JPH0368512A - Cataplasm - Google Patents

Abstract

PURPOSE:To obtain a cataplasm having excellent lenitive and antiphlogistic action without reducing effect of a medicine even after storage for a long period of time by using saponified polymer of ethylene-vinyl acetate copolymer satisfying specific condition as fiber material for base cloth of the cataplasm. CONSTITUTION:The surface layer of fiber aggregate (e.g. nonwoven cloth) containing >=10% fiber composed of saponified ethylene-vinyl acetate copolymer containing 25-70mol% ethylene and having >=95% degree of saponification, 0.05-0.15l/g intrinsic viscosity [eta] and <=5 denier single fiber denier is coated with vegetable oils (e.g peppermint oil) dissolving and dispersing non steroid- based endermatic lenitive and antiphlogistic agent to afford the aimed cataplasm. The non steroid-based endermatic lenitive and antiphlogistic agent is selected from ketoprofen, indomethacin, flurbiprofen, methyl salicylate, diclofenac and ibuprofen menthol.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a patch that has excellent analgesic and anti-inflammatory effects without decreasing its medicinal efficacy even after long-term storage.

[Conventional technology]

Many inflammatory pain diseases, such as arthritis, myositis, and keyitis, occur locally and relatively close to the body surface. Therefore, if it is possible to absorb non-steroidal anti-inflammatory drugs transdermally and obtain high drug distribution in the bloodstream and in the inflamed area, it would be possible to achieve high local efficacy and prevent gastrointestinal disorders that often occur when applied systemically. It is expected to reduce the side effects of

Currently, ointments containing non-steroidal anti-inflammatory drugs are being evaluated for their usefulness in the treatment of orthopedic diseases because they are safer than oral preparations and because they are easier to administer to the joints of the extremities. However, due to the characteristics of the formulation, ointments cannot be said to fully meet the objectives in terms of uniformity of dosage, stability of the formulation after administration, or persistence of drug efficacy.

Another preparation that is expected to have the same effect is a patch.

This is generally in the form of a poultice, in which an ointment is applied to one side of a piece of cloth, and compared to ointments, it has superior formulation stability, uniformity of dosage, and long-lasting medicinal effect. It is a formulation that

However, the medicinal efficacy of conventional patches often decreases compared to the initial state when the storage period is long before actual use, and the efficacy of conventional patches often decreases during actual use. However, there was a problem in that the medicinal efficacy decreased significantly when the usage time became long. Particularly in recent years, synthetic fibers such as polyethylene terephthalate fibers have been increasingly used as base fabrics for pasting and opening, and the above-mentioned problems have often occurred.

[Problem that the invention seeks to solve]

Therefore, the object of the present invention is to obtain a patch that has excellent analgesic and antiinflammatory effects that do not reduce its medicinal efficacy even when stored for a long period of time. The present inventors have diligently studied what kind of structure and what requirements should be adopted for a patch for such purposes, and as a result, they have arrived at the present invention.

[Means to solve the problem]

The present invention has an intrinsic viscosity [η) of 0.05 to 0.15 t/y.
, to a fiber aggregate surface layer containing 10% or more of fibers made of a saponified ethylene-vinyl acetate copolymer having a single fiber denier of 5 denier or less, an ethylene content of 25 to 70 moles, and a saponification degree of 95φ or more; This patch is coated with vegetable oil in which a non-steroidal transdermal analgesic and anti-inflammatory agent is dissolved and dispersed, and has excellent analgesic and anti-inflammatory effects without decreasing its medicinal efficacy over time.

As the non-steroidal transdermal analgesic and anti-inflammatory agent used in the present invention, basically all drugs currently recognized to be effective as non-steroidal anti-inflammatory analgesics can be used. Among them, ketoflofen, indomethacin, flurbiprofen, methyl salicylate,
Diclofenac and ibuprofe≠Shishio are effective drugs.

For example, to explain in detail a few of the above drugs, flurbiprofen has a prostaglandin 7
(prost, aglandine) biosynthesis inhibitory effect, vascular permeability increase inhibitory effect, leukocyte migration inhibitory effect, protein thermal denaturation inhibitory effect, cell membrane stabilizing effect, and bradykinin release inhibitory effect. It is thought that powerful anti-inflammatory and analgesic effects are exerted by these actions working cooperatively in the inflamed area. Transdermal non-steroidal anti-inflammatory using flurbiprofen; painkiller is 198
It was approved on March 29, 2008, and three products are currently on the market: Atofeed J, Zebolus, and Stayvan.

Indomethacin is also a non-steroidal anti-inflammatory and analgesic agent, and the mechanism of action of indomethacin, which is currently recognized as the most effective substance, is to inhibit prostaglandine 7 biosynthesis and to inhibit vascular permeability. It is said to be involved in the following actions: inhibiting leukocyte migration, inhibiting protein thermal denaturation, stabilizing cell membranes, and inhibiting bradykinin release, and these actions work cooperatively at the inflamed local area. It is thought to exert strong anti-inflammatory and analgesic effects. Since the manufacturing approval of indomethacin gel in 1980, it has been in the spotlight as it has been used as oral preparations, injections, and suppositories1. Indomethacin was approved on March 29, 1988, and three types of products are currently on the market: ``Katletubu'', ``Indomethin Kowa Pap'', and ``Inside Pap''.

Another representative drug is ketoprofen, which is thought to have a similar mechanism of action to indomethacin, and is increasingly used. Ketoprofen was approved on March 29, 1988, and three types of products are currently on the market: "Morus,""Mirtax," and "Kefina."

Among the above non-steroidal transdermal analgesic and anti-inflammatory agents, only one type may be used, or two or more types may be used in combination.

Usually, one type of drug is sufficient to exert its medicinal effect.

Generally, patches have a structure in which a mixture of drugs and drugs is applied to a base fabric made of fiber aggregates, and a release paper is pasted on top of the base fabric, but in recent years, synthetic fibers such as polyethylene terephthalate have been increasingly used as the base fabric. Since it came into use, it has been observed that the medicinal efficacy of the patch often decreases when it is stored for a long period of time.

As a result of intensive research into the cause of this problem, the present inventors have found that a major factor lies in the base material applied together with the drug. The vegetable oils used to dissolve the drug are absorbed into the fibers while the patch is stored for a long time, and the amount of effective drug gradually decreases. I understand. Therefore, the present inventors have clarified what kind of fiber material should be used in order to suppress such phenomena that have a negative effect on the medicinal efficacy.

The vegetable oils mentioned here are those that dissolve drugs,
A medium for applying to a fiber base fabric together with other base materials for adhesion to the skin, such as gelatin mixed with titanium oxide, and skin surface infiltrating agents, such as glycerin. Ahies oil, amyris oil, angelica oil, amprettondo oil, ylang ylang oil, Ko 1/
i oil, oak moss oil, onitsha oil, origanum oil, orris oil, cantan oil, cananga oil, chamomile oil, cypress oil, calamus oil, galbanum oil, guaiacu wood oil,
Grapefruit oil, costus oil, azalea oil, citronella oil, jasmine oil, ginger oil, sweet orange oil, styratux oil, spearmint oil, cedarwood oil, geranium oil, davana oil, tansy oil, turpentine oil, tuberose flower essential oil, Neroli oil, pine oil, patchouli oil, honeysuckle oil, vanilla oil, balsam/cobaiba oil, balsam toru oil, balsam/peru oil, harmarosa oil, hirutup oil, bitter almond oil, bitter orange oil, hiba oil, vetiver oil, Peppermint oil, Pennyroyal oil, Perilla oil, Belcamot oil, Benzoin oil, Bois de Rose oil, Aromatic oil, Mandarin oil, Eucalyptus oil, Lavandin oil, Lavender oil, Lemon oil, Lemongrass oil, Rose oil, Rosemary Natural vegetable oils such as oil, and synthetic compounds that imitate the main components of these natural vegetable oils, such as terpene hydrocarbons such as α-pinene, β-pinene, camphene, limonene, myrcene, β-caryophyllene, linalool, keraniol, nerol, citronellol,
Lavender oil, myrcenol, α-terhineol, Z
-,! Terpene alcohols such as ntol, borneol, nopol, inbornyl clohexanol, farnesol, nerolitol, santaol, cedrol, baculi alcohol, benzyl alcohol, phenethyl alcohol, γ-phenylglopyl alcohol, cinnamon alcohol, anth alcohol , d-α-dimethylphenethyl alcohol, α-phenylethanol, β-phenylethyldimethylcarbinol, phenoxyethanol, Bachon, etc. +7) Flucol, Cyphenyletherin safroeukenol, p-methylanilyl, Anethole, Eugenol, In Phenols and their derivatives such as eugenol, methyleugenol, methylisoeugenol, benzylisoeugenol, safrole, insafrole, methyl-β-naphthyl ether, ethyl-β-naphthyl ether, heptanal, octanal, nonanal, decanal, undecanal, dodecanal , 2-methylundecanal, tridecanal, tetradecanal, hexadecanal, trans-2-hexenal, aliphatic aldehydes such as 2,6-nonajenal, citral, citronellal, hydroxycitronellal, perilaldehyde, citronellyloxy Acetaldehyde, terpene aldehydes such as Lyral and Sinensal, benzaldehyde, phenylacetaldehyde, 3-phenylprohionaldehyde,
cinnamaltehyde, α-amyl cinnamaldehyde,
α-hexylcinnamaldehyde, anisaldehyde,
Aromatic aldehydes such as dialdehyde, biperonal, cyclamen altehyde, p-t-fur-α-methyldihydrocinnamaldehyde, vanillin, pulbonal, citral methyl acetal, citral diethylacetal, hydroxycitronella dimethyl acetal, phenyl Acetaldehyde dimethyl acetal etc. Acetal a, 2-to7'tanone, 3-octanone, 2
- Aliphatic ketones such as octanone and 2-undecanone, terpene ketones such as carvone, menthone, and prevone, p-methylacetophenone, p-methoxyacetophenone, benzophenone, benzylideneacetone, anisylacetone, p-hydroxybenzylacetone, 2-acetonaphtone, etc. Aromatic ketone, α-β-γ-ionone, α-n1
β-n1 γ-n methylionone, α-β-γ-yne methylionone, α-β-1γ-ilone, α-β-damascenone, α-β-γ-damascone, theaspiran, theaspiran, ezran, rosefuran, Nootkaton, α
- Vetivone, cis-jasmone, dihydrojasmone, methyl jasmonate, methyl dihydrojasmonate, jasmine lactone, aldol, cyclotene, furaneol, etc. Alicyclic ketone alicyclic ether, alicyclic lactone, muscone, civetone, cyclopentadeca Non,
Cyclopentadecanolide, ampretlide, cyclopentadecanolide, ethylene brasilard, 12-oxahexadecanolide, 11-oxahexadecanolide, 1
Macrocyclic ketones such as 0-oxahexadecanolide, lactones, musk xylene, musk ketones, musk amplets, Mosken, Celestrite.

Synthetic musks such as fantolide, tonalide, and polakirylide, cyclic ethers such as rose oxide, oxide ketone, linalool oxide, l,8-cineole, vinclodihydrohomofarnesyl oxide, indole,
Skatole, 6-methylquinoline, 7-methylquinoline, 6-impropylquinoline, 2-methyltetrahydroquinoline, 6-methyltetrahydroquinoline, 2-4butylthiazole, 2-furylmethanethiol, 2-methylpyrazine, 2, 5-dimethylpyrazine, 2,3,5
-Heterocyclic compounds such as trimethylpyrazine, esters of aliphatic acids such as geranyl formate, benzyl formate, ethyl acetate, geranyl acetate, methyl benzoate, inlar benzoate, ethyl anisate, methyl salicylate, methyl cinnamate, etc. Aromatic It is a synthetic vegetable oil consisting of a mixture of esters of group acids, etc.

This will be explained by taking peppermint oil, which is typically used, as an example. Various polymers were made into films and tested for their permeability to menthol, the main component of peppermint oil. As a test method, various plastic films 1
A 5-25 μm thick bag was made into a 5×10 − pouch, filled with menthol 12, and sealed with di-impulse sealer. Each sachet was placed in a 250 cc deodorized glass bottle, and the time spent in the smelly trench was measured. As a result, while polyethylene terephthalate, polycarbonate, polyethylene, etc. start to smell in glass bottles within a week, saponified films of ethylene-vinyl acetate copolymer do not smell even after two weeks or more. It can be seen that it has excellent barrier properties without causing any discomfort. This ethylene-
It can be said that the present invention was discovered by utilizing the oil-resistant properties of a saponified vinyl acetate copolymer.

That is, an important point of the present invention is to use a saponified ethylene-vinyl acetate copolymer (hereinafter abbreviated as EV and AL) as the fiber material for the base fabric on the application side. E
Although it is of course possible to obtain fibers made of VAL alone, it is difficult to perform fiberization while maintaining a certain degree of fiberization processability unless a fiber with an appropriate intrinsic viscosity is used. The intrinsic viscosity [η] needs to be in the range of 0.05 to 0.15 A/f. The intrinsic viscosity described here was measured using an Ostwald viscometer at 30°C using an 85-hydrous phenol solution prepared with phenol (35 wt%) and 15 wt% distilled water. [η] was 0. .05
If it is less than 1, the melt viscosity is low and the spinnability and drawability are poor. In particular, the stretchability is poor, single fiber breakage and yarn breakage occur frequently, and the strength of the obtained fibers is low, which is not desirable. When [η] exceeds 0.15, the melt viscosity becomes too high, resulting in extremely poor spinnability when draft is applied during spinning, resulting in frequent yarn breakage, which is undesirable.

EVAL has a high saponification degree of 95 or more and an ethylene content of 25 to 70 moles, that is,
The optimal one is one with a vinyl alcohol component of 30 to 75 moles. When the vinyl alcohol component content in EVAL becomes low, the oil resistance against vegetable oils decreases due to a dramatic decrease in hydroxyl groups (OH), as will be discussed in detail later.
It is not possible to obtain the desired durability of good medicinal effects and it is not suitable. Furthermore, if the content of the vinyl alcohol component becomes too large, the melt moldability decreases, and when it is made into fibers, the spinnability becomes poor, and single yarn breakage and yarn breakage occur frequently, making it undesirable. In particular, during melt molding, gel-like substances are generated in the line, which often causes druffles, which is a problem. Therefore, it can be said that a fiber having a high densitivity [EVAL] and a vinyl alcohol component content of 30 to 75 moles is suitable for obtaining the desired fiber.

Dimensions. EVAL is produced by saponifying copolymerization of ethylene and vinyl acetate using a caustic powder, and the degree of saponification at this time is preferably 95% or more. When the degree of saponification decreases, not only does the crystallinity of the polymer decrease, resulting in a decrease in fiber properties such as strength, but also problems occur during the processing process as the polymer tends to soften, and the resulting fiber structure deteriorates. The texture of the item is also bad and it doesn't look good. Furthermore, oil resistance is also significantly reduced, resulting in a reduction in the desired effects of the present invention.

Further, the single fiber denier is preferably 5 denier or less. 5
It was found that when the denier was exceeded, it felt uncomfortable when it came into contact with the skin as a base fabric on the application side, had a hard texture, was unsuitable, and was prone to tearing.

To explain the conditions for fiberization of EVAL, the predetermined [η
] Melt extrusion of EVAL pellets at 230-260℃
Approximately 1000 m
It is wound at a spinning speed of around 7 tnin, and then in the case of filaments, the roller plate is stretched under heating conditions of 50 to 90°C, and in the case of staples, the water bath is heated at 50 to 90°C.
Good quality fibers can be obtained by drawing at a temperature of .

The obtained fibers are then produced in the form of various fiber aggregates required depending on the purpose. A fiber aggregate may be prepared using 100 g of the fibers, but the effects of the present invention can also be obtained by mixing other fibers. However, it is natural that the effect obtained will decrease if the blending ratio of the fibers becomes less dense, so it is preferable to maintain it at 4J, 10% or more! Lion.

The fiber aggregate may be in any form such as nonwoven fabric, knitted fabric, or woven fabric, but nonwoven fabric is optimal in terms of cost.

Next, the present invention will be specifically explained using examples.

[Example 1] Using a saponified ethylene-vinyl acetate copolymer with a degree of saponification of 99 and an ethylene content of 32 moles and [η] of 0.099, it was melt-extruded with an extruder and a spinneret of 260 °C
At the bottom, the spun yarn was discharged from the spinneret and wound up at a winding speed of 1000 m/min to collect the spun yarn. Thereafter, the obtained spun yarn was subjected to roller plate stretching approximately 2.5 times under the condition that both the roller plate and the roller plate were at 55° C. to obtain a drawn yarn having a 75 denier 24 filament single yarn denier and approximately 3 denier.

Next, a knitted fabric is created using a conventional method, and further processed according to a conventional method to obtain a fabric with a fabric weight of approximately 100? / m' knitted fabric was obtained.

A 5% peppermint oil solution of indomethacin was applied to the surface of the knitted fabric together with other bases such as gelatin, titanium oxide, and glycerin, and a patch was prepared under conditions such that 70η of indomethacin was applied to 12 of the weight of the knitted fabric. A storage test was conducted with release paper pasted on the surface. Thereafter, the concentration of indomethacin applied was estimated from a calibration curve by measuring the absorption intensity at a wavelength of 319nrn in the ultraviolet absorption spectrum over time, and the remaining amount was measured. The results are shown in Table 1, and no decrease in the amount of the applied drug over time was observed. Regarding the effectiveness of the patch as a rolled patch, it was tested on 10 men and women, and the medicinal efficacy was found to be good.

[Comparative Example 1] A polyethylene terephthalate polymer was spun and drawn in a conventional manner to obtain a drawn yarn of 24 filaments of 75 denier. Thereafter, a knitted fabric having a perforation of approximately 1002/m' was prepared by a conventional method, and used as a patch layer base fabric. Thereafter, a drug and a base were applied under the same conditions as in Example 1, and a leaving test was conducted with a release paper pasted on the surface. The results are shown in Table 1, and it was observed that the amount of the applied drug decreased over time, which indicates that the amount of the drug applied to the fiber base fabric progressed and the effective amount of the drug on the coated surface decreased. was estimated. Even in actual use tests, it was observed that the medicinal efficacy decreased over time.

[Comparative Example 2] A polyglobylene polymer was spun and drawn by a conventional method to obtain a 75
A drawn yarn having a denier of 24 filaments was obtained. After that, the area weight is about 100? A knitted fabric of /m' was prepared and used as a base fabric for the application side. Thereafter, under the same conditions as in Example 1, a drug and a base were applied, and a release test was carried out with a release paper pasted on the surface. The results are shown in Table 1, and it was observed that the amount of the applied drug decreased over time, which indicates that the amount of the drug applied to the fiber base fabric progressed and the effective amount of the drug on the coated surface decreased. was estimated. ! In addition, in actual use tests, it was observed that the medicinal efficacy decreased over time.

Note 1) 10 men and women conducted a usage test, and the number of people who recognized the effectiveness of the medicinal effect [Examples 2 to 4] Example 2 has an ethylene content of 48 moles, [η) o, os.

t/y, Example 3 has an ethylene content of 27 moles,
[η) 0.1.14 t/f was used in Example 4, and the ethylene content was 44 mol, [η 10.094 t/f], and the rows were conducted in the same manner as in Example 1.

In either case, no decrease in the amount of applied drug over time was observed. In addition, as for the effect as a patch, actual test results showed that the medicinal effect was good.

[Examples 5 to 7] Using the same polymer as in Example 1, it was discharged from a nozzle heated at 260°C, and spun yarn was collected at a winding speed of 1000 m/min. Thereafter, the obtained spun yarn was drawn at a water bath temperature of 65°C, and then the shrinkage was reduced by 55°C at a water bath temperature of 80°C.
A drawn yarn was obtained. Then, it was mechanically crimped in a conventional manner, and then a general oil agent was applied to it at a concentration of Q, l wt%, and it was subjected to relaxation heat treatment at 100°C for 15 minutes, and then 5 minutes.
It was cut into lengths of 1' to obtain raw cotton with a single yarn denier of 2.0.

Then, a binder fiber (■Kuraray Nfit N-720) 2 denier x 51 fibers containing polyethylene terephthalate as a core component and copolymerized polyester as a sheath component was prepared in Example 5.
After mixing 20% cotton, 50% cotton in Example 6, and 70% cotton in Example 7, a web of 100 f/m' was prepared, and then hot air treatment was performed at 110°C to release the nonwoven fabric and the pasting side was It was used as a base fabric. Process performance from spinning to final nonwoven fabric production was good and there were no problems.

After that, the drug was applied in the same manner as in Example 1, and the change over time was investigated. As a result, even with a mixture ratio of 30%, more than 70% of the effective drug remained even after 6 months, and it was found that the drug had actual medicinal efficacy as a patch. The effects were also good.

[Example 8] The same method as Example 1 was carried out except that ketoprofen was used as the drug. However, the remaining amount of applied ketoprofen was measured by measuring the wavelength of 283 nm in the ultraviolet absorption spectrum.

No decrease in the amount of applied drug over time was observed. In addition, as for the effect as a patch, actual test results showed that the medicinal effect was good.

[Comparative Example 3] A polymer with an ethylene content of 20 moles was used as the A polymer, but the fluidity during melt spinning was poor and the spinnability was poor, so that it could not be made into fibers.

[Comparative Example 4] A polymer with an ethylene content of 80 moles was used as the A polymer, and the same method as in Example 1 was performed except for the following.

However, the performance with the patch was at the same level as Comparative Example 2;
) was not desirable.

[Comparative Example 5] A saponified ethylene-vinyl acetate copolymer having a degree of saponification of 80% was used as the saponified ethylene-vinyl acetate copolymer. Problems with adhesion between single filaments occurred during the spinning and drawing steps, and an FR fiber structure worthy of evaluation could not be obtained.

[Comparative Example 6.7] In Comparative Example 6, fiberization was carried out using [η)O, Q45 and other conditions similar to those of Example 1, but the viscosity was too low and the spinning and drawing properties were poor.

In Comparative Example 7, fiberization was carried out under the same conditions as [[eta], 10.170, other examples], but on the contrary, the viscosity was too high and the spinnability was poor.

[Comparative Example 8] A drawn yarn of 7'5 f-neel 10 filaments having a single filament denier of about 7.5 tenier was obtained by spinning and drawing using the same method as in Example 1. Next, as a result of evaluating the performance of the patch using the same method as in Example 1, it was found that, contrary to expectations, the effective drug amount decreased by about 20% over time compared to Example 1. The results also showed that the medicinal efficacy was slightly reduced.

The data and results for the above Examples and Comparative Examples are listed in Table 2. x% lower margin (effect of the present invention) As described above, the present invention provides a saponified ethylene-vinyl acetate copolymer that satisfies specific conditions, spins it into fibers by a method that satisfies the predetermined conditions, and processes it into the fiber aggregate. We have discovered a patch that maintains good and durable medicinal effects even after long-term storage by applying a vegetable oil containing a non-steroidal analgesic and anti-inflammatory agent that is highly absorbable to the skin. It is something that

Claims (2)

[Claims] (1) Intrinsic viscosity [η] 0.05-0.15 l/g, single fiber denier 5 denier or less, ethylene content 25-0.
A vegetable oil in which a non-steroidal transdermal analgesic and anti-inflammatory agent is dissolved and dispersed in a fiber aggregate containing 10% or more fibers made of saponified ethylene-vinyl acetate copolymer with a saponification degree of 70 mol% or more and a saponification degree of 95% or more. A patch characterized by being coated with a similar substance. (2) The non-steroidal transdermal analgesic and anti-inflammatory agent comprises one or more selected from ketoprofen, indomethacin, flurbiprofen, methyl salicylate, diclofenac, and ibubrofenmenthol. patch.