JPS604125A - Plaster - Google Patents

Abstract

PURPOSE:A plaster having high adhesivity in spite of low tackiness, capable of containing and dispersing a large amount of a drug such as an anti-inflammatory agent, an antiphlogistic analgestic, etc., having high effect, obtained by laminating a plaster material consisting of a pressure-sensitive adhesive and a drug, having specific viscoelastic properties to a base sheet. CONSTITUTION:A plastic material consisting of a pressure-sensitive adhesive and a drug (e.g., anti-inflammatory agent, antiphologistic analgesic, coronary vasodilator, antasthmatic, etc.) is laminated into a base sheet (e.g., cloth, nonwoven farbic, etc.), to give a plaster. The plaster material has 2X10<4>-9X10<5>dyn/cm<2> dynamic shear modulus (G') at 10-100Hz frequency at 60-70 deg.C, 0.10-1.50 tandelta (lag angle), and 100-500g/15mm. intrinsic viscosity. The pressure-sensitive agent consists essentially of a copolymer of an acrylic acid ester, methacrylic acid ester, etc. It neither tears body hair no injures the skin, when peeling off and the drug is easily penetrated to the affected part, with high remedying effect.

Description

[Detailed description of the invention] TECHNICAL FIELD The present invention relates to patch medicines.

Conventional adhesive patches generally have too strong an adhesive force, and when removed from the skin, hair may be pulled out or even the epidermis may be removed, causing great pain and damaging the skin. There was a problem that the weaker If was, the more damage was left on the paste mark.

When looking at this from a compositional standpoint, 1. For example, in the case of acrylic adhesives, this is due to the fact that monomers that provide high cohesiveness and adhesiveness, such as acrylic acid and methacrylic acid, are copolymerized; Adhesives polymerized by excluding only such highly cohesive and adhesive monomer components from the system lose the balance of cohesive force, causing problems such as cohesive failure of the adhesive and residual residue when removed from the skin. .

Furthermore, even when the adhesive is not an acrylic adhesive (for example, a natural rubber adhesive), the same problem occurs because the adhesive strength is even greater than that of an acrylic adhesive.

This is because conventional adhesives are polymerized or compounded with emphasis on the interfacial adhesive properties of the surface layer of the adhesive layer, and adhesion to the skin relies solely on surface adhesive strength.

Adhesives may be used repeatedly on the same spot, so
(b) No rash or irritation to the application surface; (b) No displacement or peeling during application; (c)
It is necessary that the drug should not cause pain or damage to the skin surface when it is removed, and (d) the drug should be absorbed quickly into the skin9.

In view of these points, the present invention has a weak adhesive force that can adhere well to the skin surface and contains a large amount of drug.

The purpose of the present invention is to provide an adhesive patch having an adhesive layer having sufficient softness to allow diffusion and cohesive coverage enough to overcome its adhesive force.

The present invention will be described in detail below based on examples.

In the adhesive patch according to the present invention, a plaster consisting of an adhesive and a drug is laminated on a base sheet. The plaster is.

The vibration frequency is 10 to 10011Z and the temperature is 60℃ to 70℃.
C, the dynamic shear modulus (G') is 2. OX1
0″dyn/cnl to 9.OX 10’dyn
/cl+ value is shown.

In addition, the tan δ (delay angle) at this time is 0.10 to 1.50, and the inherent adhesive force is 100 g to 500 g/15.

The base sheet is, for example, a cloth base material, a nonwoven fiber base material, or a flexible brass latic sheet base material.

First, as a result of researching the relationship with adhesive strength, we found that in an index called specific adhesive strength,
15 I have come to the conclusion that it is necessary to be a dragon.

The specific adhesive strength here refers to an adhesive tape in which an adhesive tape is laminated to a thickness of 30μ (±5μ) on a polyester film having a thickness of 50μ, in accordance with JIS-24522 (normal adhesive strength). It is a value.

We investigated whether it would be possible to create an adhesive that adheres well to the skin despite having such a low adhesive strength value.
Results of exploring various polymers and formulations in relation to various physical properties.

We have discovered that the key lies in the properties of dynamic viscoelasticity. Therefore, its dynamic shear modulus (G') is 2-OX 10'fdyn/cJ to 9.0X10'dyn/c+a at a loading frequency of 10 to 100 Hz and a temperature of 60 to 70°C. within the range of, and.

tan δ is 0.10 to 1 in the same measurement condition range.
．． We have found that a range of 50 is optimal.

Here, the frequency was selected to be 10 to 100 Hz and the temperature was selected to be 60 to 70 degrees Celsius due to the correlation between the temperature of the object of use (human body), the mechanical condition range related to use, and the characteristics of the adhesive itself. The reason is from.

That is, the human skin temperature and the actual mechanical and time scale area applied to the plaster applied to the skin, when converted to its viscoelastic properties, are 6 at a frequency of exactly 10 to 100 Hz.
Corresponding to the temperature range of 0°C to 70°C, an adhesive with optimal physical properties has a G' value, tan
This region was set because both δ have relatively flat values.

Even if adhesives with such physical properties have weak adhesive strength, they can penetrate into every corner of small irregularities on the surface to be adhered to create a close bond, and their well-balanced elastic properties prevent them from slipping. The adhesive does not flow and has a low interfacial adhesive strength, so it does not peel off from the skin and causes great pain to the skin. No layer remains on the skin.

Adhesives with this physical property can easily encapsulate general drugs, and since they do not seal in the encapsulated adhesive, they can flow freely inside the adhesive layer and are not re-released onto the skin. .

It is also highly effective when absorbed into the skin.

The optimum range of G' value and tan δ is here determined empirically, and under such measurement conditions (frequency 10 to 10011z, temperature 60°C to 70°C), for example, G' is 9. OX greater than 10″’dyn.

If tan δ is smaller than 0.1, the adhesive becomes too elastic and hard, making it difficult to fluidly adhere to the skin surface, and at the same time, the low adhesive force value cannot be balanced. So.

It becomes easy to peel off from the skin. Also, in that case.

The drug gradually appears to be trapped in the adhesive, and its internal diffusivity and re-release properties become low. Conversely, Q + is 2. OX 10″dyn/
The adhesion of the adhesive improves when the value is smaller than the self and becomes larger than 50 months.

The condensability of the adhesive is too low, making it easy to shift or flow, and when it is peeled off, it loses its adhesive strength, leaving sticky lumps on the surface of the skin scraps. Adhesives with special properties can be obtained by polymerizing or copolymerizing acrylic acid alkyl esters and methacrylic acid alkyl esters.
Alternatively, they can be synthesized by copolymerizing them with other vinyl monomers. In that case, the component for promoting adhesion is an alkyl acrylate ester in which the alkyl group has 4 or more carbon atoms, and the component for increasing cohesive force while somewhat assisting in adhesion is an alkyl methacrylate ester having 8 or more carbon atoms. It is an ester, and the component that lowers adhesiveness and increases cohesive force is a methacrylic acid alkyl ester having 6 or less carbon atoms. Other vinyl monomers include 1, for example, diacetate I-
vinyl stearate, vinyl pyrrolidone, dimethyl acrylamide, vinyl acetate, vinyl propionate, etc. 9 As a monomer component for adjusting the adhesive strength essential to the present invention, vinyl stearate or vinyl stearate as a side chain may be used. An acrylic ester or a methacrylic ester having a stearyl group or the like can be synthesized and used.

Another group of compositions is tackifying resins such as styrene-isoprene-styrene or styrene-butadiene-styrene block copolymers 9-oil resins.

There are adhesive systems suitable for Botmelt coating, which are mainly composed of oils and fats and liquid softeners such as liquid paraffin. In particular, f& is suitable for applications such as anti-inflammatory analgesics that require thick application with high tlJI. In that case, in order to maintain the physical property range of the present invention and adjust the adhesive strength, a vinyl stearate polymer or copolymer, or IJI
! Acrylic ester or methacrylic ester having a stearyl group etc. via a urethane bond as the I chain [e.g. G)l, =CHCOO(CL)20NHCOC
, 'rl13v) and the like into this system.

The drugs used in the adhesive patch of the present invention include anti-inflammatory drugs, anti-inflammatory and analgesic drugs, coronary vasodilators, asthma drugs, tranquilizers, and the like.

Anti-inflammatory drugs include diclofenac, indomethacin, acemexin, and alclofenac.

These include fenbufen, tolmetin, mefenamic acid, flufenamic acid, aspirin, and ibuprofen.

As anti-inflammatory analgesics, methyl salicylate, glycol salicylate,! Menthol, d1 camphor.

Peppermint oil, chili pepper extract, nonylic acid vanylamide,
These include roth extract, diphenhydramine, etc.

Coronary vasodilators include nitroglycerin, isosorbite cinitrate, glycol cinitrate, triethanolamine trinitrate, pentaerythritol 4-nitrate, propyl nitrate, and the like. ' Asthma medications include ephedrine, prednisolone, epinephrine, and aminophylline.

As tranquilizers, fluphenazine, thioridacin,
Diazepam etc.

When using an acrylic adhesive in manufacturing a product, select the monomer components and their composition ratios so that the physical properties of the polymer after bipolymerization fall within the above-mentioned range, and polymerize by solution polymerization or emulsion polymerization. However, in the case of a solution, the drug is added as it is, or once dissolved in an easily soluble solvent and mixed, and in the case of emulsion polymerization, the drug is also made into an emulsion and then added to it. and mixed. A drug-mixed adhesive solution or emulsion can be used directly.

It is coated on a base material base, or it is once coated on a silicone-treated release paper, and after drying, it is pressed and transferred to a predetermined base material sheet. If the substrate base is a plastic film, both of the above steps are possible, but in the case of cloth or non-woven fabric, the transfer method is preferred.

On the other hand, when a solvent-free hot melt adhesive system is employed, the chemicals are heated and melted and mixed within a temperature range in which they do not decompose or volatilize. It is applied by the commonly known bot melt method. This is done by passing the sticky side mass through an extruder and heating it above its melting temperature.

It is applied directly to the base material at a predetermined thickness by passing it through the gap between two rolls or through a mold with slits, and after passing through a cooling roll, it is overlaid with silicone-treated release paper to produce a product.

Next, examples of the adhesive patch of the present invention will be specifically described.

<Example 1> Lauroyl methacrylate 25.4 g (0.10 mo
l) 2-ethylhexyl acrylate 128.8g (0,70
mol) Vinyl stearate 62.0 g (0.20 mol) Methyl ethyl ketone 50.0 g Ethyl acetate 50.0 g Toluene 40.0 g The above solution was maintained at 70°C under Nλ gas substitution.

0.7 g of the polymerization solvent azobisisobutyronitrile was dissolved in 100 ml of ethyl acetate and added over a period of 18 hours.

During this time, in response to an excessive increase in viscosity, a 1=1 mixed solvent of methyl ethyl ketone and ethyl acetate was added, and the temperature was then maintained at 78° C. for an additional 12 hours to complete the polymerization reaction. In this way, an adhesive solution with a polymer concentration of 31.8% was obtained.

Next, 6 parts by weight of diclofenac as an anti-inflammatory drug was added and mixed per 100 parts by weight of the polymer component of this solution.

From this adhesive paste solution, a small area sheet (approximately 5 cm diameter circle) with a thickness of about 1.2 mm was created by repeated casting and drying, and samples were cut from this sheet.

Using a viscoelastic spectrometer (manufactured by Maekata Seisakusho).

The dynamic shear modulus was measured at a vibration frequency of 5011z and a temperature of 65°C.

G'... 4.6 X 105dyn/cJta
nδ−0.59”.

Apply this adhesive paste solution to a polyester film with a thickness of 50 μm at a coating thickness such that the thickness after drying is 30 μm.
After drying, a tape-shaped sample with a width of 15 mm was taken and its adhesion strength was measured.

It was 374 g/15 cm.

Next, apply the same adhesive paste solution using a coating machine.

On silicone-treated release paper, the weight after drying is 100 cr.
It was coated and dried at 0.5 g per liter, and rolled up on a take-up roll while pressing and laminating a 70μ thick ethylene/vinyl acetate copolymer soft film as a material film.

An original adhesive sheet covered with release paper was obtained. A circular sample of 60 mφ was taken from this original sheet, and a IA (2
0℃, 65% RH) and after storage for 20 days at 65℃, remove the release paper and add 50ml of methyl alcohol.
1 at 30° C. for 3 hours, and the amount of the drug extracted into the solvent was comparatively quantified by liquid chromatography, and the conversion ratio was determined from the ratio with the calculated content value of the two elements.

91.4% re-release after 20 days at room temperature 83.5% re-release after 20 days at 70℃ showed a high standard.

This adhesive sheet was cut into approximately 5 cm square pieces and applied to the abdomen, and when observed 24 hours later, there was no movement or peeling, and no pain was felt when peeled off from the skin.

No adhesive residue was observed.

<Example 2> (Preliminary synthesis of monomer for adjusting adhesion) Dihydroxyethyl acrylate...34.8 g (0
, 30 mol) Octadecyl isocyanate...80.0 g (0
, 27 mol) Toluene...40.0 g The above solution was continuously stirred at 90'C under N2 substitution for 5 hours to obtain a solution of the adhesion adjusting monomer by addition reaction.

(Synthesis of adhesive) Solution after the above addition reaction Total 2-ethylhexyl acrylate 55.2 g (0.30 g
mol) Butyl acrylate 51.2 g (0.40 mol > ethyl acetate 70.0 g The above mixed solution was maintained at 75°C under Nλ substitution.

As a polymerization catalyst, 1.2 g of lauroyl peroxide was dissolved in 100 ml of hexane:ethyl acetate-1:1, and 20
It took time to put it in. Meanwhile, for excessive increase in viscosity,
Continue adding ethyl acetate.

The reaction was continued for 20 hours to complete the polymerization. In this way, a solution with a polymer concentration of 28.9% was obtained. Per 100 parts by weight of the polymer component of this solution, 2.0 parts by weight of pentaerythritol tetranitrate, which is a coronary vasodilator, was mixed and dissolved.

From this adhesive paste solution, by the same method as in Example 1,
A viscoelasticity measurement sample was prepared and its viscoelasticity was measured under the same conditions.

G'-6,7X I O'dyn/cJtan
δ...0.48 was obtained.

Next, in order to measure the inherent adhesive force, a sample was prepared by the same method as in Example 1, and the adhesive force was measured.

The specific adhesive strength was 296 g/1.51111.

Next, apply the same adhesive paste solution using a coating machine.

The weight after drying is 100 on silicone release paper.
Example 1
Using the same base film and winding up the laminate in the same manner as above, an original adhesive sheet was prepared. A circular sample of 60 m1φ was taken from this original sheet and left at room temperature for 20 days, and then sealed and packaged in aluminum foil and stored at 65°C for 20 days.

In 50 ml of water:ethyl alcohol-95:5.

The sample was immersed at 30°C for 24 hours, and the composition rate was determined from the amount of drug extracted into the solvent.

After 20 days at 20°C 82.2% After 20 days at 65°C 71.7% Furthermore, cut this adhesive sheet into approximately 5 cm square pieces.

The tape that was applied to the chest for 24 hours did not shift or peel off, and no pain was felt even if it was not removed. Further, no adhesive layer remained after peeling off.

<Example 3> Distilled water 450.0g Hydroxyethylcellulose 4.0g Sodium phosphate dibasic 3.0g Potassium persulfate 0.5g Emulsifier 6.0g Add this solution under N2 atmosphere and stirring.

258.0 g (1,4
mol) N-octylacrylamide 36.6 g (0.2 m
ol) Vinyl stearyl ether 59.2 g (0,2
1/4 of the mixed solution (mol) was added, stirred at 70"C for 1 hour, then raised to 75"C, stirred for another 1 hour, and the remaining mixed solution and...

Potassium persulfate 1.5g Water 30.0g and the aqueous solution at the same rate after 4 hours.

Furthermore.

Potassium persulfate 0.5g Water 1. After adding O and Og, the temperature was raised to 80°C and stirring was continued for 5 hours, after which the polymerization was completed. In this way, an emulsion with a solid content concentration of 44.7% was obtained.

Next, per 100 fii parts of solid content of this emulsion.

As a drug.

Heparin sodium 1.0@i part Water 10.0 parts by weight The solution was added and mixed to obtain an emulsion of adhesive paste.

A sample was prepared from this emulsion in the same manner as in Example 1,
Dynamic elasticity was measured under the same conditions (50i!z, 65°C).

G'"' 8. I X I Q'dyntanδ ・
...0.34 Next, in order to measure its inherent adhesive strength, a sample was prepared and measured using the same method as in Example 1, and the inherent adhesive strength was found to be 423 g/15u+.

Next, a coating machine is used to coat a non-plasticized soft polyvinyl chloride film (thickness: 90 μm) with a dry weight of 100 μm.
Directly apply and dry so that it is 0.5g per cJ,
Finally, roll up the silicone-treated release paper and
An original adhesive sheet with anti-inflammatory and anticoagulant efficacy was obtained.

This sheet was cut into approximately 3 cm square pieces and pasted on the abdomen, and even after 24 hours, it did not shift by one position, did not peel off, and even when it did not peel off, no pain was felt, and no adhesive residue was observed at all. There wasn't.

<Example 4> Monoglycol salicylate 10 parts by weight Methyl salicylate 3 parts by weight β-menthol 3 parts by weight B camphor 2 parts by weight Thymol 1 part by weight Diphenhydramine hydrochloride 1 part by weight Water 50 parts by weight Emulsifier 1.0 parts by weight Emulsification having the above composition The liquid was added to the emulsion obtained in Example 3 so that the solid content was 100 parts by weight.

By mixing, a water emulsion of an anti-inflammatory and analgesic adhesive paste was obtained.

A sample was prepared from this emulsion in the same manner as in Example 1, and its dynamic viscoelasticity was measured under the same conditions.

G'-9,2X10dyn/anttanδ...
・It was 0.93.

Next, in order to measure the inherent adhesive strength, a sample was prepared and measured using the same method as in Example 1.

Intrinsic adhesive strength was 282 g/15+n.

Next, as a base material, a filter cloth fabric that has been treated with a sealing undercoat is used, and a coating machine is used to reduce the weight after drying to 100 c.
After applying and drying 5g per J.

It was wound up with a silicone-treated release paper interposed therebetween to obtain a raw anti-inflammatory and analgesic pressure-sensitive adhesive sheet. When this sheet was cut into approximately 5 squares and applied to the upper back and back waist, it was found that the effect lasted for approximately 5 hours, and it was removed after 24 hours.

Peeling off caused very little pain, and even the thin epidermis was not peeled off, and no adhesive paste remained on the skin.

<Comparative Example 1> 2-Ethylhexyl acrylate...184g Ethyl acetate...200g This solution was maintained at 70°C under nitrogen substitution, and a solution of 0.8g of azobisisobutyronitrile and 100ml of ethyl acetate was mixed with 6 Adding ethyl acetate in case of excessive increase in viscosity caused by time-consuming addition, 4 hours after catalyst addition was completed, the temperature was raised to 78°C, and the polymerization reaction continued for another 8 hours to complete the polymerization reaction.
/% polymer solution was obtained.

This and the same drug as in Example 1 were added to the polymer component.
A viscoelastic test piece was prepared using the same method with the same proportions added, and its viscoelastic behavior was measured under the same method and two conditions.

G'・"1.4 X 10vdyn/cata
nδ...1.67.

From this adhesive solution, an adhesive sheet for measuring the inherent adhesive strength was prepared by the same method as in Example 1.

When this was measured, the inherent adhesive force was 469 g.

Next, an adhesive sheet for skin application was prepared using the same method as in Example 1 and applied to the skin using the same method as in Example 1. However, the position shifted during application and the adhesive oozed out around the skin.
More than 5 cranes were formed, and a thin adhesive layer remained after the test piece was peeled off. Therefore, it was judged to be unsuitable for medical purposes.

<Comparative Example 2> Isobutyl methacrylate 56.8 g Butyl acrylate 76.8 g Polypropylene glycol dimethacrylate 0.5 g Ethyl acetate 30.0 g The above solution was kept at 60°C under Nz gas substitution, and azobisisobutyl A solution of 0.4 g of ronitrile and 100 ml of ethyl acetate was added over a period of 24 hours, while ethyl acetate was added to prevent excessive increase in viscosity, and after adding the catalyst, ? FA degree 75
℃ and continued for another 8 hours to complete polymerization, concentration 19.2
% solution was obtained.

A viscoelasticity test sample was prepared from this solution by blending the same drug in the same amount as in Example 1, and the sample was measured.

G’-2,8xlOdyn/d tanδ...0.08 Met.

In addition, the inherent adhesive strength was measured using the same method as in Example 1.

Intrinsic adhesive strength...65g Met.

An adhesive sheet for skin application was prepared in the same manner as in Example 1, and when it was applied to the skin, it did not adhere unless it was strongly pressed several times.
In addition, natural side scree occurred within 12 hours, and it was judged that it could not be said to be highly practical.

<Comparative Example 3> Lauroyl methacrylate 63.5 g Acrylic acid-2
Ethylhexyl 138-0g Ethyl acetate 128.0
g The above solution was kept at 70°C under N2, and a solution of 0.1 g of azobisisobutyronitrile and 100 ml of ethyl acetate was added to
After adding the catalyst, while adding ethyl acetate in case of excessive increase in viscosity, the temperature was further raised to 78° C. and continued for 8 hours to complete the polymerization, yielding a polymer solution with a concentration of 24.6%.

The same drug was added to this solution using the same method and amount as in Example 1, and the viscoelasticity and intrinsic adhesive force were measured using the same method.
...0.42 Inherent adhesive force...781g.

A pressure-sensitive adhesive sheet for skin application was prepared in the same manner as in Example 1, and skin I9 was applied in the same manner.

I felt a lot of pain when I removed it from my skin.

In addition, it was observed that the skin surface caused slight redness, and it was judged that the product was not suitable for repeated use on the same area.

<Example 5. Comparative Examples 4 to 6> The composition shown in Table 1 was put into a high-temperature melting pot.

N-1, stirred and mixed at 150°C under substitution, and this was added to 11
Lower to 0℃.

A temperature-sensitive pumping agent consisting of 4 parts by weight of nonylic acid vanillamide and 4 parts by weight of hot pepper extract was added, stirred, and mixed to obtain an adhesive paste mass.

A sample was taken from this adhesive paste mass, a sample having the same shape as in Example 1 was prepared, and the dynamic viscoelasticity was measured. The results are shown in Table 1.

Next, take a part of this lumpy plaster and add ethyl acetate to make a solution with a concentration of 35%, and from this solution, use the same method as in Example 1 to prepare a sample for measuring the intrinsic adhesive strength. The intrinsic adhesive strength values were measured and shown in Table 1.

Next, from this lumpy adhesive paste, using a heated roll type coating machine, the thickness after cooling is 100C.
Hot melt coating was carried out so that the amount was 8.0g per J.
After cooling, it was wound up with a silicone-treated release paper interposed therebetween to obtain an original adhesive sheet for temperature-sensitive ships.

A pressure-sensitive adhesive sheet of about 5 cm square was cut from this original sheet and applied to the upper back and lower back.The state of adhesion was observed after 24 hours and is shown in Table 1.

Table 1 The adhesive patch of the present invention as described above has the following effects.

(i) The adhesive strength itself is low (suppressed), so when it is removed from the skin, it does not cause pain or damage the skin, and there is no or very little adhesive residue left.

(ii) The viscoelastic properties of the adhesive paste mass sufficiently compensate for its low adhesive strength, allowing it to adhere to the skin surface as if it were wet and exhibit excellent therapeutic effects.

No misalignment or peeling occurs.

(iii) Since the internal cohesive force is low (but not too low), many drugs can be included in high contents.

Moreover, since it is easy to internally diffuse, it is easily re-released and has a high therapeutic effect.

Applicant: Sekisui Chemical Co., Ltd. Representative Motoshi Fujinuma

Claims (1)

[Claims] ■) Consists of an adhesive and a drug, and has a vibration frequency of 10 to 100.
11z when the temperature is between 60℃ and 70℃. Dynamic shear modulus (G') is 2. OX 10 dyn
/C shi or 9. OX 10dyn/c (indicates direct force). At that time, tan δ (delay angle) is 0.10 to 1.5
1. A adhesive patch comprising a base sheet and a base sheet having an adhesive strength of 100 g to 500 g/15 ml. 2) The drug is an anti-inflammatory drug, an anti-inflammatory analgesic drug, a coronary vasodilator,
The adhesive patch according to claim 1, which is an asthma drug, a tranquilizer, or the like. 3) The adhesive mainly consists of acrylic esters, methacrylic esters, or copolymers of these and other vinyl monomers, or styrene, isoprene,
2. The adhesive patch according to claim 1, which mainly comprises styrene or a block copolymer of the styrene-butadiene-styrene type, a tackifying resin, and a plasticizing liquid.