JPS5976013A - Gelatinous pharmaceutical for surgical use - Google Patents

Abstract

PURPOSE:A gelatinous pharmaceutical for surgical use, prepared by formulating ''Diclofenac Sodium'' which is an active constituent with a specific medium, a carboxyvinyl polymer which is a gelling agent and a weakly basic substance which is a neutralizing agent, useful as an anti-inflammatory and analgesic agent, and having improved stability and feeling of use. CONSTITUTION:A gelatinous pharmaceutical for surgical use prepared by formulating ''Diclofenac Sodium'' of the formula with water, a lower alkanol or a glycol as a medium, a carboxyvinyl polymer as a gelling agent and a weakly basic substance as a neutralizing agent. The content of the compound expressed by the formula is preferably 0.5-2wt%. A combination of water, lower alkanol, e.g. ethanol or isopropanol, glycol, e.g. propylene glycol or 1,3-butylene glycol is required for the medium. An aliphatic amine is preferred for the weakly basic substance. The pharmaceutical has improved anti-inflammatory and analgesic effects by the percutaneous absorption and further improved stability and feeling of use.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external gel preparation containing diclofenac sodium as an active ingredient and exhibiting good stability and usability.

Diclofenac sodium is a phenylacetic acid derivative represented by the formula: Not known. When administered orally or in small doses,
Diclofenac sodium exhibits excellent anti-inflammatory and analgesic effects, but there are problems with side effects such as gastrointestinal, liver, and kidney damage when administered in a single dose. Analgesics are desired.

From this point of view, a topical gel preparation of indomethacin, a non-steroidal drug, is known (Special I5N 1983-1981).
616). However, this formulation has stability problems,
Also, because indomethacin itself is yellow, v! It also has a yellow color and has the disadvantage of staining clothes when applied to the skin. Therefore, the inventor of the present invention developed a solution consisting of another non-steroidal anti-inflammatory analgesic compound and a sufficient amount of peppermint oil and at least one salicylic acid ester to dissolve the compound, and a topical base. He invented a topical preparation (Japanese Patent Application No. 56-128032), but all of the anti-inflammatory and analgesic compounds are water-insoluble.

In view of the above-mentioned situation, the inventor of this invention conducted research into a drug for diclofenac sodium, which has excellent anti-inflammatory and analgesic effects, and came up with this invention.The active ingredient is diclofenac sodium. To provide a gel preparation for external use, characterized in that it is formulated with water as a hindering agent, lower alkanols and glycols, a carboxyvinyl polymer as a gelling agent, and a weakly basic substance as a neutralizing agent. It is something. The external gel preparation of the present invention has excellent anti-inflammatory and analgesic effects due to transdermal absorption, is excellent in stability, and has a good feel when used.

The content of diclofenac sodium, the active ingredient in the gel preparation of this invention, is usually 0.3 to 3.0%,
Preferably it is 0.5 to 2.0% by weight.

Water, lower alkanols and glycols are used as vehicles for this active ingredient.

Although it is possible to prepare stable gels by combining water and lower alkanols or consolidating water and glycols in these media, the use of water and lower alkanols may cause skin irritation. When applied, it dries too well, causing crystals to precipitate on the skin surface, resulting in poor absorption of the active ingredient diclofenac sodium.-1
When water and glycols are used, a small amount (more than 30% of both is required) considering skin irritation due to pH. However, if more than 30% of glycols are used in this gel, it may dry out when applied to the skin. Glycols also cause skin irritation, which is a problem.

A combination of water, lower alkanols and glycols is therefore required.

The amount of the medium used in the preparation of this invention is small (at least an amount sufficient to dissolve the active ingredient, and an amount that constitutes the remainder of the total of the gelling agent, neutralizing agent, active ingredient, etc. in the preparation). .

Further, the weight ratio of water and other organic medium is, for example, 8:2.
~4:6. In particular, water is preferably 80% by weight or less, lower alkanols are preferably 60% by weight or less, and glycols are preferably 40% by weight or less. A preferred mixing weight ratio of the medium used in this invention is about 60=30:10 of water:lower alkanol nigericol.

Examples of lower alkanols include methanol, ethanol, propatool, impropatol, butanol, and among these, ethanol and impropatol are preferred.

Examples of glycols include ethylene glycol, propylene glycol, and 1,3-butylene glycol, among which propylene glycol and 1,3-butylene glycol are preferred.

The most preferred combination of the above three media is water-ethanol-propylene glycol or water-ethanol-1,3-butylene glycol.

Carboxyvinyl polymers used as gelling agents are
It is a hydrophilic polymer obtained by polymerizing acrylic acid as a main component, and it is desirable to use commercially available products. Commercially available products include Hibiswako-103, 104, and 105 manufactured by Wako Pure Chemical Industries. Carboball 934 and 940 manufactured by Gutdrich Chemical Co., USA. 941
Examples include.

In the formulation 1 according to the present invention, a weakly basic substance is used as a neutralizing agent, and its use is limited to medium (around /1, i.e., pTT 6-8, preferably pTT 6.5-7.
It can be adjusted to fit 5 tumors. This M may be achieved, for example, with 0.1-5W1% in the formulation.

The weakly basic substance is preferably an aliphatic amine. The aliphatic amine C includes primary, secondary and tertiary alkanolamines or alkylamines. Specific examples of alkanolamines include monoethanolamine, jetanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, and the like.

Examples of the alkylamine include dimethylamine, diethylamine, trimethylamine, and triethylamine. Particularly preferred among these are triethanolamine and diisopropanolamine. The use of this neutralizing agent is one of the features of the present invention, and it has been found that the use of strong bases such as IJium hydroxide as a neutralizing agent is unsuitable. That is,
Comparing the acid strength of carboxyvinyl polymer and diclofenac in the free acid form, carboxyvinyl polymer has stronger acid strength. However, carboxyvinyl polymer itself is a weak acid, so when it is neutralized with a strong base such as sodium hydroxide, pT (pT) increases to around 9. Diclofenac sodium gel is prepared using the gel in this state as a base. However, if it becomes too basic to around pH 9, it is not suitable for external use because it irritates the skin.On the other hand, if a diclofenac sodium gel is prepared with Sumima, which does not neutralize the ruboxyvinyl polymer with sodium hydroxide, Even if the carboxyvinyl polymer has a pT (nearly 7), this polymer has a stronger acid bar than diclofenac, so the sodium ions of diclofenac sodium combine with the carboxyvinyl polymer. The free acid form of diclofenac is formed in the gel formulation. Although diclofenac is stable in its sodium salt form, it itself has low solubility, and the active ingredient in the formulation also has poor stability over time. In addition, the gel formulation of this invention has
If desired, a small amount (one or more) of peppermint oil, l-menthol, salicylic acid methyl ester, salicylic acid ethyl ester, and monosalicylic acid glycol ester may be added. has the effect of promoting the absorption of the active ingredient into the skin and increasing the analgesic effect by being applied as an stimulant when people complain of pain.The amount of these auxiliary agents added is usually 0.5 to 5% by weight in the gel preparation. be.

Although there are no particular limitations on the method for producing the gel preparation of the present invention, it can be produced, for example, by the following method. Add a carboxyvinyl polymer aqueous solution and glycol to a solution of diclofenac sodium dissolved in lower alkanol, stir well, and add a neutralizing agent while stirring until the pH of the gel formulation is approximately 6.
The gel of the present invention can be obtained by adding a vessel length of .about.8.

Alternatively, the gel preparation of the present invention can also be produced by adding an aqueous carboxyvinyl polymer aqueous solution with stirring to a solution of diclofenac sodium dissolved in a mixture of lower alkanol and glycol, and adding a neutralizing agent while stirring. can.

In addition to the above-mentioned salicylic acid ester, the gel preparation of the present invention may optionally contain a small amount of aromatic agents, preservatives, coloring agents, etc. that can be used in the field. However, it is usually not necessary to add such additives (good formulations are obtained).

The gel preparation of the present invention obtained as described above has excellent stability, does not change in viscosity even at high temperatures (and does not precipitate crystals even at low temperatures), and has good skin spreadability and excellent spreadability. It is a gel formulation with excellent drying properties and no sticky feeling.

Next, the present invention will be explained by showing examples of formulations of the present invention and reference examples of formulations with similar compositions and low pH.

Example 1 Diclofenac sodium 1y in 95% ethanol 3
Stir to dissolve at 0y. On the other hand, propylene glycol 1
0g, carboxyvinyl polymer car ice ball 940
25 g of 4% aqueous solution and 20 g of purified water were uniformly stirred,
Add 1.5 y of triethanolamine while continuing to stir to prepare a gel paste.

Add the alcohol solution of diclofenac sodium prepared earlier to this gel paste, and then add purified water to make a total volume of 1.
00y and stirred sufficiently to obtain a gel preparation.

Viscosity 20,000 centivoise p'H7,15 Example 2 Diclofenac Sodium 0.5. Dissolve in 25 y of 95% ethanol with stirring. -1.3- Butylene glycol 20g, Carbopol 9404% aqueous solution 25g
Then, 20 g of purified water was stirred, and while stirring was continued, 1.5 f of triethanolamine was added to prepare a gel paste. The previously prepared alcoholic solution of diclofenac sodium was added to this gel paste, and purified water was added to make a total amount of 100 g. The gel paste was thoroughly stirred to obtain a gel preparation.

Viscosity 22,000 centipoise pH 7.15 Example 3 3.0 g of diclofenac sodium and 0.51 l-menthol are dissolved in 40 y of 95% ethanol with stirring. Whereas propylene glycol log, force - bopol 9
25y of 404% aqueous solution and 15g of purified water were uniformly stirred, and while stirring was continued, diisopropanolamine was added.3.
Add Of to prepare gel paste.

Add the previously prepared alcoholic solution of diclofenac sodium to this gel paste, and then add purified water to make a total
k 100y and stirred thoroughly to obtain a gel preparation.

Viscosity 17,000 centivoise p)T, 7.20
Reference Example 1 Diclofenac sodium 1.0y and peppermint oil 3.
Dissolve Og in 40p of 95% ethanol with stirring. −
10,000 Carbo Ball 9403% Propylene Glycol Solution 2
0y, Carbopol 9404% aqueous saline 25y, citric acid 0.31 and purified water 8. Oy was stirred uniformly 7, and while stirring was continued, triethanolamine 0. Os, is added to prepare a gel paste.

First, add 1 to this gel pace. M? An alcoholic solution of diclofenac sodium and peppermint oil were added thereto, and purified water was further added to make a total amount of 100 g, followed by sufficient stirring to obtain a gel preparation.

Viscosity 22,000 centiboise pT (5,2 Reference Example 2 Dissolve 1.0 g of diclofenac sodium in 40 g of 95% ethanol by stirring.-10,000 Carbobol 94
20 y of 03% propylene glycol solution, 25 g of Carbopol 9404% aqueous solution, and 10 y of purified water were uniformly stirred, and while stirring was continued, 0.0 y of triethanolamine was added.
051/ to prepare a gel paste.

Diclofenacna previously prepared in this gel paste)
An alcoholic solution of IJum was added, and purified water was further added to the mixture, and the mixture was thoroughly stirred to obtain a gel preparation.

Viscosity: 23,000 centipoise pT (5,4 Reference Example 3 Dissolve 1.0 g of diclofenac sodium in 20.1 of 95% ethanol with stirring.-10,000 Carbopol 94
03% propylene glycol solution 40. , Kerr, jE.
? -/l/9404% aqueous solution 1% 16Jl: %71
Stir 25 g of water uniformly and add 0.8 y of triethanolamine while continuing to stir to prepare a gel paste.

Add the previously prepared alcoholic solution of diclofenac sodium to this gel paste, and then add purified water to completely dissolve the W.
100. The mixture was thoroughly stirred to obtain a gel preparation.

Viscosity 71f 21,000 centiboise pH 5.8 Next, the stability over time of diclofenac sodium in the gel formulations of the above Examples and Reference Examples was compared.

That is, diclofenac sodium containing #1 in each formulation was measured by the following analysis method immediately after the formulation and after m-times, and the changes over time were shown in Figure 1.
Figures 2 to 4 show the formulations of Reference Examples 1 to 3, respectively (horizontal axis: elapsed days, vertical axis: content when the active ingredient immediately after formulation is taken as 100%).

As a result, it is clear that the formulation of Example 1 has significantly higher stability of the active ingredient over time than the formulations of other reference examples.

The diclofenac sodium content in the formulation was determined by first extracting the diclofenac sodium in the formulation with ethanol, and then performing high performance liquid chromatography [Column: Lichrosorb RP14 mobile phase: methanol/water/acetic acid, 600:400:5
.

Room temperature] and separated, and analyzed by measuring ultraviolet absorbance (254 nm).

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes over time in the diclofenac sodium content in the formulation of Example 1 of the present invention;
Figures 2 to 4 are graphs showing changes over time in the diclofenac sodium content in the formulations of Reference Examples 1 to 3, respectively. 15- Figure 1 Figure 2 16- Figure 3 Figure 4

Claims (1)

[Claims] 1. The active ingredient diclofenac sodium is formulated with water as a medium, lower alkanols and glycols, a carboxyvinyl polymer as a gelling agent, and a weak basic substance as a neutralizing agent. An external gel preparation characterized by: 2. Diclofenac sodium content is 0.3~
3% by weight of the formulation according to claim 1. 3. The preparation according to claim 1, which is a weakly basic substance or an aliphatic amine. 4. The preparation according to claim 3, wherein the aliphatic amine is a primary, secondary or @tertiary alkanolamine or alkylamine. 5. The preparation according to claim 1, wherein the lower alkanol is ethanol or propatool, and the glycol is ethylene glycol, propylene glyconyl, or 1,3-butylene glycol. 6. The formulation according to claim 1, wherein the pH is adjusted to 6 to 8 with a neutralizing agent. 7. The preparation according to claim 1, to which peppermint oil, l-menthol or salicylic acid ester is added. 8. The preparation according to claim 7, wherein the salicylate is methyl salicylate, ethyl salicylate, or glycol salicylate.