is made by esterifying a non-steroidal anti-inflammatory drug that has a carboxyl group in its molecule and is solid at room temperature with an alcohol having 1 to 8 carbon atoms. A pharmaceutical preparation that is uniformly blended in an adhesive layer, and one side of the adhesive layer is provided with a flexible member that follows the application surface.