KR20000066357A - Pharmaceutical preparations for external application containing ketorolac - Google Patents

Abstract

PURPOSE: A ketorolac(nonsteroidal anti-inflammatory analgesic) or an external liquid preparation of ketorolac is provided, which minimize skin irritation, and enhances skin permeation rate of drug; and does not show any side-effects by oral administration, so can be applied for a long time. CONSTITUTION: A manufacturing process of external preparation of ketorolac(5-benzoyl-2,3-dihidro-1H-pyrolidine-1-carboxylate) comprises of: boiling the poloxamer(polyoxyethylene-polypropylene copolymer) 407 200mg at 70°C, and adding distilled water 300mg drop by drop at room temperature to the poloxamer 407 to form a gel; dissolving ketorolac 20mg in 95% ethanol 400mg, and adding isopropyl myristrate 5mg, polyethylene(4)-hydrogenized castor oil 25mg, hydroxy propyl cellulose 50mg to the ethanol; and adding the mixed ethanol compound to the gel, and mixing well.

Description

Pharmaceutical preparations for external application containing ketorolac}

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external solution for the purpose of external anti-inflammatory drugs, and relates to an external solution containing ketorolac (common name) or a salt thereof, which is a nonsteroidal anti-inflammatory drug, as an active ingredient.

The compound, which is the active ingredient of the present invention, is called ketorolac by the general name, and is a pyrrolo-pyrrolo-based drug, and its official chemical name is (±) -5-benzoyl-2,3-dihydro-1H. -Pyrrolidine-1-carboxylic acid (alias = 5-benzoyl-1,2-dihydro-3H-pyrrolo ([1,2-a]) pyrrole-1-carboxylic acid).

Ketorolac is a nonsteroidal anti-inflammatory drug with strong analgesic effect. It has a strong analgesic effect in small doses compared to other nonsteroidal analgesics, morphine, and meridine. It is mainly used for surgical operation and has slower expression than opium. This length is used a lot. This ketorolac was first synthesized by Syntex Co., Ltd. of the United States, and has already been disclosed in Japanese Patent Application Laid-Open No. 62-54109 as a compound having analgesic action. Moreover, as a preparation using this ketorolac or a salt, it is disclosed about oral preparation and injection in Unexamined-Japanese-Patent No. 61-191686. Japanese Unexamined Patent Application Publication No. 58-172314 describes topical eye drops. In the case of Japanese Patent Application Laid-Open No. 91-246665, research on the dermal permeable poultice in the form of an anti-inflammatory analgesic patch has been conducted, and various poultry poultices have been disclosed.

As described above, in the prior art, only a preparation consisting of an oral preparation, an injection, an eye drop and a poultice is disclosed, but the disclosure of a ketorolac external preparation has not been suggested at all. Therefore, there is no description regarding a ketorolac containing external preparation and a description regarding a specific prescription at all.

As mentioned above, the external preparation which contained ketorolac as an active ingredient until today is not considered at all, and has not been examined at all. Nor has it been put to practical use.

While ketorolac has a strong anti-inflammatory analgesic effect, it cannot be used for more than 5 days when used as an injection and oral preparation, and it can not be used for more than 5 days because the side effects are doubled when used for more than 5 days.

Therefore, the present invention eliminates such side effects, and can be applied quickly to the anti-inflammatory analgesic site ketorolak having a significant anti-inflammatory analgesic action, minimize the side effects of the drug, the rapid release effect on the anti-inflammatory area is excellent The present invention aims to provide a stable external preparation having no stimulation and no allergic reaction when attached to the skin.

Another object of the present invention is (i) ketorolac or a salt thereof as the active ingredient, (ii) an accelerator capable of effectively skin permeation of ketorolac or a salt thereof, and (iii) a gelling agent which can stably contain a drug. , (iv) Other additives, The external preparation of the present invention having such a configuration is to provide an external preparation which has an optimum skin permeability, acts quickly on the anti-inflammatory area, and can reduce skin irritation.

1A and 1B are graphs showing the results of a hairless mouse skin permeation test,

Figure 2a and 2b is a graph showing the absorption rate according to the ethyl alcohol content of ketorolac tromethamine and ketorolac, respectively.

In order to achieve the above object, the present invention provides i) an active nonsteroidal ketorolac or salt thereof, ii) a skin permeation accelerator capable of promoting skin permeation, and iii) a gelling agent which can stably contain a drug. , iv) other additives, and the like.

Herein, skin permeation accelerators capable of promoting skin permeation are transesterification reaction products of polyalkylenepolyols, polyethyleneglycolated natural or hydrogenated vegetable oils, polyoxyethylene- sorbitan fatty acid esters, polyoxyethylene alkyl ethers, alkyls Lenglycol monoalkyl ethers, esterification products of natural vegetable oils with polyoxyethylene glycols, and the like. These skin penetration accelerators can be divided into several types.

The first plasticizer-type skin permeation promoter is fatty acid alcohol, fatty acid, which is fat-soluble about 150-300, and is representative of stearyl alcohol, oleyl alcohol, oleic acid, lauryl acid, myristeic acid, paryleneic acid, sterol The number of carbon molecules is about 10-12 with aryl acid, isopropyl myrist acid, oleate which has a methyl, ethyl ester derivative, or laurate acid. And as a polyoxyethylene derivative, Bridge R30, 52, 72, 92 etc. are mentioned as a brand name bridge.

Second, ethanol, propanol, butanol, isopropanol, benzyl alcohol, glycerin, propylene glycol, or ethylene glycol substituents are used as a solvent-type skin permeation accelerator.

Third, the skin permeation accelerator in the form of a plasticizer and the skin permeation promoter in the form of a solvent are used together. First, the form of skin permeation according to the amount of ethanol of ketorolac or its salt is represented in the form as shown in FIGS. As the experimental example of the present invention), the solvent-type skin permeation accelerator first moves to the stratum corneum of the skin to promote the initial skin permeation of the skin, and the plasticizer-type skin permeation accelerator moves toward the skin later than the solvent-type skin permeation accelerator, The drug acts synergistically to permeate the skin. Based on these data, ethanol content and skin permeation accelerator in the drug were determined.

Suitable content of the skin permeation accelerator for the present invention is 1-30% of polyoxyethylene derivative, 1-30% of diethylene glycol monoethyl ether, 1-30% of isopropyl myristate, and 0.1-50% of oil substituted with polyethylene, It contains only one or two or more.

As the gelling agent that can be used in the composition of the present invention, any additive that can form a gel upon contact with alcohol with water can be used. Generally, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC), sodium Cellulose derivatives such as carboxymethyl cellulose (Na-CMC), carboxyvinyl polymers (trade name: Carbopol, carbopol), polyoxyethylene-polypropylene copolymers (trade name: poloxamer, poloxamer), and the like. It can also be used in a mixed form.

Other additives were water-insoluble skin permeation accelerators, but in order to prepare a transparent gel, an appropriate amount of lower alcohol was used in combination with water and oils substituted with polyethylene (trade name: Cremophor cremophor) as surfactants.

And as an alkalizing agent that can adjust the pH, using triethanol amine, sodium hydroxide was adjusted to the pH to give skin comfort. Suitable pH of the gel preparation of the present invention is 4-8.

The present invention will be described in more detail in the following examples, but the present invention is not limited to the following examples.

Example 1

200 mg of poloxamer 407 was heated to a temperature of about 70 ° C., and 300 mg of water was dropped at room temperature to form a gel. 20 mg of ketorolac was dissolved in 400 mg of ethanol (95%), 5 mg of isopropyl myristate, 25 mg of polyethylene (4) -dehydrogen castor oil, and 50 mg of hydroxy propyl cellulose were added to the prepared poloxamer gel and mixed well.

Example 2

First swell 20 mg of Carbopool 940 in ethanol / water. In a small amount of 400 mg of ethanol (95%), 20 mg of ketorolac, 5 mg of isopropyl myristate, and 25 mg of polyethylene (4) -dehydrogen castor oil are dissolved together and then added to the swollen carbopool pregel. And gel was prepared by adjusting the pH to 18 mg with triethanol amine.

The following Examples 3 to 10 were prepared in the same manner as in Examples 1 and 2 with the following compositions.

Example 3

Concentrates Containing Drugs

Ketorolac 20mg

Bridge 30 100mg

300 mg of ethanol (95%)

Hydrogel

Carbofull 940 12mg

555mg of purified water

23 mg triethanol amine

Example 4

Concentrates Containing Drugs

Ketorolac 20mg

Ethanol (95%) 400 mg

Isopropyl Myristate 5mg

Polyethylene (4) -hydrogenated castor oil 25 mg

Bridge 30 100mg

Hydrogel

Carbofull 940 20mg

412 mg of purified water

Triethanol Amine 18mg

Example 5

Concentrates Containing Drugs

Ketorolac 20mg

Ethanol (95%) 400 mg

Bridge 30 100mg

Diethylene Glycol Monoethyl Ether 50mg

Hydrogel

Carbofull 940 20mg

462 mg of purified water

Triethanol Amine 18mg

Example 6

Concentrates Containing Drugs

Ketorolac Tromethamine 20mg

Ethanol (95%) 400 mg

Isopropyl Myristate 5mg

Polyethylene (4) -hydrogenated castor oil 25 mg

Hydrogel

Poloxamer 407 200 mg

Hydroxypropyl Cellulose 50mg

Purified water 300mg

Example 7

Concentrates Containing Drugs

Ketorolac Tromethamine 20mg

Ethanol (95%) 400 mg

Isopropyl Myristate 5mg

Polyethylene (4) -hydrogenated castor oil 25 mg

Hydrogel

Carbofull 940 20mg

462 mg of purified water

Triethanol Amine 18mg

Example 8

Concentrates Containing Drugs

Ketorolac Tromethamine 20mg

Ethanol (95%) 400 mg

Isopropyl Myristate 5mg

Polyethylene (4) -hydrogenated castor oil 25 mg

Bridge 30 100mg

Hydrogel

Carbofull 940 20mg

407 mg of purified water

Triethanol Amine 18mg

Example 9

Concentrates Containing Drugs

Ketorolac Tromethamine 20mg

Ethanol (95%) 400 mg

Isopropyl Myristate 5mg

Polyethylene (4) -hydrogenated castor oil 25 mg

Bridge 30 100mg

Diethylene Glycol Monoethyl Ether 50mg

Hydrogel

Carbofull 940 20mg

412 mg of purified water

Triethanol Amine 18mg

Example 10

Concentrates Containing Drugs

Ketorolac Tromethamine 20mg

Ethanol (95%) 400 mg

Bridge 30 50mg

Diethylene glycol monoethyl ether 50mg

Polyethylene (4) -hydrogenated castor oil 50 mg

Hydrogel

Carbofull 940 20mg

Purified water 392mg

Triethanol Amine 18mg

Experimental Example: Transdermal Permeation Experiment Using Hairless Mouse

In order to measure the skin permeability of the drug of the embodiments of the present invention, skin of a hairless mouse was extracted, and then ketorollock in a receptor solution in each receptor time period using a Franz-type cell. The concentration of was measured using high performance liquid chromatography (HPLC).

The hairless mice were sampled at 4-6 weeks old, dorsal side of the females, and the area of the Franz type cells was 1.77 cm 2 and the volume was 12 ml. The solution of the receptor was analyzed using phosphate physiological buffer solution (pH 7.4). The conditions of high speed chromatography (HPLC) used in the analysis are as follows.

Column: μ-bondapack C18 (3.9 x 300 mm, WATERS)

Detector: UV 280nm

Mobile phase: Acetonitrile / 0.067M phosphate buffer solution / triethylamine = 30/70 / 0.02

Flow rate: 1.0ml / min

Injection volume: 50µl

The results measured by the experiment are shown in FIGS. 1A and 1B. The experimental results suggest that the side effects of ketorolac are minimized and can be applied to the skin.It is safer than oral administration and the side effects are doubled when used for 5 days or more. It can be administered, and it acts very quickly on the stimulation part.

The ketorolac external preparation of the present invention is an anti-inflammatory analgesic, and is effective because it is directly applied to the inflammatory site, and has no side effects that occur during oral administration.

Claims (4)

A ketorolac gel preparation consisting of ketorolac or a salt thereof, a gelling agent, a skin permeation accelerator and a pharmaceutically acceptable conventional adjuvant as an active ingredient. The ketorolac gel according to claim 1, which is used alone or in combination of two or more selected from hydroxy methyl cellulose, hydroxy propyl cellulose, sodium carboxymethyl cellulose, carboxy vinyl polymer, and polyoxyethylene-polypropylene copolymer as a gelling agent. Formulation. 2. The skin permeation accelerator of claim 1, wherein the skin permeation promoter is a transesterification reaction product of a polyalkylenepolyol, polyethyleneglycolated natural or hydrogenated vegetable oil, polyoxyethylene-srubitan fatty acid ester, polyoxyethylene alkyl ether, alkylene glycol monoalkyl A ketorolac gel preparation which mixes one or more selected from esterification products of ether, natural vegetable oil and polyoxyethylene glycol. The oil according to claim 1 or 3, wherein the skin permeation accelerator is 1-30% of a polyoxyethylene derivative, 1-30% of diethylene glycol monoethyl ether, 1-30% of isopropyl myrilate, and 0.1-50 of an oil substituted with polyethylene. A ketorolac gel preparation containing% alone or two or more.