JP3477211B2 - Ketorolac-containing reservoir patch - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a reservoir type patch containing ketorolac as a pharmacologically active substance and having a remarkable inflammatory and analgesic effect.

[0002]

The chemical name of ketorolac, which is a pharmacologically active substance of the present invention, is (±) -5-benzoyl-2,3-dihydro-3H-pyrrolidine-1-carboxylic acid (alias: 5-).
Benzoyl-1,2-dihydro-3H-pyrrolo [1,2
-A] pyrrole-1-carboxylic acid). Ketorolac was first synthesized at Syntex, Inc. in the United States, and its method is disclosed in JP-A-62-54109. Ketorolac is a compound with excellent anti-inflammatory and analgesic effects, and is a non-steroidal anti-inflammatory analgesic that has excellent effects in the treatment of rheumatoid arthritis, osteoarthritis, myalgia, trauma and post-operative analgesia. It is an agent. A preparation containing ketorolac or a salt thereof is disclosed in Japanese Patent Laid-Open No.
No. 1-191186 discloses oral agents and injections. Further, JP-A-58-172314 describes eye drops.

[0003]

Among the ketorolac-containing preparations disclosed hitherto, first of all, although oral preparations have excellent anti-inflammatory / analgesic effects, there are gastrointestinal, hepatic and renal disorders caused by continuous use. There is a high possibility of causing side effects, and such side effects are not preferable in terms of safety and are one of the important problems to be solved. Injectables are expected to have fast-acting effects, but patients must suffer new pain, and it is a problem that many problems are desired to be solved, especially when the number of administrations overlaps and depending on the injection site. Further, in the case of eye drops, there is a basic problem as a formulation in which it is difficult to precisely set the drug dose for obtaining a predetermined therapeutic effect.

[0006] Although analgesic patch preparations containing narcotics are on the market, there is a problem of addiction of patients and there is a limitation in that prescribing in a hospital must follow the support of an anesthesiologist. The present invention overcomes the problems of oral preparations, injections, and eye drops, and further provides a new preparation that does not involve any restrictions on the formulation.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that ketorolac is applied transdermally without a reservoir-type patch and is superior in skin permeability. Further, they have found that a preparation having high anti-inflammatory and analgesic effects and high safety can be formed, and thus completed the present invention. That is, the reservoir-type patch of the present invention is a gel base consisting of a pharmacologically active substance consisting of ketorolac or a medically acceptable salt thereof and glycols, lower alcohol, water and a water-soluble polymer, or an aliphatic alcohol and a polyalcohol. The present invention relates to a reservoir-type patch having a drug reservoir made of a gel base made of a polyhydric alcohol or a gel base made of paraffins or silicones.

The present invention will be specifically described below. The reservoir patch of the present invention is a transdermal reservoir patch containing ketorolac or a medically acceptable salt as a pharmacologically active substance and having excellent anti-inflammatory and analgesic effects. In addition, the medically acceptable salt of ketorolac is
An inorganic base such as sodium, potassium, ammonium, calcium, magnesium, and aluminum, or one of organic bases such as isopropylamine, diethylamine, ethanolamine, tromethamine, lysine, arginine, histidine, piperidine, piperazine, choline, and caffeine. Alternatively, it is a salt formed from two or more kinds. Hereinafter, they are collectively referred to as ketorolac, including medically acceptable salts.

It is preferable that ketorolac is contained in an amount of 10 to 100 mg in one sheet of the patch of the present invention, and if it is less than 10 mg, a sufficient analgesic effect and its sustainability cannot be obtained. May cause damage to the digestive tract or skin, which is not preferable. 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.

First, regarding the drug, it is necessary to obtain a therapeutically effective amount of the skin permeability of ketorolac, and it is less irritating to the skin and excellent in safety.
It is desirable that no substantial chemical alteration occurs during storage. In addition to containing ketorolac, the drug storage tank contains a transdermal absorption enhancer, a gelling agent, a bactericidal agent, and a base component as needed.
Antioxidant, UV absorber, filler, thickener, emulsifier,
Additives known as external preparations such as pH adjusting agents, skin irritation reducing agents, preservatives, moisturizers, water, and solubilizers can be added.

Among these additives, the percutaneous absorption enhancer is 50 to 200 in the case where only the local action of ketorolac is expected as the skin permeation rate of ketorolac.
When the systemic therapeutic effect is expected at the rate of μg / hr, the rate is set at 200 to 2000 μg / hr. In this case, a sufficient local action cannot be obtained at a permeation rate of less than 50 μg / hr, and 2000 μg / hr
When it exceeds the above range, side effects are likely to occur on the skin and digestive tract, which is not preferable. As examples of the transdermal absorption enhancer, known ones such as ethanol, oleic acid, 1-dodecylazacycloheptan-2-one, 1-menthol and d-limonene can be used.

The gelling agent or thickening agent is preferably blended so that the drug viscosity is in the range of 500 to 20000 cps. When the viscosity of the drug is less than 500 cps, applying the patch to the skin surface is not preferable because the drug easily leaks from the drug storage tank. Drug viscosity is 20000cp
If it exceeds s, it becomes difficult to obtain the necessary skin permeability of the drug. The gelling agent or thickening agent is a polymer soluble in the drug system, for example, alginic acid, sodium carboxymethyl cellulose, agar, gelatin, hydroxypropyl cellulose, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose. , Methyl vinyl ether-maleic anhydride copolymer and the like can be used.

Regarding the pH adjuster, the pH of the drug system is 3
It is desirable to mix them in a range of -8. System p
When H is lower than 8, it is disadvantageous in terms of skin irritation. Further, when the pH is higher than 7, it is disadvantageous in terms of skin irritation and is not preferable in terms of skin permeability of the drug component. As the pH adjuster, known ones such as citric acid, acetic acid and sodium phosphate can be used.

As one embodiment, the formulation of the base of the drug storage tank is a gel base containing glycols, lower alcohols, water, and a water-soluble polymer. put it here,
Glycols have a moisturizing effect on the skin and generally reduce the skin irritation of the drug, and also increase the concentration of the main ingredient ketorolac dissolved in the drug or enhance the skin permeability of the drug. Have an effect. Specifically, the glycols are preferably ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, polypropylene glycol and the like. The blending amount of glycols is preferably 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 90 wt%, it is not sufficient in terms of skin permeability of the drug.

The lower alcohol is mainly used for the purpose of enhancing the transdermal absorbability of the main ingredient. What is lower alcohol?
Specifically, ethanol, propanol, butanol,
Examples include amyl alcohol and hexanol. The lower alcohol content is preferably in the range of 5 to 50 wt%. If it is less than 5 wt%, the required skin permeability of the drug cannot be obtained. When 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 and prevent the drug from leaking from the patch when the patch is applied to the skin. Therefore, in this case, the water-soluble polymer means a polymer that is soluble in the drug system of the present embodiment,
Known external preparations can be used, including alginic acid, sodium carboxymethyl cellulose, agar, gelatin, hydroxypropyl cellulose, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, methyl vinyl ether-maleic anhydride. A copolymer etc. can be used conveniently.

In the method of preparing the drug in this embodiment, for example, first, (a) a water-soluble polymer is swollen in water, and (b)
It can be obtained by dissolving a ketorolac derivative in glycols and a lower alcohol, then adding (b) to (a), and then making the pH alkaline and gelling. Also, as another embodiment that serves as the base of the drug storage tank,
Examples thereof include gel bases containing an aliphatic alcohol and a polyhydric alcohol.

Examples of the aliphatic alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, aralkyl alcohol and oleyl alcohol. Here, an aliphatic alcohol having a smaller number of carbon atoms than lauryl alcohol is not preferable because it has relatively strong skin irritation. On the other hand, an aliphatic alcohol having a carbon number higher than that of aralkyl alcohol is not preferable because a wax-like lump is formed in the drug. The amount of the aliphatic alcohol compounded is preferably in the range of 10 to 50 wt%. If it is less than 10 wt%, the fluidity of the drug is so high that the drug may leak out of the application surface while the formulation is attached to the skin. When it is more than 50 wt%, the skin irritation of the drug becomes high, which is not preferable.

As the polyhydric alcohol, propylene glycol, butylene glycol, polyethylene glycol, polypropylene glycol, glycerin, polyglycerin and the like are preferable because they are less irritating to the skin. The polyhydric alcohol content is preferably in the range of 25 to 60 wt%. If it is less than 25 wt%, the fluidity of the drug becomes too small, which is disadvantageous in terms of the release property of ketorolac. On the other hand, if the amount is more than 60 wt%, the drug fluidity is too high, causing a problem of drug leakage. In the present embodiment, if necessary, olive oil, carnauba wax, hydrogenated oil, sesame oil, soybean oil, castor oil, lanolin, liquid paraffin, oils and fats such as vaseline, diisopropyl adipate, isopropyl palmitate, isopropyl myristate, Alternatively, fatty acid esters such as monoolein, monomyristin and monolaurin can be blended.

In the preparation method of the drug in this embodiment, for example, ketorolac is added to an aliphatic alcohol and a polyhydric alcohol and heated to 60 ° C. to uniformly dissolve them. continue,
This can be adjusted by gradually stirring and cooling.
Furthermore, as another embodiment that serves as the base of the drug storage tank, there is a gel base containing paraffins and silicones. The paraffins are preferably liquid paraffin (Pharmacopoeia), liquid polyisobutylene, squalane, petrolatum (Pharmacopoeia, cosmetic base) and the like for safety. The silicones are not particularly limited, but polydimethylsiloxane is preferable in terms of safety. Regarding the compounding ratio of this embodiment, the viscosity of the drug is adjusted by the ratio of the soft wax component such as petrolatum or polydimethylsiloxane and the other liquid component. The ratio of soft wax component to liquid component is preferably between 5: 1 and 2: 3. If necessary, ethanol, crotamiton, peppermint oil or the like may be added as a ketorolac solubilizer.

In the method of preparing the drug in the present embodiment, for example, ketorolac is heated and dissolved in a dissolving agent. This can be adjusted by uniformly mixing this in paraffin and then adding and mixing the soft wax component. On the other hand, the reservoir-type administration device for applying the drug to the skin surface is not particularly limited, but a well-known external preparation can be used. The configuration of the administration device is generally such that a backing material layer that is substantially impermeable to the drug, a drug release material layer for delivering the drug layer to the skin surface, and a device for adhering the device to the skin surface. And a release liner layer for protecting the pressure-sensitive adhesive layer. Here, the drug is enclosed between the backing material layer and the drug release material layer to form a drug reservoir. When the device is used, the release liner layer is peeled off and the device is stuck and fixed on the skin surface of the patient.

The film used as the backing material layer is required to have a so-called barrier property against a drug, and it is desirable that it can be easily adhered to the drug releasing material layer. In particular,
Aluminum, ethylene-vinyl acetate copolymer,
Materials such as cellulose, cellulose acetate, nylon, polyester, polyethylene, polyvinylidene chloride, polyvinyl chloride and polypropylene can be used. These materials can be laminated as needed to adjust the flexibility as a film, the adhesiveness with the drug release material layer, and the barrier property against the drug component.

The film material serving as the drug-releasing material layer is used for physically retaining the drug to make the drug administration area constant and for adjusting the skin permeability of the drug. Therefore, it is not always necessary to provide the drug-releasing material layer as long as the drug is kept solid so that the drug does not flow when the device is applied to the skin surface. The drug release material layer is specifically an ethylene-vinyl acetate copolymer, a styrene-isoprene-styrene block copolymer, a hydroxymethacrylate, a polyisoprene, a polyester,
Materials such as polyethylene, polybutadiene, polypropylene and polydimethylsiloxane can be used as necessary. The membrane material may be processed into a non-porous or porous membrane, paper or non-woven fabric to adjust the permeability of the drug to the membrane.

The pressure-sensitive adhesive layer is required to have adhesiveness for adhering and fixing the device to the skin surface, and is preferably excellent in safety to the skin. Specifically, based on acrylic acid ester polymer, sodium carboxymethyl cellulose, styrene-isoprene-styrene block copolymer, natural rubber, vinyl ether copolymer, sodium polyacrylate, polydimethylsiloxane, methacrylic acid ester polymer, etc. An example of the pressure sensitive adhesive is a polymer, and well-known additives can be added as necessary for adjusting the adhesiveness and safety. Further, it is no problem to preliminarily mix a part of the drug composition in the pressure-sensitive adhesive layer.

As the film to be the release liner layer, known materials can be used, and specifically, aluminum, cellulose, polyester, polyethylene, polypropylene and the like are preferable, and these films are laminated as necessary. Good. Further, the surface thereof is treated with silicon, a surfactant, fluorocarbon, or the like, or a known additive is added to the release liner material,
By making the surface of the release liner uneven, the releasability at the time of peeling from the pressure-sensitive adhesive may be adjusted.
If necessary, as a constitution of the administration device, there is no problem in adding a film for sealing the drug storage tank in order to prevent leakage of the drug during storage of the device and improve stability and usability of the device.

The shape of the drug administration device is not particularly limited as long as it does not hinder the use of the device, but a shape such as a circle, an ellipse or a polygon is preferable. The angular shape is not desirable for the adhesion of the device to the skin. Regarding the size of the device, the area of the surface from which the drug is released is 2 to
It is desirable that the range is 200 cm ² . Area is 2c
When it is smaller than m ² , handling becomes difficult when peeling the release liner or when the device is attached to the skin surface, and when the area is larger than 200 cm ² , the device is uncomfortable to wear.

[0025]

The reservoir type patch of the present invention contains ketorolac as a pharmacologically active substance, is less likely to cause damage to the digestive tract, etc. due to continuous use, has less pain during administration such as an injection, and is a constant drug. It is a transdermal preparation having an anti-inflammatory / analgesic effect that can be administered. In addition, compared to other transdermal dosage forms such as tapes and poultices, the flexibility of the drug composition is wide and high transdermal permeability can be obtained, so that not only local but systemic therapeutic effects are expected. be able to.

[0026]

EXAMPLES Next, reference examples and examples for formulating the reservoir type patch of the present invention will be shown, but the formulation is not necessarily limited to the following. Example 1 1) Backing material layer Polyester film 2) Drug storage layer 4 g of the gel composition shown below was enclosed. Ketorolac 5 parts 1-menthol 3 parts Carboxyvinyl polymer 2 parts Propylene glycol 30 parts Triethyl citrate 19 parts Purified water 39.4 parts 2-Hydroxy-4-methoxybenzophenone 0.5 parts Diisopropanolamine 1.1 parts 100% by weight 1 part of carboxyvinyl polymer was swollen in 23 parts of purified water, and a solution prepared by mixing 30 parts of propylene glycol, 20 parts of triethyl citrate, 5 parts of ketorolac and 0 and 5 parts of 2-hydroxy-4-methoxybenzophenone was added thereto. It was stirred. Next, a solution prepared by dissolving 3 parts of 1-menthol and 1.1 parts of diisopropanolamine in 16.4 parts of purified water was added, and the mixture was sufficiently stirred until the whole became uniform to obtain a gel agent. 3) Drug-releasing material layer Duraguard 4) Pressure-sensitive adhesive layer Acrylic pressure-sensitive adhesive (peripheral part of support) This reservoir type patch is composed of 1-4, and the release liner is used as the pressure-sensitive adhesive on the drug-releasing surface and its periphery. An applied laminate was made on the adhesive side.

Example 2 1) Backing material layer Polyester film 2) Drug storage layer 4 g of the same gel composition as in Example 1 was enclosed. 3) Drug-releasing material layer Duraguard 4) Pressure-sensitive adhesive layer This reservoir type patch was composed of silicone adhesive 1-4, and a release liner was applied to the pressure-sensitive adhesive surface to form a laminate.

Example 3 1) Backing material layer Polyester film 2) Drug storage layer 4 g of the oily gel composition shown below was enclosed. Ketorolac 5 parts Liquid paraffin 70 parts Stearyl alcohol 20 parts d-Limonene 5 parts 100% by weight 3) Drug release material layer Coatlan 4) Pressure sensitive adhesive layer SIS adhesive (peripheral part of the support) 1-4 with this reservoir The mold patch was constructed and a release liner was applied to the drug release surface and the pressure sensitive adhesive surface to create a laminate.

Example 4 1) Backing material layer Polyester film 2) Drug reservoir layer 4 g of the composition of Example 3 was enclosed. 3) Drug-releasing material layer Coatlan 4) Pressure-sensitive adhesive layer This reservoir-type patch was composed of the polyisobutylene adhesives 1-4, and a release liner was applied to the pressure-sensitive adhesive surface to form a laminate.

Example 5 1) Backing material layer Aluminum laminated polyester film 2) Drug reservoir layer 4 g of the following gel composition was enclosed. Ketorolac 5 parts Silicon 80 parts Glycerol monolaurate 5 parts 1-Menthol 10 parts 100% by weight 3) Drug release material layer Coatlan 4) Pressure-sensitive adhesive layer Silicon-based adhesive (peripheral part of support) The reservoir patch was constructed and a release liner was applied to the pressure sensitive adhesive surface to create a laminate.

Example 6 1) Backing material layer Aluminum laminated polyester film 2) Drug storage tank layer 4 g of the gel composition of Example 5 was enclosed. Ketorolac 5 parts Silicon 80 parts Glycerol monolaurate 5 parts 1-Menthol 10 parts 100% by weight 3) Drug release material layer Coatlan 4) Pressure-sensitive adhesive layer Silicon adhesive 1-4 This reservoir type patch is composed. A release liner was applied to the pressure sensitive adhesive surface to form a laminate.

Example 7 1) Backing material layer Aluminum laminated polyester film 2) Drug storage layer 4 g of the gel agent shown below was enclosed. Ketorolac 5 parts Stearyl alcohol 10 parts Cetyl alcohol 10 parts Behenyl alcohol 10 parts Propylene glycol 20 parts 1,3-butylene glycol 40 parts Lauryl alcohol 5 parts 100% by weight 3) Drug release material layer Coatlan 4) Pressure-sensitive adhesive layer Silicon adhesive This reservoir type patch was composed of Agent (peripheral part of support) 1-4, and a release liner was applied to the drug release surface and the pressure sensitive adhesive surface to form a laminate.

Example 8 1) Backing material layer Aluminum laminated polyester film 2) Drug storage layer 4 g of the gel composition of Example 7 was enclosed. 3) Drug Release Material Layer Coatlan 4) Pressure Sensitive Adhesive Layer This reservoir type patch was composed of silicone adhesive 1-4, and a release liner was applied to the pressure sensitive adhesive surface to form a laminate.

Comparative Example 1 1) Purified water 44.7 parts 2) Gelatin 6 parts 3) Polyvinyl alcohol 3 parts 4) Kaolin 5 parts are dissolved in a mixer at 50 C to obtain a uniform dispersion. Next, 5) 25 parts of glycerin prepared in advance 6) a dispersion of 3 parts of sodium polyacrylate, and 7) 10 parts of purified water 8) a solution of 2.5 parts of polyacrylic acid were added and mixed by stirring. A uniform kneaded product is obtained. To this, ketorolac 0.
Add 3 parts, mix and dissolve to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric using a spreading machine so as to have a weight of 10 g per 140 cm ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product. Next, specific effects of the present invention will be described in detail with reference to test examples.

Test Example 1 Analgesic Test with Mice Preparations up to Examples 1-8 and Comparative Examples Using the oral agent as a control by the acetic acid writhing method, a group of 10 mice each weighing about 20 g was treated under the following conditions under the following conditions: (Drug release area 4 cm ² ) was applied to the back, and 1 hour later, it was adjusted to 0.
7% acetic acid solution (0.1 ml / 10 g) was injected intraperitoneally,
After 5 minutes, the number of risings developed in 10 minutes was measured and compared with the control group. The test results are shown in Table 1.

[0036]

[Table 1]

Test Example 2 Gastric mucosal injury test in rats 8 groups of male Wistar rats weighing about 200 g were fasted under free water for 24 hours, and then the test compounds were applied. At that time, the reservoir type patch of the example was applied with 2.4 cm square on the back of the rat shaved with an electric razor, and the ketorolac bulk powder was orally suspended in 0.5% tragacanth gum physiological saline. Was administered. Six hours after the administration, the animals were sacrificed, their stomachs were excised, and they were incised along the bay. The presence or absence of an ulcer on the gastric mucosa was visually observed, and the ulcer incidence was calculated by the following formula. Ulcer incidence (%) = (number of animals with ulcer /
The number of animals used in the experiment) x 100 test results are shown in Table 2.

[0038]

[Table 2]

[0039]

The systemic analgesic effect of the ketorolac-containing reservoir type patch of the present invention is higher than that of the usual poultice preparation as is clear from the test results of Test Example 1, and is equivalent to that of intravenous injection and oral administration. Indicates. Further, as is clear from the test results of Test Example 2, the reservoir type patch of the present invention did not show any ulcer formation on the gastric mucosa, and it was proved that it is an extremely safe administration method. Further, it is useful as a pharmaceutical preparation useful for society from the viewpoints of not only its systemic analgesic action but also the relief of pain and pain of patients at the time of injection and avoidance of the first-pass effect of the liver.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI A61P 29/00 A61P 29/00 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/407 A61K 9/70 A61K 47/10 A61K 47/34 A61K 47/44 A61P 29/00 BIOSIS (STN) CAPLUS (STN) MEDLINE (STN) EMBASE (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A pharmacologically active substance consisting of ketorolac or a medically acceptable salt and an aliphatic alcohol in an amount of 10 to 50 times.
% And polyhydric alcohol 25-60% by weight
A reservoir-type patch having a drug storage tank containing a non-aqueous gel base. 2. A reservoir-type patch having a drug reservoir containing a pharmacologically active substance consisting of ketorolac or a medically acceptable salt and a non-aqueous gel base containing paraffins or silicones. 3. A reservoir-type patch comprising the drug reservoir according to claim 1 and an administration device for applying the drug to the skin surface. 4. The drug reservoir according to claim 2 and the drug on the skin.
Reservoir type patch consisting of a dosing device for surface adaptation .