JPH06145055A - Medicine for local administration - Google Patents

Abstract

PURPOSE: To provide a medicament adequate for treatment by topical administration or as an analgesic-inflammatory agent for animals. CONSTITUTION: This medicament is obtd. by using L-lysine salt of 2-[(3chloro-2- methyl phenyl)amino]-3-pyridinecarboxylic acid at 1 to 10 wt.% as an essential component, a pharmaceutically permissible emulsifying agent 2 to 15 wt.%, a pharmaceutically permissible emollient agent at 2 to 20 wt.% and a pharmaceutically permissible antiseptic at 0.01 to 0.2 wt.%, adding water thereto to make 100 wt.% or further adding 0.2 to 5 wt.% florid agent at need thereto and adding the corresponding volume of water to the mixture to adjust the total amt. to 100 wt.%.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention preferably has a cream or gel as a dosage form and has the general formula (1) as an active ingredient.
L- of 2-[(3-chloro-2-methylphenyl) amino] -3-pyridinecarboxylic acid represented by Chemical formula 1
Lysine salt (hereinafter lysine clonixinate (lysi
(also referred to as “ne clonixinate”).

[0002]

[Chemical 1]

The pharmaceutical agent of the present invention is useful as a topical analgesic and anti-inflammatory agent.

[0004]

2. Description of the Related Art Drugs or injection solutions to be administered orally or rectally containing lysine clonixinate as an active ingredient are described in, for example, German Published Patent Specification No. 2,253,1.
No. 34 and US Pat. No. 3,973,027, and are commercially available.

However, although the drugs in these dosage forms are excellent in analgesic and anti-inflammatory action, they may not be suitable or may not be administered depending on the case. For example, after a bruise or a blow or a minor accident,
In the case of pain in a part of the body, bruises, sprains, dislocations, arthritis, arthritis, tendon pain, bursitis, muscle aches, sports trauma, topical administration of the drug is generally the most suitable method of administration, Therefore, it is considered to be the optimal treatment method. In addition, by using more than necessary active ingredients to reduce or cure pain inflammation, it may cause unnecessary secondary effects, or may induce addiction or dependence on the active ingredients, or conversely It should be avoided that sufficient improvement cannot be obtained by using the active ingredient. In conclusion, topical agents such as creams or gels are more preferable, especially if the patient is free to buy generic drugs and treat them themselves.
Less dangerous than tablets. Therefore, providing a drug for local administration having an average analgesic and anti-inflammatory effect is an important medical problem.

Topical agents containing analgesic and anti-inflammatory agents as active ingredients are widely known in the literature. For example, concerning diclofenac amine salt, Dutch published patent specification No. 8,100,917 (1982), Chinese patent specification 651,474 (1985) and US patent specification No. 4, 407, 82
There is No. 4 (1983). Further, German Published Patent Specification No. 2,935,776 (1981) lists anti-inflammatory agents with various organic salts suitable for topical administration.

The present inventors have found that the L-lysine salt of 2-[(3-chloro-2-methylphenyl) amino] -3-pyridinecarboxylic acid is suitable for formulating a composition for topical administration, and this route of administration is preferable. It has been found that the product has an extremely excellent effect.

[0007]

SUMMARY OF THE INVENTION Therefore, the present invention provides
2-[(3-chloro-2-methylphenyl) by weight
Amino] -3-pyridine L-lysine salt of carboxylic acid as an active ingredient is 1 to 10% by weight, a pharmaceutically acceptable emulsifier is 2 to 15% by weight, a pharmaceutically acceptable emollient (em).
2 to 20% by weight, 0.01 to 0.2% by weight of a pharmaceutically acceptable preservative, and 1 to which water is added.
A drug for topical administration (topical analgesic and anti-inflammatory agent) in which the amount is 00% by weight, and preferably the dosage form is a cream or gel.
Is provided. If necessary, the above pharmaceutical composition may contain 0.2 to 5 redefactants.
% By weight, 3-18% by weight of pharmaceutically acceptable lubricant in the case of cream, or pH-in the case of gel.
It is possible to add 0.5 to 5% by weight of a regulator and water to adjust to 100% by weight in any case.

The drug of the present invention has the following excellent properties. -It is a local action. -The reaction is quick because of the fast absorption. -Low toxicity in tissues or organs without injury or damage.

In one embodiment of the present invention, the pharmaceutical composition for topical administration contains 3 to 7% by weight of L-lysine salt of 2-[(3-chloro-2-methylphenyl) amino] -3-pyridinecarboxylic acid as an active ingredient. , A pharmaceutically acceptable emulsifier 3-1
3% by weight, 3 to 10% by weight of a pharmaceutically acceptable emollient,
A pharmaceutically acceptable preservative was used in an amount of 0.02 to 0.1% by weight and 100% by weight of water added thereto. If necessary, 0.5 to 2% by weight of a reddening agent, 8 to 12% by weight of a pharmaceutically acceptable lubricant in the case of cream, and 1 to 3% by weight of a pH adjusting agent in the case of gel. In any case, the total amount can be 100% by adding water and adding water.

The emulsifiers are glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, ketostearyl alcohol / lauryl sulphate (eg sodium lauryl sulphate or potassium lauryl sulphate).
cohol / lauryl sulphate fore
xample potassium and sodi
um lauryl sulphate) (emulsified wax)
It is advantageous to choose from the group consisting of and carbomers. .

The emollient (softening agent) is preferably selected from propylene glycol, glycerol, sorbite and isopropyl myristate.

The above preservatives include methyl paraben,
Ethyl paraben and propyl paraben have proven suitable.

It is advantageous to use menthol as the reddening agent.

As described above, the medicine of the present invention is preferably a general medicine in the form of cream or gel.

When formulating the medicament of the invention as a cream, it is advantageous to use ketostearyl alcohol / lauryl sulphate ("emulsifying wax") as emulsifier,
The lubricant is selected from the group consisting of mineral oil, petrolatum and fatty acids.

When the medicine of the present invention is formulated as a gel, the emulsifier is a carbomer,
Propylene glycol is advantageously used as a emollient (softening agent), and the pH-adjusting agent, that is, the buffer is sodium hydroxide, triethanolamine, trimethamine (tris (hydroxymethyl) aminomethane).
And lysine.

In both cases of cream and gel, isopropyl myristate is most suitable as a emollient (softening agent).

Preferred preservatives are methyl paraben and propyl paraben.

According to the present invention, 2-[(3-chloro-2-
Methylphenol) amino] -3-pyridine Carboxylic acid L-lysine salt can be used to produce a topical analgesic and anti-inflammatory agent for medical or veterinary use.

[0020]

EXAMPLES Next, the present invention will be described in more detail by way of examples. Example 1: Preparation of topical medicine in the form of a cream without addition of a reddish agent A cream was prepared according to the following composition. Lysine clonixinate 5.0% by weight Isopropyl myristate 9.0% by weight Methyl paraben 0.1% by weight Emulsifying wax 13.0% by weight Mineral oil 10.0% by weight Water added 100.0% by weight Lubricants, emulsifiers and The moderators melted together at 65-70 ° C. The active ingredient and the preservative were dissolved in water, the above oil phase was added to this aqueous solution with continuous stirring, and the mixture was cooled to room temperature to prepare a desired cream.

Example 2: Preparation of a topical medicine in the form of a cream containing a reddishing agent A cream was prepared according to the following composition. Lysine clonixinate 5.0% by weight Isopropyl myristate 10.0% by weight Methyl paraben 0.1% by weight Propyl paraben 0.02% by weight Emulsified wax 10.0% by weight Vaseline 10.0% by weight Menthol 1.0% by weight Water In addition 100.0 wt% lubricant and emulsifier melted together at 65-70 ° C. The active ingredient and the preservative were dissolved in water, and the above oil phase was added to this aqueous solution while continuously stirring. Menthol was dissolved in a relaxation agent to obtain a menthol / relaxation agent solution. The mixture was cooled to 40 ° C., the menthol / relaxation agent solution was added to the above emulsion with continuous stirring, and the mixture was cooled to room temperature to prepare a desired cream.

Example 3: Preparation of a topical drug in the form of a gel without addition of a erythrocyte A gel was prepared according to the following composition. Lysine clonixinate 5.0% by weight Carbomer 3.0% by weight Propylene glycol 5.0% by weight Isopropyl myristate 3.0% by weight Glycerol 3.0% by weight Methyl paraben 0.1% by weight Propyl paraben 0.02% by weight % Sodium hydroxide 1.5% by weight Water was added and 100.0% by weight of the active ingredient was dissolved in a mixture of propylene glycol and glycerol (solution A). The preservative was dissolved in water, the emulsifier was dispersed in this aqueous solution, and a buffer (pH-adjusting agent) was added (dispersion B). Solution A was poured into dispersion B and finally isopropyl myristate was added.

Example 4: Preparation of topical medicine in the form of gel with reddish agent A gel was prepared according to the following composition. Lysine clonixinate 5.0% by weight Carbomer 3.0% by weight Propylene glycol 6.0% by weight Isopropyl myristate 3.5% by weight Methyl paraben 0.1% by weight Sodium hydroxide 2.0% by weight Menthol 1.0 100.0 wt% active ingredient was dissolved in propylene glycol and one third of the total amount of water (solution A). The preservative was dissolved in the remaining two thirds of the water, the emulsifier was dispersed in this aqueous solution, and a buffering agent (pH-adjusting agent) was added (dispersion B). Solution A was poured into dispersion B with stirring, and finally menthol dissolved in isopropyl myristate was added thereto.
After measuring the pH value, it was adjusted to 8.2 to 8.9.

The following Examples 5 and 6 show that the topical agents of the present invention are advantageous by comparing with conventional analgesic anti-inflammatory agents (Diclofenac) for improvement of inflammation and (transdermal) absorption. It is shown.

Example 5 Anti-inflammatory effect [carrageenan (ca produced on the paw of an experimental animal)
edema derived from rragjeenin)] Wistar rat weighing 175 to 200 g (Wist)
er rats) for both sexes
ter) et al. (J. Pharmacol. and
Exp. Therap. 1949, 96; 9
Carrageenan 1%, that is, 0.1 ml, was administered to the paw in the same manner as 9). The experimental animals consisted of 6 animals per group and 3 groups, and 30 minutes before the above administration, each group was treated with the following composition: The rat's back was shaved beforehand. A 20 cm ³ portion was treated with 20 mg / k of the same lysine clonixylate 5% cream as in Example 1.
g, or diclofenac sodium 5% added to the vehicle was treated with 20 mg / kg. Three and five hours after carrageenan administration, Hugo basil (Ug
oBasile) plethysmometer was used to measure paw inflammatory edema. The degree of reduction of inflammation, that is, the degree of reduction was calculated as a percentage compared with the control group. The results are summarized in Table 1 below.
Shown in.

[0026]

[Table 1]

Example 6 Transdermal absorption [Comparative test was carried out between creams and gels each containing lysine clonixylate and their corresponding conventional commercial products] Fressieusia giant rabbit ( A 10 cm ³ region of the back of the Flemish giant rabbits was shaved beforehand and used as an experimental animal. Each group had 3 animals, and the experimental animals were treated with the following formulation and dose. a) Lysine clonixylate 5% cream, prepared in the same manner as in Example 1, 20 mg / kg [LC in FIG. 1]
(Cream)] b) Lysine clonixate 5% gel, prepared in the same manner as in Example 3, 20 mg / kg [LC (Ge in FIG. 1)
l)] c) Diclofenac sodium 5% cream, 2
0 mg / kg [D (Cream) in FIG. 1] d) Diclofenac diethyl ammonium salt 5
% Gel, 20 mg / kg [D (Gel) in FIG. 1] A blood sample was taken from the central artery of the ear, and the concentrations of two active ingredients were measured. The measurement results are shown in Table 2 below and FIG.

[0028]

[Table 2]

[0029]

EFFECTS OF THE INVENTION As is clear from the above description, according to the present invention, there is provided a medicine excellent as a medical or animal analgesic and anti-inflammatory agent by local administration.

[Brief description of drawings]

FIG. 1 is a graph showing the concentration of lysine clonixinate (LC) and diclofenac (D) by dosage form and elapsed time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 47/32 H 7433-4C 47/44 H 7433-4C

Claims (13)

[Claims] 1. 2-[(3-Chloro-2-methylphenyl) amino] -3-pyridine Carboxylic acid L-lysine salt as an active ingredient 1 to 10% by weight, a pharmaceutically acceptable emulsifier 2 to 15 % By weight, pharmaceutically acceptable emollient 2
~ 20% by weight, 0.01 to a pharmaceutically acceptable preservative
0.2% by weight, which contains 100% by weight of water, or 0.2 to 5% by weight of a reddening agent, if necessary, and a corresponding amount of water is added to make the total amount. A pharmaceutical for topical administration, which comprises 100% by weight of 2. A cream or gel is used as a dosage form, and in the case of a cream, a pharmaceutically acceptable lubricant 3 to the above composition is used.
18% by weight, and in the case of gel, 0.5 to 5% by weight of a pH-adjusting agent is added to each of them, and water is added in an amount corresponding to each case to adjust to 100% by weight. 1. The medicine according to 1. 3. 2-[(3-Chloro-2-methylphenyl) amino] -3-pyridine Carboxylic acid L-lysine salt as an active ingredient 3 to 7% by weight, pharmaceutically acceptable emulsifiers 3 to 13 % By weight, pharmaceutically acceptable emollient 3 to
10% by weight, pharmaceutically acceptable preservative 0.02-0.
1% by weight, 100% by weight with the corresponding amount of water
Or 2 to 10% by weight of a reddening agent, if necessary, 8 to 12% by weight of a pharmaceutically acceptable lubricant in the case of cream and p in the case of gel.
3. 1 to 3% by weight of H-conditioning agent are added to each, and in each case a corresponding amount of water is added to adjust in each case to 100% by weight. Medicine. 4. The method according to claim 1, wherein the emulsifier is selected from the group consisting of glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, ketostearyl alcohol / sodium lauryl sulphate and carbomer. The drug according to any one of claims. 5. The relaxation agent is propylene glycol,
It is selected from the group consisting of glycerol, sorbite and isopropyl myristate.
4. The medicine according to any one of 4. 6. The medicine according to any one of claims 1 to 5, wherein the preservative is selected from the group consisting of methyl paraben, ethyl paraben and propyl paraben. 7. The medicine according to claim 1, wherein the reddening agent is menthol. 8. The medicine according to any one of claims 2 to 7, wherein, in the case of a cream, the emulsifier contains ketostearyl alcohol / sodium lauryl sulfate. 9. The medicine according to claim 2, wherein when it is a gel, it contains carbomer as the emulsifier. 10. A propylene glycol as the easing agent, which is characterized by containing propylene glycol.
The drug according to any one of 1. 11. The medicine according to claim 2, which contains isopropyl myristate as the emollient. 12. The medicine according to any one of claims 2 to 11, which contains methylparaben or propylparaben as the preservative. 13. An analgesic and anti-inflammatory agent for topical administration for medical or animal use, which comprises an L-lysine salt of 2-[(3-chloro-2-methylphenyl) amino] -3-pyridine carboxylic acid.