JPH08283161A - Analgesic external preparation - Google Patents

Abstract

PURPOSE: To obtain an analgesic external preparation containing a salicylamide- based compound having a specific structure, excellent in analgesic effect, having stability with time, safety and low irritation. CONSTITUTION: This analgesic external preparation contains preferably 0.1-20wt.% of a compound of the formula (R is H, a lower alkyl or a carboxy lower alkyl) (e.g., ethenamide or salicylamide) based on the total of the external preparation (not including a substrate, container, etc.). In the case wherein the compound of the formula is not sufficiently dissolved in a used base, the compound is preferably dissolved in a solvent such as water, an alcohol, etc., and used. The external preparation, for example, is obtained as an external liquid agent by mixing the compound of the formula with glycerol, etc., adding an emulsifying agent to the mixture. An ointment, for example, is obtained by blending the compound of the formula with a base such as a hydrophilic vaseline, etc., and homogenizing the mixture.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a general formula (1) having a lower heat and analgesic action.

An analgesic external preparation characterized by containing a compound represented by the formula (wherein R is hydrogen, lower alkyl or carboxy lower alkyl group) (hereinafter referred to as "salicylamide compound").

[0002]

2. Description of the Related Art Drugs having various pharmacological actions have hitherto been known.
Generally, it was used as an oral preparation, and in some cases, as an injection preparation, but in recent years, with the progress of drug metabolism, formulation, etc., an ointment, a suppository, which considers the first-pass effect of the drug on the liver, Various external preparations such as patches have been applied depending on the disease, and there are many known examples in which a reliable therapeutic effect is actually achieved. Also in the case of analgesics, such preparations have been studied, and in particular, an external preparation using a narcotic or non-narcotic strong analgesic represented by morphine, buprenorphine and the like has already been put into practical use.

Recently, various ointments using acetylsalicylic acid (aspirin), which is a typical compound having hypothermia and analgesic action, have been manufactured as so-called in-hospital preparations at a hospital pharmacy and used for patients in hospitals. Reported results of good therapeutic effects (eg Tsuchiya et al .: Hospital Pharmacy Vol. 15, 404-
408 (1989), Imai et al .: Hospital Pharmacy Vol. 18, 496.
-499 (1992), Tsuchiya, etc .: Hospital Pharmacy Volume 20, 50
2-508 (1994)) and patent application (JP-A-3-7)
2426). The main drug, aspirin, is not a so-called strong analgesic drug but a general extremely safe hypothermia and analgesic drug. Therefore, the good analgesic therapeutic effect of this ointment is remarkable.

However, as is well known, aspirin is liable to cause hydrolysis or alcohol decomposition with removal of an acetyl group, and lacks stability over time. Therefore, it is difficult to produce aspirin while industrially producing it. It has not been widely marketed.

[0005]

The present invention has been made in view of the above-mentioned circumstances, and an object thereof is to provide an external preparation for analgesia, which has an excellent analgesic effect, is stable over time, and is safe. That is, external use liquid, ointment, cream, suppository,
Alternatively, it is to provide a patch such as a poultice and a plaster.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in order to achieve the above-mentioned object, a drug selected from the salicylamide compounds described above was used and various external bases were used. Various external preparations obtained by mixing with or uniformly dissolving or suspending, and dispersing, have excellent stability and therapeutic effect, and have found that side effects such as gastrointestinal disorders and skin irritation are not observed, and the present invention It came to completion.

That is, the present invention is an external preparation for analgesia, which comprises one or more salicylamide compounds as an active ingredient. The compound represented by the general formula (1) is a typical antipyretic and analgesic drug listed in the 12th revised Japanese Pharmacopoeia as etenzamid when R = C ₂ H ₅ , and R = CH ₂ In the case of COOH, salicylamide-O
-Acetic acid, in the case of R = H, it is an analgesic known as salicylamide, and it is a group of compounds that are not only safe but also stable in terms of chemical structure. Only as an internal medicine, it has never been considered to be used as an external preparation such as an ointment or a patch, and there has been no case in which it was carried out.

In the present invention, the amount of the salicylamide compound compounded in the external preparation can be arbitrarily selected according to the necessity of treatment and is not particularly limited, but generally the total amount of the external preparation (support It is preferable to add 0.1 to 20% by weight based on the total amount (excluding body, container, etc.).

The salicylamide compound used in the present invention may not be sufficiently dissolved in the base material as it is depending on the blending amount, and in this case, it may be used as a suspension or dispersion. However, it can also be mixed uniformly with the external base material in a dissolved state by using an appropriate dissolving agent.

Examples of such a dissolving agent include water,
Lower alcohols such as ethanol and propanol, linear or branched higher alcohols such as lauryl alcohol, dimethyloctanol and 2-octyldodecanol, glycerin, propylene Polyhydric alcohols such as glycol, polyhydric alcohol ethers such as diethylene glycol monomethyl ether, terpenes such as limonene and pinene, and natural essential oils containing them, isopropyl myristate, dioleic acid Various substances such as higher fatty acid esters such as propylene glycol and ester type nonionic surfactants can be appropriately used. The blending amount of these solubilizers varies depending on the dosage form, but generally, it is 0.
2 to 100 times is appropriate.

The method for producing the external preparation of the present invention comprises
Although it depends on the content, a general method known for each dosage form of the external preparation can be adopted. For example, the liquid preparation for external use is a salicylamide-based compound glycerin,
It can be produced by mixing it with an alcohol or the like and adding an emulsifier, and the ointment is produced by homogenizing a salicylamide compound and a base such as hydrophilic ointment, hydrophilic petrolatum or paraffin by a kneading method or a melting method. be able to.

The cream can be prepared by mixing it with white paraffin, stearyl alcohol, propylene glycol, etc., and the suppository can be prepared by using a water-soluble base, an oily base or an emulsifier. Furthermore, the patch can be produced by mixing a salicylamide compound with a mineral base, glycerin, an acrylic acid polymer or the like.

Further, in the external preparation of the present invention, generally used surfactants, buffers, stabilizers, preservatives, percutaneous absorption enhancers, thickeners, gels are used depending on the dosage form and the like. Any one kind or two or more kinds can be selected and mixed from the agent, the moisturizing agent and the like.

The external preparation of the present invention formulated and formulated as described above is as shown in the following examples.
It is stable over time, has an excellent analgesic effect, and even when actually applied to patients, good results have been obtained. Furthermore, the external preparation of the present invention has almost no taste, is mild to skin and mucous membranes, and can be used for a long period of time.

[0015]

EXAMPLES Examples will be described below, but the present invention is not limited thereto. [Example 1] 78 parts of plastibase (Taisho Pharmaceutical Co., Ltd.) was gradually added to 2 parts of finely powdered etenzamid (pharmaceutical product) and mixed well, and 20 parts of a mixture of sodium carboxymethyl cellulose was added thereto. Was gradually added and thoroughly mixed so that the whole quality was uniform to obtain an ointment suitable for oral use and the like.

Example 2 An ointment for oral cavity was obtained in the same manner as in Example 1 except that salicylamide was used instead of ethenamide in Example 1.

Example 3 Fine powdered etenzamid 2
Part, polysorbate 805 was added and mixed thoroughly, and then 93 parts of plastibase was gradually added and mixed well to obtain an ointment of uniform quality which can be applied to, for example, herpes zoster. It was

[Example 4] Polyoxyethylene hydrogenated castor oil 605 (5 parts) and hydrogenated rapeseed oil (30 parts) were heated and dissolved,
After cooling, 58 parts of isopropyl myristate was gradually added and mixed well, and a solution prepared by dissolving 2 parts of etenzamid in 5 parts of isopropanol was added to the mixture and kneaded until the whole quality became uniform. Then, an ointment suitable for rheumatoid arthritis and the like was obtained.

[Example 5] 0.3 part of methylparaben was dissolved in 33.6 parts of purified water under heating, and a solution prepared from 2 parts of etenzamid and 13 parts of propylene glycol was added, and then 2 parts of dimethylacetamide and lauryl. Sodium sulfate 1.
5 parts sequentially added liquid and 25 parts white paraffin separately,
A liquid obtained by heating and melting 22.6 parts of stearyl alcohol was mixed, emulsified, and cooled to obtain a cream agent.

Example 6 Oleyl alcohol 4.65
Parts, 2.85 parts of dimethylstearylamine and 5 parts of ethenzamid were mixed together with 5 parts of sorbitan fatty acid ester and 82.5 parts of glycerin fatty acid ester, heated and melted at 70 ° C., stirred, and then heated to a shell-shaped form. It was dispensed inside and cooled from the outside to obtain a suppository.

Example 7 A mixture of 30 parts of glycerin and 10 parts of propylene glycol was mixed with 6 parts of sodium polyacrylate and 0.2 parts of aluminum hydroxide to prepare 0.8 parts of tartaric acid. It is dissolved in 43 parts of water, added to a dispersion containing 1 part of carboxyvinyl polymer and 1 part of polyacrylic acid, and kneaded. To this, a solution prepared by adding 6 parts of N-methyl-2-pyrrolidone to 2 parts of etenzamid and kneading the mixture sufficiently to form a base, and spreading the base onto a non-woven fabric to give a patch. Got

[Example 8] 2 parts of etenzamide were added to 23.3 parts of N-methylpyrrolidone and 23.
3 parts by weight, then 3.8 parts by weight of polyvinylpyrrolidone K-90 and stirred under vacuum, then 47.6 parts by weight of acrylic acid copolymer (Primal N-580NF) were added and further mixed to obtain The obtained uniform adjusting solution was applied onto a release paper and dried to obtain a plaster agent.

[Example 9] 2 parts of propylene glycol,
Nikkor BC20TX 0.6 parts, Nikkor SO-
10 1.4 parts, ethanol 5 parts, and water 85 parts were mixed to prepare a base for a liquid preparation for external use. In this base, 2.8 parts of D-limonene, 1.2 parts of dimethylstearylamine, and etenzamid were prepared. The liquid prepared from 2 parts was added with vigorous stirring with a homogenizer, and then placed in a plastic container with a sponge for coating to obtain a liquid agent for external use.

[Preparation stability test and results] (1) Preparation of sample 20 mg of 2% ethenzamid ointment prepared in Example 1 was precisely weighed, and isopropanol 9 ml and salicylic acid aqueous solution (600 mg / distilled water 1000 ml) 1 ml were prepared. Add 1
It was extracted by sonication twice for 0 minutes each. Extract 5
Add 500 μl of distilled water to 00 μl and mix to mix
Filter with a C3JP filter and add 30 μl to HPL.
It was injected into C and the etenzamid content was measured.

(2) HPLC measurement conditions As target liquids, 100 µl of an ethenamide aqueous solution (80 mg / distilled water 1000 ml) and a salicylic acid aqueous solution (120
mg / distilled water 1000 ml) 100 μl, distilled water 200
μl was mixed and 50 μl was injected on the HPLC. Column: TSKgcl ODS80TM (4.6
mm id × 150 mm) Transfer phase: CH ₃ CN—H ₂ O (35:65 V / V)
+ 0.1% TFA Flow speed: 1 ml / min Detection wavelength: UV λ = 290 nm Chart speed: 1 cm / 2 min

(3) Results As shown in FIG. 1, those stored at 5 ° C., 20 ° C. and 30 ° C. were quite stable even after 6 months.

[Animal Analgesic Test and Results of Preparation] (1) Analgesic Test Method A beer yeast-induced inflammatory foot pain suppression test was carried out by the Randall-Selitto method. Weight 200-230g
6-week-old male Wistar rats of 20% beer yeast physiological saline suspension 0.1 was added to the right hind footpad of the rat.
ml was subcutaneously injected to induce inflammatory paw edema. Immediately before starting the test (immediately before ointment application) using a pressure-stimulating analgesic effect measuring device from 1 week after injection of beer yeast to every 5 hours after 1 hour
The pain threshold was measured with the value of 1 as 1. For the measurement, sample A described below was used, and 1 week after injection of beer yeast, 1
It was applied by g / paw and capped. For comparison, the same test was performed when the sample B described later was used as a comparative sample and when no sample was used (no drug was applied).

(2) Sample Sample A is a 2% etenzamid ointment prepared in Example 1.
Sample B is a 2% aspirin ointment manufactured in exactly the same manner as in Example 1 except that the main drug etenzamid of Example 1 was changed to aspirin. (3) Results Sample A was 2% used as a comparative sample as shown in FIG.
It was as effective as aspirin ointment.

[0029]

As described above, the external analgesic agent of the present invention is remarkably excellent in drug stability as compared with an external preparation (ointment, patch) using aspirin as an active ingredient,
It has low irritation and is comparable to the analgesic effect. Therefore, the present invention makes it possible for the first time to provide a marketable external medicine for analgesia, and its practical value is great.

[Brief description of drawings]

FIG. 1 is a graph showing the stability of etenzamid in the external preparation according to the present invention.

FIG. 2 is a graph showing a pain threshold value ratio when the external preparation according to the present invention is used and when the external preparation according to the comparative example is used.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 9/70 341 A61K 9/70 341

Claims (1)

[Claims] 1. A compound represented by the general formula (1): An analgesic external preparation containing a compound represented by (R is hydrogen, lower alkyl or carboxy lower alkyl group).