WO1993024114A1

WO1993024114A1 - Reservoir-type plaster containing ketorolac

Info

Publication number: WO1993024114A1
Application number: PCT/JP1993/000674
Authority: WO
Inventors: Katsuya Mukae
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 1992-05-22
Filing date: 1993-05-21
Publication date: 1993-12-09
Also published as: JPH06166619A; JP3477211B2; AU4089093A

Abstract

A reservoir-type plaster containing a nonsteroidal anti-inflammatory analgesic comprising ketorolac as a pharmacologically active substance. The plaster is composed of a pharmacologically active substance comprising ketorolac or a medically acceptable salt thereof, a drug reservoir and a device for applying the drug to the skin surface, the reservoir being one prepared from a gel base comprising a glycol, a lower alcohol, water and a water-soluble polymer, a gel base comprising an aliphatic alcohol and a polyhydric alcohol, or a gel base comprising a paraffin or a silicone.

Description

Description Reservoir-type patch containing ketorolac Technical field

TECHNICAL FIELD The present invention relates to a reservoir-type patch containing ketorolac as a pharmacologically active substance and having a remarkable inflammatory and analgesic effect. '

Background art

Chemical name is (±) —5—Benzoyl—2,3—Dihydro-1 3 H—Pyrrolidine—1 One-strand rubonic acid (also known as: 5—Venzoyl-1,2—Dihydro-1-3 Ketorolac, which is H—pyro-mouth [1,2—a] pyrrole-1—carboxylic acid), was first synthesized at CITX Corporation in the United States, and its synthesis method was disclosed in It is a pharmacologically active substance disclosed in No. 4109. This ketorolac is a compound with excellent anti-inflammatory and analgesic effects, and has excellent effects in the treatment of rheumatoid arthritis, osteoarthritis, myalgia, trauma and post-operative analgesia. It is a non-steroid anti-inflammatory analgesic having

As a preparation containing this ketorolac or a salt thereof, an oral preparation and an injection are disclosed in Japanese Patent Application Laid-Open No. 61-191686. Also, Japanese Patent Application Laid-Open No. Sho 58-177 The bulletin describes eye drops.

However, in the case of the conventionally disclosed ketorolak-containing preparations, first, although oral preparations have excellent anti-inflammatory and analgesic effects, side effects such as gastrointestinal, liver, and kidney damage due to continuous use are considered. Therefore, such side effects were not favorable in terms of safety but were one of the important issues to be solved. Injectables can be expected to be quick-acting, but patients must suffer new pain, especially when the number of administrations is repeated or depending on the site to be injected. There was a fundamental problem with the formulation that it was difficult to strictly set the dose of the drug to achieve the desired therapeutic effect.

In addition, analgesic patch preparations containing narcotics are available on the market, but have the problem of addiction to the study and the restriction that hospital prescribing must follow the support of anesthesiologists , Disclosure of the invention

Therefore, the present invention solves the above-mentioned drawbacks of the prior art, overcomes the problems of oral preparations, injections, and eye drops, and furthermore, provides a new ketolora free from restrictions on prescription. The purpose is to provide a drug-containing product.

That is, the inventors of the present invention have conducted intensive research to solve the above-mentioned problems, and as a result, have attached a ketorolac in a reservoir type. It has been found that transdermal application without a drug can produce a highly safe formulation with excellent skin permeability, excellent anti-inflammatory, analgesic effects and high safety.

The present invention has been made based on the above findings, and provides a reservoir-type patch containing ketorolac or a pharmaceutically acceptable salt thereof as a pharmacologically active substance. That is what you do. Further, a gel base comprising the pharmacologically active substance and glycols, a lower alcohol, water and a water-soluble polymer, or a gel base comprising an aliphatic alcohol and a polyhydric alcohol, or paraffin The present invention provides a reservoir-type patch having a drug reservoir made of a gel base such as a silicone or a silicone.

BEST MODE FOR CARRYING OUT THE INVENTION

The reservoir-type patch of the present invention contains ketorolac or a pharmaceutically acceptable salt thereof as a pharmacologically active substance, and has an excellent anti-inflammatory action and an analgesic action. It is a patch.

Here, a medically acceptable salt of ketorolac is an inorganic base such as sodium, potassium, ammonium, canolemium, magnesium, and aluminum, or isopept. Pyramin, getylamine, ethanolamine, tromethamine, lysine, arginine, histidine, piperidine It is a salt formed from one or more organic bases such as piperazine, colin and caffeine. Hereinafter, it is generically referred to as ketorolac, including medically acceptable salts.

Ketorolac preferably contains 10 to 10 Omg as the amount in one reservoir type patch of the present invention, and if it is less than 10 nig, it will have a sufficient analgesic effect and If its sustainability is not obtained and it exceeds 100 mg, it may cause damage to the digestive tract or skin, which is not preferred.

The reservoir-type patch of the present invention for transdermally administering ketorolac comprises a drug reservoir composed of ketorolac and a gel base, and an administration device for applying the drug to the skin surface. It is composed.

First, for drugs, it is necessary that a therapeutically effective amount of ketorolac be obtained and have skin permeability, and that it is less irritating to the skin, has excellent safety, and has a substantial effect during storage. It is desirable that no chemical deterioration occurs. The drug storage tank contains ketorolac and, if necessary, as a base component, a transdermal absorption enhancer, gelling agent, bactericide, antioxidant, ultraviolet absorber, filler, thickener Additives known as external preparations such as agents, emulsifiers, pH adjusters, skin irritation reducing agents, preservatives, humectants, water, and solubilizers can be blended.

Of these additives, percutaneous absorption enhancers are As the permeation rate of Lorak, a velocity of 50 to 20 when only the local action of ketorolac is expected, and a rate of 200 to 20 when a systemic therapeutic effect is expected. Set to a speed of 200 g / hr. In this case, if the permeation rate is less than 50 p.g κ hr, sufficient local action cannot be obtained, and if it exceeds 2000 / g Z hr, there is a high possibility that side effects in the skin and gastrointestinal tract will occur. I don't like it. Examples of percutaneous absorption enhancers include well-known agents such as ethanol, oleic acid, 1-dodecylazacyclohexane-2-one, 1-menthol, d-limone. can do.

It is desirable that the gelling agent or the thickening agent is blended so that the drug viscosity is in the range of 500 to 2000 cps. When the viscosity of the drug is less than 500 cps, the patch is stuck to the skin, and the drug easily leaks from the drug storage tank, which is not preferable. When the drug viscosity exceeds 2000 cps, it becomes difficult to obtain the necessary skin permeability of the drug. The gelling agent or thickener is a polymer that is soluble in the drug system, such as alginic acid, sodium phorboxyl cellulose, agar, gelatin, hydroxypropyl pill cellulose, and polyacrylic acid. , Sodium polyacrylate, polyvinyl alcohol, polyvinylinole propylidone, methyl cellulose, methyl vinyl ether-maleic anhydride copolymer, and the like. so Wear.

It is desirable that the pH adjuster be blended so that the pH of the drug system is in the range of 3 to 8. If the pH of the system is lower than 8, it is disadvantageous in terms of skin irritation. Also, when the pH is higher than 7, it is disadvantageous in terms of skin irritation, and it is not preferable in terms of skin permeability of drug components. As the pH adjuster, for example, well-known ones such as citric acid, acetic acid, and sodium phosphate can be used.

In one embodiment, the formulation serving as the base of the drug storage tank includes a gel base containing glycols, lower alcohol, water, and a water-soluble polymer.

Here, glycols have a moisturizing effect on the skin and generally relieve the skin irritation of the drug, and also increase the dissolution concentration of the main drug ketorolac in the drug. Or, it has an effect such as enhancing skin permeability of the drug. Specifically, glycols are preferably ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, polypropylene glycol and the like. It is desirable that the blending amount of glycols be in the range of 5 to 90 wt%. If it is less than 5 wt%, it is not preferable in terms of skin irritation, and if it exceeds 9 O wt%, it is not sufficient in terms of skin permeability of the drug. Lower alcohols are mainly used for the purpose of enhancing the transdermal absorbability of the main ingredient. Specific examples of lower alcohols include phenol, brono, phenol, phenol, and hexanol. The blending amount of the lower alcohol is preferably in the range of 5 to 50 wt%. If the content is less than 5 wt%, the required drug permeability through the skin cannot be obtained. If it exceeds 50 wt%, it is disadvantageous in terms of skin irritation of the drug.

The water-soluble polymer is used to adjust the viscosity of the drug to prevent the drug from leaking from the patch when the patch is applied to the skin. Therefore, in this case, the water-soluble polymer refers to a polymer that dissolves in the drug system of the present embodiment, and a force that can use a well-known external preparation, alginic acid, carboxymethylcellulose naphthalene, etc. Tritium, agar, gelatin, hydroxypropylcellulose, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose Further, a methyl vinyl ether-maleic anhydride copolymer or the like can be preferably used.

For example, the embodiment of the present invention will be described in more detail. As a method for preparing a drug, first, (a) swelling a water-soluble polymer in water, and (b) ketolac derivative It can be obtained by dissolving in glycols and lower alcohol, then adding (b) to (a), and then making the pH alkaline and gelling. In another embodiment, which is a base for a drug storage tank, there is a gel base containing an aliphatic alcohol and a polyhydric alcohol.

Aliphatic alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, aralkyl alcohol, and oleyl alcohol. Here, aliphatic alcohols having fewer carbon atoms than lauryl alcohol are not preferred because of their relatively strong skin irritation. On the other hand, aliphatic alcohols having a higher carbon number than aralkyl alcohol are not preferred because they form waxy masses in the drug. The amount of the aliphatic alcohol is preferably in the range of 10 to 5% by weight. If the amount is less than 10 wt%, the drug may have too high a fluidity and may leak out of the application surface when the drug is applied to the skin. If the content is more than 50 wt%, the skin becomes irritating to the skin, which is not preferable.

Polyhydric alcohols such as propylene glycol, butylene glycol, polyethylene glycol, polypropylene glycol, glycerin, and polyglycerin are preferred because they are less irritating to the skin. The blending amount of the polyhydric alcohol is preferably in the range of 25 to 60 ^%. If the amount is less than 25 wt%, the flowability of the drug will be too low and the It is disadvantageous in terms of rack release. If the content is more than 6 O wt%, on the other hand, the drug fluidity is too high, causing a problem of drug leakage.

In the embodiment, as required, oils and fats such as olive oil, carnauba baro, hydrogenated oil, sesame oil, soybean oil, castor oil, lanolin, liquid paraffin, and petrolatum, etc. , Diisopropyl, adipate. Fatty acid esters such as isopropyl luminate, isopropyl myristate, or monoolein, monomyristine, and monolaurin can be added.

In this embodiment, in the method of preparing a drug, for example, ketorolac is added to an aliphatic alcohol and a polyhydric alcohol, and the mixture is heated to 60 ° C. and uniformly dissolved. Subsequently, it can be adjusted by cooling it while gradually stirring it.

In another embodiment, the base of the drug storage tank is a gel base containing paraffins and silicones.

In this case, the paraffins include liquid paraffin (pharmacopoeia), liquid polyisobutylene, skullane, and petrolatum (pharmacopoeia, cosmetic primordia), etc. for safety. I like it. Silicones are not particularly limited, but polydimethylsiloxane is preferred in terms of safety. Regarding the mixing ratio, the viscosity of the drug is adjusted by the ratio of a soft component such as {celline} polydimethylsiloxane to another liquid component. The ratio of the soft wax component to the liquid component is

A value between 5: 1 and 2: 3 is preferred. Ethanol, crotamiton, heart oil, and the like can also be added as a dissolving agent for kettle lacquer, if necessary.

In the method of preparing a drug according to this embodiment, for example, ketorolac is dissolved by heating in a dissolving agent. This can be adjusted by mixing it uniformly in paraffin, adding a soft wax component, and mixing.

On the other hand, the reservoir-type administration device for applying the medicine to the skin surface is not particularly limited, but a well-known external preparation can be used. The configuration of the dispensing device is generally comprised of a backing layer that is substantially impermeable to the drug, a drug release layer for delivering the drug layer to the skin surface, and the device is adhered to the skin surface. And a release liner layer for protecting the pressure-sensitive adhesive layer. Here, the drug is sealed between the backing material layer and the drug release material layer to form a drug storage tank. Also, when using the device, the device is applied to the skin of the patient by applying a release liner layer.

The film that forms the backing layer is a so-called It is desirable that the material has a rear surface and that it can be easily bonded to the drug release material layer. Specific examples include aluminum, ethylene-vinyl acetate copolymer, cellulose, and cell openings—acetate, nylon, polyester, polyethylene, polyvinylidene chloride, polyvinyl chloride, and polyvinyl chloride. And other materials. These materials can be laminated as needed to adjust the flexibility as a film, the adhesion to the drug release material layer, and the barrier property to drug components. The film material serving as the release material layer is used for physically holding the drug, making the administration area of the drug constant, and adjusting the skin permeability of the drug. Therefore, it is not always necessary to provide a drug release material layer as long as the solidity is maintained so that the drug does not flow when the device is applied to the skin surface. The drug and release material layers are, specifically, an ethylene-vinyl acetate copolymer, a styrene-isoprene-styrene block copolymer, a hydroxymethacrylate, a polyisoprene. Materials such as polyester, polyester, polyethylene, polybutadiene, polypropylene, and polydimethylsiloxane can be used as needed. The membrane material can be processed into a non-porous or porous film, paper or non-woven fabric to adjust the permeability of the drug to the membrane.

Pressure-sensitive adhesive layer secures the device to the skin surface It is necessary to have good adhesion to the skin, and it is desirable to have excellent skin safety. Specifically, acrylate polymer carboxymethylcellulose sodium, styrene-isoprene-styrene block copolymer, natural rubber, vinyl ether copolymer, polyacrylic acid Pressure-sensitive adhesives based on sodium phosphate, polydimethylsiloxane, methacrylate polymer, etc. as a base polymer. If necessary, adjust adhesion and safety. Well-known additives can be blended. There is no problem if a part of the drug composition is previously blended in the pressure-sensitive adhesive layer.

The film used as the release liner layer can be made of a well-known material. Specifically, aluminum, cellulose, polyester, polyethylene, polypropylene, etc. are preferable and necessary. These films may be laminated according to the requirements. Also, the surface is treated with silicone, surfactant, fluorocarbon, etc., or a known additive is mixed into the material of the release liner, or the surface of the release liner is made uneven. By doing so, the releasability when separating from the pressure-sensitive adhesive may be adjusted.

If necessary, add a film to seal the drug storage tank to prevent leakage of the drug during storage and to improve the stability and usability of the device as needed. thing No problem.

The shape of the drug administration device is not particularly limited as long as the use of the device is not hindered. For example, a shape such as a circle, an ellipse, and a polygon is preferable. The angular shape is not preferred because of the adhesiveness of the device to the skin. Also, the dimensions of the device are desirably in the range of 2 to 20 O cnf as the area of the surface from which the drug is released. If the area is smaller than 200 cnf, it will be difficult to handle the separation liner or attach the device to the skin surface, and the area will be larger than 200 cnf. And the feeling of wearing the device becomes poor.

As described above, the reservoir-type patch of the present invention contains ketorolac as a pharmacologically active substance, is less likely to cause damage to the gastrointestinal tract and the like due to continuous use, and can be administered like an injection. It is a transdermal preparation having an anti-inflammatory and analgesic effect, which can be administered with a constant amount of drug with little pain at the time. Also, compared to other transdermal dosage forms such as tapes and patches, the drug composition has a greater degree of freedom and high transdermal permeability, so that not only topical but also systemic treatments can be performed. The effect can be expected.

Next, examples for formulating the reservoir-type patch of the present invention will be described. Of course, the present invention is not limited to the following formulation.

Example 1 A reservoir patch was constructed according to 1) to 4> below, and a release liner was applied to the drug release surface and the surrounding pressure-sensitive adhesive surface to form a laminate.

1) Backing material layer Polyester film

2) Drug storage layer 4 g of the following gel composition was enclosed.

Ketorolac 5 copies

1 — Menthol 3 parts Carboxyvinyl polymer 2 parts Propylene glycol 30 parts Triethyl citrate 1 9 parts Purified water 39.4 parts

2 — Hydroxy 4 1

0.5 parts of methoxybenzophenone diisoprono. Normin 1.1

100% by weight In other words, 1 part of carboxyvinyl polymer is swollen in 23 parts of purified water, and 30 parts of propylene glycol, 20 parts of triethyl citrate, and A solution obtained by mixing 5 parts and 0.5 part of 2-hydroxy-4-methoxydibenzophenone was added and stirred. Next, 3 parts of 1 menthol and 1.1 parts of diisopropano-lamine were dissolved in 16.4 parts of purified water. The mixture was added and stirred sufficiently until the whole became uniform to obtain a gel.

3) Drug release material layer

4) Pressure-sensitive adhesive layer Acrylic adhesive (periphery of support) Example 2

A reservoir-type patch was constructed by 1) to 4) below, and a release liner was applied to the surface of the pressure-sensitive adhesive to form a laminate.

1) Backing material layer Polyester film

2) enclosing the same gel composition 4 g drug reservoir layer in Example 1 ₀

3) Drug release material layer

4) Pressure-sensitive adhesive layer Silicone adhesive

Example 3

A reservoir-type patch was constructed according to 1) to 4) below, and a release liner was applied to the drug release surface and the pressure-sensitive adhesive surface to form a laminate.

1) Backing material layer Polyester film

2) Drug reservoir layer The following oil-based gel composition (4 g) was enclosed.

Ketorolac 5 parts Liquid paraffin 70 parts Stearyl alcohol 20 parts d — 5 parts of remote

100% by weight

3) Drug release material layer

4) Pressure-sensitive adhesive layer S ISS adhesive (peripheral part of support)

A reservoir-type patch was constructed by the following 1) to 4), and a release liner was applied to the pressure-sensitive adhesive surface to form a laminate.

1) Backing material layer Polyester film

2) Drug reservoir layer 4 g of the composition of Example 3 was enclosed.

3) Drug release material layer

4) Pressure-sensitive adhesive layer Polyisobutylene-based adhesive Example 5

1) Backing material layer Aluminum laminated polyester film

2) Drug storage layer 4 g of the following gel composition was enclosed.

Ketororak 5 parts Silicone 80 parts Glycerol monolaurate 5 parts

1 One meter 10 0 100% by weight

3) Drug release material layer

4) Pressure-sensitive adhesive layer Silicone-based adhesive (peripheral part of support)

A reservoir-type patch was constructed according to 1) to 4) below, and a release liner was applied to the surface of the pressure-sensitive adhesive to form a laminate.

1) Backing material layer Aluminum laminated polyester film

2) Drug reservoir layer 4 g of the following gel composition of Example 5 was enclosed.

Ketorolac 5 parts Silicone 80 parts Glycerol monolaurate 5 parts

1 — Menthol 10 0

100% by weight

3) Drug release material layer

4) Pressure-sensitive adhesive layer Silicone adhesive

Example 7

A reservoir-type patch was constructed by 1) to 4) below, and a release liner was applied to the drug release surface and the pressure-sensitive adhesive surface to form a laminate.

1) Backing material layer Aluminum laminated polyester film 2) Drug reservoir layer 4 g of gel with the following composition is enclosed.

Ketorolac 5 parts Stearyl alcohol 10 parts Cetyl alcohol 10 parts Beheninoleanoreco 1 part 10 parts Propylene glycol 20 parts 1 and 3 — Butyrange Call 40 parts Lauryle alcohol 5 parts

100% by weight

3) Drug release material layer

4) Pressure-sensitive adhesive layer Silicone adhesive (periphery of support)

A reservoir type patch was constructed according to the following 1) to 4), and a release liner was applied to the surface of the pressure-sensitive adhesive to form a laminate.

1) Backing material layer Aluminum laminated polyester film

2) Drug reservoir layer 4 g of the gel composition of Example 7 was sealed.

3) Drug release material layer

4) Pressure-sensitive adhesive layer Silicone adhesive

Comparative Example 1

1) Purified water 4 4.7 parts 2) Gelatin 6 parts

3) Polyvinyl vinyl 3 parts

4) Kaolin 5 parts

In a mixer at 50 ° C to obtain a uniform dispersion

Next, I adjusted it in advance

5) Glycerin 2 5 parts

6) Sodium polyacrylate 3 parts

A dispersion of, and

7) Purified water 10 parts

8) 2.5 parts of polyacrylic acid

Is added and stirred and mixed to obtain a uniform kneaded product. To this, 0.3 part of ketorolac is added and mixed and dissolved to obtain a uniform kneaded product. Using a spreading machine, apply it to a predetermined birch cloth so that the weight becomes 10 g per 14 O cnf, then cover it with polypropylene film and cut it to a predetermined size. Product.

Next, working effects of the reservoir-type patch of the present invention will be described in detail with reference to test examples such as the above Examples and Comparative Examples.

Test Example 1 Analgesic test using mice

Experimental Example 18 The oral preparation was used as a control by the acetic acid ligation method for up to 18 preparations and the comparative example, and mice weighing about 20 g were added to 10 mice per group under the following conditions under the following conditions. A release area of 4 cnf) was applied to the back, and 1 hour later, a 0.7% acetic acid solution (0.10 g) was intraperitoneally injected. It was measured and compared with the control group.

Table 1 shows the test results.

table 1

Test Example 2 Gastric mucosal damage test using rat

A group of 8 Wistar male rats weighing around 200 g was fasted for 24 hours under free water supply, and then the test compound was applied. Was. At that time, the reservoir type patch of Example was stuck with a 2.4 cm square on the back of a rat shaved with an electric razor. The bulk of Ketorolac was orally administered in suspension in 0.5% tragacanth saline solution. Six hours after administration, the animals were sacrificed, the stomach was removed, and an incision was made along the bay. The presence or absence of ulcers in the gastric mucosa was visually observed, and the ulcer incidence was calculated by the following equation.

Number of animals with ulcers

Ulcer incidence (%) =-X 100

Number of animals used in the experiment

Table 2 shows the test results.

Table 2 Administration

Study drug Number of animals Incidence Route (%) Control group (no treatment) 80

Reservoir-type patch of Example 1 Transdermal 80 (containing 50 mg of ketorolac)

Ketorolac bulk powder (50 mg) Oral 8 1 0 0 Industrial applicability

The overall analgesic effect of the ketorolac-containing reservoir-type patch of the present invention is higher than that of an ordinary poultice formulation as is clear from the test results of Test Example 1, and is equivalent to that of intravenous injection and oral administration Is shown. Further, as is clear from the test results of Test Example 2, the reservoir-type patch of the present invention has no ulcer formation on the gastric mucosa, and is an extremely safe administration method. Not only systemic analgesic effect but also pain and pain relief of patients at the time of injection It is useful as a pharmaceutical preparation useful to society from the viewpoint of avoiding the first-pass effect of the liver.

Claims

The scope of the claims

1. A reservoir-type patch containing ketorolac or a pharmaceutically acceptable salt thereof as a pharmacologically active substance.

2. A drug storage tank comprising a pharmacologically active substance comprising ketorolac or a pharmaceutically acceptable salt thereof and a gel base of glycols, lower alcohol, water and a water-soluble polymer. Reservoir-type patch.

3. The reservoir type 1 patch according to claim 1, which has a drug reservoir comprising a gel base of an aliphatic alcohol and a polyhydric alcohol and a pharmacologically active substance comprising ketorolak or a pharmaceutically acceptable salt thereof.

4. The reservoir type according to claim 1, which has a drug Jf tank composed of a gel base of ketolac or a pharmaceutically acceptable salt thereof and a pharmacologically active substance thereof and a paraffin or a silicone. Patches.

5. A reservoir type patch comprising the drug reservoir according to claims 2 to 4 and an administration device for passing the drug through the skin surface.