JPS5823367B2 - Adhesive tape formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an adhesive tape preparation mainly used for treating integumentally diseased areas or areas remote from the administration site.

In general, for the treatment of external skin diseases, drugs are administered orally, in the form of injections, or in the form of ointments (or creams), and for the treatment of internal diseases of the human body, drugs are administered orally, in the form of injections, or suppositories. The method of administration is used.

However, when administering drugs orally or in the form of injections for local treatment of integumentary diseases, there are problems with side effects such as putting stress on internal organs, and ointment (or cream) type drugs may be rubbed off. There is a problem that the loss of drug and the amount of drug administered cannot be quantified.

Similar problems also exist in internal diseases, and there is a particular desire to eliminate side effects.

Recently, to solve these problems, tape preparations containing drugs in the pressure-sensitive adhesive layer have been proposed; Currently, the problem of difficulty in absorbing an effective amount of drugs through the skin remains unsolved due to the high barrier function of drugs.

The present invention provides a novel adhesive tape formulation that solves the problems of the prior art and a method for producing the same. Specifically, the present invention provides a novel adhesive tape formulation that solves the problems of the prior art, and specifically, a flexible carrier and a drug-containing pressure-sensitive adhesive formed on the carrier. The drug-containing pressure-sensitive adhesive layer consists of a pressure-sensitive adhesive layer in which a gap communicating with the layer surface is formed by an aggregate of particulate pressure-sensitive adhesive, and a drug or drug filled in the gap is dissolved and/or or a dispersed drug solution.

The adhesive tape preparation of the present invention will be explained in more detail from the following explanation, but it is configured such that a drug or a drug solution in which the drug is dissolved and/or dispersed directly contacts the application surface (the outer skin of the body). Furthermore, the contact point has an adhesive structure that cannot be freely changed from a fixed position.

The flexible carrier used in the present invention can be a plastic film (including foamed film), woven fabric or non-woven fabric.

A pressure-sensitive adhesive layer in which gaps communicating with the layer surface are formed by aggregates of particulate pressure-sensitive adhesive can be obtained, for example, by the following method.

That is, a (meth)acrylic acid ester alone or a polymerizable monomer copolymerizable with the esters is stirred and dispersed in water in the presence of a water-soluble polymer material or a sparingly soluble fine powder to stabilize it, resulting in so-called suspension polymerization. and the particle size is 0.0
A particulate pressure sensitive adhesive of 1 to 10 myn is obtained.

By applying this onto a carrier and drying it, a pressure-sensitive adhesive layer having gaps communicating with the layer surface can be obtained.

The materials used to obtain the particulate pressure sensitive adhesive mentioned above are as follows.

As the (meth)acrylic ester, those in which the number of carbon atoms in the ester residue is 14 or less, such as ethyl (meth)acrylate and butyl (meth)acrylate, are preferable.

Copolymerizable monomers include vinyl ethers such as isobutyl vinyl ether and octyl vinyl ether, vinyl esters such as vinyl acetate, α- or β-monoolefin carboxylic acids such as acrylic acid, methacrylic acid, itaconic acid, and maleic anhydride, and other styrene and acrylonitrile. , vinylpyridine, acrylic acid-2-hydroxyethyl ester and the like are preferred.

Preferred water-soluble polymer materials include natural polymers such as gelatin, starch, methylcellulose, and CMC, or polyvinyl alcohol, partially saponified polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, and vinyl alcohol copolymers.

As poorly soluble fine powder, BeSO4t CaSO4,B
aCO3CaCO3, MgCO3, Ca3(PO4)2
Salts such as, clay, talc, bentonite, inorganic substances such as silica, and other metals or metal oxides are preferred.

When making particulate pressure-sensitive adhesives using these materials, organic peroxides or azo compounds are used as polymerization catalysts, and divinyl compounds are used as external crosslinking agents.
Appropriate amounts of incyanate compounds, epoxy compounds, melamine, etc. are used.

Filling the gap in the pressure-sensitive adhesive layer with a drug or drug solution is done by absorbing the drug or drug solution into the adhesive layer formed in advance. It is also possible to add the drug or drug solution in advance and apply and dry it so that it does not volatilize, leaving the drug or drug solution in the gap.

The drugs used in the present invention are absorbed through the skin either alone or with the help of auxiliary agents described below, and examples thereof are as follows.

1) Anti-inflammatory steroids: e.g. fluocinolone, acetonide, betamethacin, betamethacin-17-ester,
Dexamethacin, beclomethasone propionate, triamcinolone, lobetadur dipropionate, etc.; 2) Non-steroidal anti-inflammatory analgesics: for example, indomethacin, diclofenac, flurbiprofen, ibufenac, phenylbutacin, fluzenamic acid,
3) Antihypertensive agents and antihypertensive diuretics: such as clonidine, reserpine, hydrothiazide, bendroflunathiadide, etc. 4) Tranquilizers: such as fluphenazine, thioridazine, diazepam, nitrazepam, chlorpromazine, etc. , 5) Hypnotic sedation: For example, phenobarbital, amobarbinur, cyfrobarbital, 6) Antibiotics:
For example, erythromycin, chloramphenicol, benzylpenicillin, cephalosporins, etc.; 7) Anesthetics, such as lidocaine, dibucaine, protylene, dipropylacetic acid, etc.; 8) Coronary vasodilators, such as dipyrytamol, nitroglycerin, insorbitol. nitrate, nifedipine, etc. 9) Antifungal agents: e.g. pentamycin, pyrrolnidoline, clotrimazole, etc. [0) Antiepileptic agents: e.g. mesolobamate, dipropylacetic acid, etc. Two or more of these drugs can be used together. It can also be used after being dissolved and/or dispersed in the following auxiliary agents.

Examples of auxiliary agents include alcohols and carboxylic acids having 2 to 22 carbon atoms, esters of mono- or dicarboxylic acids having 2 to 22 carbon atoms and alcohols having 2 to 10 carbon atoms, other alkylamides, polyethylene glycol, polyethylene. Preferred are copolymers of glycol and polypropylene gellicol, dimethyl sulfoxide, phosphinic acid, isopropyldecylphosphine, dimethylacetamide, and the like.

More detailed embodiments of the present invention will be made clear from the following examples.

Example 1 In a three-loaf flask equipped with a stirrer and a reflux condenser, 600 parts by weight of ion-exchanged water (hereinafter referred to as parts) and 0.5 parts of partially saponified polyvinyl acetate as a dispersant (water-soluble polymeric material) were placed. 1 and 2 parts, and thoroughly mix and dissolve the two.

A monomer mixture consisting of 200 parts of butyl acrylate, 6 parts of methacrylic acid and 0.2 parts of benzoyl peroxide is added to the resulting aqueous solution.

This formulation was heated under an inert gas atmosphere for about 1 hour (temperature 25
°C1 rotation speed 300111m) stir, then approx. 65 °C
Copolymerize by heating and stirring for 4 to 5 hours, and further
The temperature was raised to 0°C and the copolymerization was completed by heating and stirring for 2 hours.

The average particle diameter of the copolymer in the obtained copolymer dispersion was approximately Q, 5 mm.

Next, this copolymer dispersion is applied onto a release liner, rubbed with a knife, and dried with hot air to obtain a pressure-sensitive adhesive layer having gaps communicating with the layer surface.

This is then transferred to the treated surface of a polyethylene film that has been treated with corona discharge.

On the other hand, polyoxyethylene (1 stearyl ether 3
A drug solution is prepared by mixing 0 parts of diisopropyl adipate, 5 parts of diisopropyl adipate, and 8.1 parts of diclofenacundium.

Next, the drug solution is applied from the layer surface of the pressure-sensitive adhesive layer on the film and absorbed into the gap to obtain an adhesive tape formulation containing 250 μg of drug per d.

Example 2 A copolymer dispersion (average particle diameter of the copolymer is about 2.2 mm) is obtained using the following formulation in the same manner as in Example 1.

Ion exchange water 600 parts Polyvinyl alcohol 0.3 parts (saponification degree 78
5 to 81.5%) 2-ethylhexyl acrylate 200 parts N,N-diethyl methacrylate 14 parts aminoethyl α,α'-azobisisobutyronitrile 0.2 parts Next, the dispersion was prepared in Example 1. A pressure-sensitive adhesive layer having a gap communicating with the layer surface is formed on the polyester film surface by a similar operation.

On the other hand, a drug solution is prepared by mixing 20 parts of isostearyl alcohol, 10 parts of diethyl sebacate, 5 parts of polyethylene oxide-polypropylene oxide block copolymer, and 0.24 parts of beclomethasone propionate.

Next, the drug solution is applied from the surface of the pressure-sensitive adhesive layer on the film and absorbed into the gap to obtain an adhesive tape formulation containing 10 parts g of drug per d.

Example 3 A copolymer dispersion liquid (average particle diameter of the copolymer: about 1.0m) was obtained using the following formulation in the same manner as in Example 1.

Ion exchange water 600 parts Polyvinyl alcohol 0.4 parts (saponification degree 883
%) Isooctyl acrylate 200 parts Acrylic acid 10 parts Lauryl peroxide 0.2 parts Ethylene glycol dimethacrylate 0.05 parts Next, the dispersion was treated in the same manner as in Example 1 to form a gap in the polyethylene film surface that communicates with the layer surface. Form a pressure-sensitive adhesive layer having a

Meanwhile, a drug solution is prepared by mixing dibutyl sebacate, diisopropyl adipate, 5 parts of polyethylene glycol (15) stearyl ether, and 16.2 parts of nitrazepam.

Next, the drug solution is applied from the surface of the pressure-sensitive adhesive layer on the film and absorbed into the gap to obtain an adhesive tape formulation containing 100 μg of drug per d.

Next, the test results of Examples 1 and 2 are shown in Table 1.

Test method in Table 1 Male Rice Couple rats (10 rats per group, weight 180-2
01), shave the hair on the back in advance and leave it for 24 hours.

Attach two sample pieces (2c/rt x 2 warm angles) and two control pieces (drug-free tape) to this area, and
Peel off after some time.

Next, 0.1 ml of 0.5% carrageenan saline was intracircularly injected into each of the peeling marks of the sample piece and the control piece, and the same amount of physiological saline was injected into each of the remaining pieces.

After 4 hours, the animal was killed by dislocating its cervical vertebrae, and its skin was removed.
n7IL was cut out, the weight of the skin was measured, and the iron edema inhibition rate was calculated using the following formula.

-1- (where Ws and Wt indicate the weight of the site where physiological saline solution and carrageenan physiological saline solution were injected subcutaneously, respectively.

) Next, the test results of Example 3 are shown in Table 2.

Test method in Table 2 The abdomen of DD mice (10 males per group) was depilated, and a sample piece (2 crrL x 2 crIL square) was placed in this area of one group.
A control piece was attached to the other group, and a blink reflex test was conducted 10 minutes later.

Example 4 The particulate copolymer dispersion used in Example 2 (with a solid content of 26
．． (adjusted to 2%) 100 copies with 1.
31 parts of diethyl sebacate 2.62i1 and 0.301 parts of clonidine as an anti-hyperpressure agent were added and mixed and formed into a polyester film (thickness 25μ) with a thickness of 1 mm. Obtain an adhesive tape formulation containing the following.

When this preparation was applied to the back of a spontaneously hypertensive rat (sample size: 2CIrL x 2cIrL) and observed, the blood pressure lowering effect as shown was obtained.

Example 5 The particulate copolymer dispersion used in Example 2 (with a solid content of 26
．． (adjusted to 2%) to 100 parts, lidocaine 0.2
Add 62 parts dissolved in an appropriate amount of alcohol little by little and mix uniformly. Apply this to the surface of a polyester film (thickness 25μ) so that the thickness after drying is 0.5ffi7g, and dry it. Obtain an adhesive tape formulation containing 500 μs of drug.

The test results of Example 5 are shown in Table 3.

Pharmacological test method in Table 3: Hair was removed from the back of a guinea pig (weight 300-350 g) on the previous day, and the exposed area was poked with a needle to confirm that there was irritation.
rL size, and pasted the hair-removed area on one side of the midline of the vertebrae.After 1 hour, the test piece was taken out and stimulated with a needle 6 times at 3-5 second intervals, and if there was no skin reaction. Find the number of times.

For the blank, the opposite side to which the test piece was attached was stimulated in the same way.

(Five animals were used.

)

[Brief explanation of drawings]

The drawing shows the test results for blood pressure lowering in Example 4 of the present invention.

Claims (1)

[Claims] 1 Consisting of a flexible carrier and a drug-containing pressure-sensitive adhesive layer formed on the carrier, the drug-containing pressure-sensitive adhesive layer has gaps communicating with the layer surface formed by aggregates of particulate pressure-sensitive adhesive. An adhesive tape preparation comprising a pressure-sensitive adhesive layer and a drug filled in the gap or a drug solution in which the drug is dissolved and/or dispersed.