JP2623580B2 - Anti-inflammatory analgesic cream - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to an anti-inflammatory analgesic cream containing ketoprofen as an active ingredient, improves the absorption of ketoprofen, and further improves the stability and feeling of use of the cream. The present invention relates to a preparation excellent in safety.

(Prior art and its problems) Ketoprofen is a non-steroidal anti-inflammatory analgesic having excellent anti-inflammatory and analgesic effects, especially osteoarthritis, tendon, tendonitis, myalgia, trauma and swelling after surgery. -It is a drug widely used for the treatment of pain and the like, and is used not only as an internal medicine but also as a suppository and an external preparation.

Examples of the external preparation include a gel preparation that has been put to practical use. Although some creams are found in patents, none of them have satisfactory absorption effects, and very few preparations satisfy the cream's stability, usability and safety. For example, when lower alcohols are added in order to enhance the solubility of ketoprofen and thereby enhance the absorbability, it is difficult to satisfy both of them, for example, the irritancy derived from the lower alcohols appears.

The present inventors have conducted intensive studies in search of an anti-inflammatory analgesic cream which satisfies the above-mentioned demand, and as a result, have found a ketoprofen preparation which is excellent in ketoprofen absorption, cream stability, usability, and safety, and the present invention Is completed.

(Means for Solving the Problems and Their Action) The anti-inflammatory analgesic cream of the present invention comprises, as an essential component, (i) ketoprofen (ii) monofatty acid glycerin and / or difatty acid glycerin (iii) polyhydric alcohol ( iv) a carboxyvinyl polymer (v) a water-soluble base substance (vi) an emulsifier (vii) water, optionally containing an absorption promoter, a preservative, an ultraviolet absorber, a fragrance, a coloring agent and the like. In the present invention, even higher effects can be exhibited by optimally blending these components.

That is, (i) the compounding amount of ketoprofen is preferably 0.1 to 5 parts by weight based on 100 parts by weight of the total amount. Ketoprofen has a small pharmacological effect when the amount is less than 0.1 part by weight, and causes problems such as irritation of ketoprofen itself when the amount is more than 5 parts by weight.

(Ii) The fatty acid of the mono-fatty acid glycerin and / or the di-fatty acid glycerin is preferably a fatty acid having 6 to 22 carbon atoms, and more preferably a fatty acid having 14 to 22 carbon atoms.
Are preferred. More preferably, the fatty acid is stearic acid and / or isostearic acid,
More preferably, the fatty acid is isostearic acid. The weight ratio of mono-fatty acid glycerin to di-fatty acid glycerin is not clearly defined, but by adding di-fatty acid glycerin, it is possible to increase the hardness of the cream, which is determined by the feeling required for the cream . The compounding amount is preferably 1 to 10 parts by weight, more preferably 1 to 6 parts by weight, and even more preferably 2 to 5 parts by weight, based on 100 parts by weight of the total amount. If the amount is less than 1 part by weight, the absorbability of ketoprofen is insufficient, and if the amount is 10 parts by weight or more, the hardness becomes high and the elongation of the cream becomes insufficient. In addition, it also acts as a surfactant, and exhibits a good skin interface effect.

(Iii) Examples of polyhydric alcohols include glycerin, polyglycerin, propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, 1,3-butylene glycol and the like. The amount is preferably from 1 to 30 parts by weight, more preferably from 2 to 20 parts by weight, and even more preferably from 3 to 15 parts by weight, based on 100 parts by weight of the total amount. If the amount is less than 1 part by weight, the solubility of ketoprofen will be insufficient, and the absorbability from the skin will be poor. If the amount is more than 30 parts by weight, the cream becomes sticky, and the feeling of use becomes worse. In this range, the irritation is extremely low.

(Iv) The carboxyvinyl polymer is a water-soluble vinyl polymer having a carboxyl group in the molecule and includes, for example, Hibiswako 103, 104 and 105 manufactured by Wako Pure Chemical Industries, Ltd. and Carbopol 934, 940 and 941 manufactured by Goodrich Chemical Company. Can be Total amount of carboxyvinyl polymer is 100
The amount can be 0.2 to 5 parts by weight, preferably 0.5 to 3 parts by weight, more preferably 0.5 to 3 parts by weight, based on parts by weight.

(V) Examples of the water-soluble base substance include triethanolamine and triisopropanolamine.
An amount that neutralizes the pH to 4.5 to 6.5 can be added. The addition amount is preferably 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight based on 100 parts by weight of the total amount.

(Vi) The emulsifier is preferably an anionic surfactant and / or a nonionic surfactant. In particular, it has been found that when both are used in combination, the stability is increased. As anionic surfactants, there are carboxylate type, sulfonate type, sulfate ester type and phosphate ester type according to the type; nonionic surfactants include ether type, ether ester type, ester type,
Examples include a block copolymer type of ether and ester. Among them, preferable examples include polyoxyethylene higher alcohol ether phosphates and / or salts thereof, and polyoxyethylene sorbitan fatty acid esters.

The mixing amount of the emulsifier is 1 to 10 parts by weight, preferably 2 to 8 parts by weight, more preferably 3 to 6 parts by weight based on 100 parts by weight of the total amount.
It can be by weight. Furthermore, it has been found that the use of these emulsifiers in this cream system results in less skin irritation.

(Vii) Water is added so that the total amount becomes 100 parts by weight in addition to the above-mentioned components (i) to (vi) and the following components which can be added and mixed as required.

In order to improve the absorbability of ketoprofen, three components of mono- and / or di-fatty acid glycerin, polyhydric alcohol, and carboxyvinyl polymer are essential, and if any of these components is missing, the absorbency decreases. Would.

In addition, it has been found that the addition of a water-soluble base substance and a selected emulsifier results in a cream having excellent cream stability and usability.

That is, the present invention can be completed only by optimally blending the components (i) to (vii).

Also, if desired, (a) absorption enhancers include, for example, Nankodo “Drug Action and Biological Membrane” Fujii,
Examples thereof include isopropyl adipate and isopropyl myristate described on page 224 of both Terada and Nomura. The mixing amount is preferably 0 to 10 parts by weight based on 100 parts by weight of the total amount.

(B) The preservatives include, for example, benzoic acid and its sodium salt, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sorbitan acid and its sodium salt, and the like, or a mixture thereof. On the other hand, 0 to 3 parts by weight is preferable.

(C) Examples of the ultraviolet absorber include p-aminobenzoic acid derivatives and benzophenone derivatives.

The anti-inflammatory analgesic cream of the present invention can be produced, for example, as follows. Ketoprofen, glycerin fatty acid ester, emulsifier and other compounding agents are added to a container heated to 70 to 80 ° C. to make a uniform solution, and then a carboxyvinyl polymer is added and dispersed. Next, the polyhydric alcohol is heated to 70 to 80 ° C.
In hot water, the mixture is added to the dispersion mixture, and the mixture is uniformly emulsified with a homomixer. It should be noted that the cream of the present invention can be obtained even if the blending procedure, blending conditions and the like are changed.

(Effect of the Invention) The anti-inflammatory analgesic cream of the present invention obtained as described above comprises:
When used by applying to the skin, it is a formulation that not only has excellent absorbability and excellent anti-inflammatory and analgesic effects, but also has satisfactory long-term storage stability, usability, and safety of the cream.
The following shows the anti-inflammatory effect of the preparation in a pharmacological test; the safety in a patch stimulation test; the feeling of use in a sensory test; and the stability in an accelerated stability test.

(Examples (including reference examples and test examples)) (Reference examples) Synthesis method of fatty acid glycerin Synthesis of glycerin diisostearate (or glyceryl distearate) 1 mol of glycerin, isostearic acid (or 2 mol of stearic acid) was added, and 0.8 g of KOH was added. The mixture was heated to 220 to 230 ° C. and reacted for 10 hours to obtain glycerin diisostearate (or glyceryl distearate).

Test Method 1 Drug Permeation Experiment Using Extirpated Skin An abdominal depilation skin of a hairless rat (purchased from an experimental animal in Saitama) was used in a Franz cell.

Each sample is applied after fixing to a cell with the exfoliated skin stratum corneum side facing upward.

After fixing the isolated skin dermis side so as to be in close contact with the physiological saline filled in the receiver container, penetrate the extracted skin,
The amount of ketoprofen transferred into the physiological saline on the receiver side was measured by high performance liquid chromatography every hour for 6 hours. Table 1 shows the amount of permeation after 2 hours and 6 hours.

Test Method 2 Carrageenan-External edema-suppressing effect experiment on rat paw edema One group of 8 male Wistar rats weighing about 130 g (purchased from JIC) was used under non-fasting condition. After measuring the volume of the left hind paw of the rat, a 100 mg sample was applied to the left hind paw. After 4 hours, the remaining unabsorbed sample was wiped off with absorbent cotton containing slightly warm water, and 0.1 ml of a 1% carrageenan (inflammatory agent) physiological saline solution was injected subcutaneously into the footpad to induce edema. Three hours after the treatment with the pro-inflammatory agent, the left paw volume was measured, and the edema rate was calculated from the paw volume before the treatment with the pro-inflammatory agent. The results are shown in Table 1.

The edema suppression rate was expressed as a percentage by dividing the value obtained by subtracting the edema rate of the sample-applied group from the edema rate of the sample-untreated group by the edema rate of the sample-untreated group. During the application period, the animals were crooked and housed in individual cages during the application period in order to prevent the sample from being taken orally.

Test Method 3 Measurement of Carrageenin Inflammation Foot Pain Threshold Increase Rate Male Wistar rat weighing around 130 g (purchased from JIC)
Was used in a group of 7 animals, and a sample of 100 mg was applied to the left hind paw. Four
After hr, the unabsorbed test substance was wiped off with absorbent cotton containing slightly warm water, and 0.1 ml of a 10% kaolin-containing 1% carrageenan physiological saline solution was injected under the same footpad.

3 hours after the injection of the proinflammatory drug, a pressure stimulus was applied to the left side using a balance-type pressurizing device, and the pain threshold value was measured using the withdrawal reflex of the foot as an index.

The pain threshold increase rate was expressed as a percentage by dividing a value obtained by subtracting the threshold value of the sample untreated group from the threshold value after application of the sample by the threshold value of the sample untreated group. Table 1 shows the pain threshold increase rate.

Test Method 4 Examination of Cream Stability The cream was kept in a constant temperature bath at 50 ° C. for one month continuously, and the change in appearance of the cream was examined. The display method was set as "stable ... ◎; separation ... x (days separated)".

The cream was continuously kept at -10 ° C for one month, and the presence or absence of ketoprofen crystals in the cream was examined. The display method was set to “no crystal precipitation .... ◎◎ あ り available .... × (number of days when precipitation began)”.

 The results are shown in Table 1.

Test method 5 Examination of feeling of use and physical properties of cream Nobi: Measured in a constant temperature room at 23 ° C. and 50% RH using a spread meter (glass plate weight: 115 g) manufactured by Rigo Co., Ltd.
A predetermined amount of a sample was taken, a glass plate was dropped on the sample, spread in a concentric direction, and the spread distance was measured every time.

The spread distance of 10 seconds was subtracted from the spread distance of 1000 seconds after the fall of the glass plate, and this was used as a measure of growth. The larger the difference, the greater the spread.

Hardness: Measured using a penetrometer in accordance with JIS K 2220. At a measurement temperature of 23 ° C, a 1/2 cone (weight 22.5
The distance at which g) penetrated for 5 seconds was indicated in mm. The higher the value, the softer it is.

Sticky …… Take about 0.5g of sample on skin, 10mm × 5mm
I went back and forth 10 times and rubbed it with my index finger so that the area became as large as possible. The finger was lightly touched, and the tackiness was examined (finger tack), and judged as follows.

◎: Refreshing feeling Δ: Slight stickiness ×: Strong stickiness Next, the contents of each drug were shown.

Example 1 Carbopol 940 1 part, isopropyl myristate 3
Parts, diisopropyl adipate 3 parts, glycerin distearate 4 parts, polyoxyethylene sorbitan monostearate 1.5 parts, polyoxyethylene stearyl ether phosphate 1 part, polyoxyethylene oleyl ether sodium phosphate 2.5 parts, ketoprofen 3 parts and 0.2 parts of propyl paraoxybenzoate was dissolved by heating at 80 ° C., 5 parts of propylene glycol was added, and the mixture was stirred for 10 minutes. Water 7
Add 3.3 parts under strong stirring, emulsify and stir for 1 hour.
After cooling to ℃, the pH was adjusted by adding 2.5 parts of triethanolamine. A white uniform ketoprofen-containing cream having a pH value of 6.0 was obtained.

Comparative Example 1 A cream was prepared in the same manner as in Example 1 except that glycerin distearate was excluded from the cream prepared in Example 1.

Comparative Examples 2 and 3 Similarly to Comparative Example 1, propylene glycol or carbopol was selected from the creams prepared in Example 1.
A cream was prepared in the same manner as in Example 1 except for 940, and Comparative Examples 2 and 3 were prepared.

Example 2 Carbopol 941 1 part, diisopropyl adipate 3
Parts, glycerin diisostearate 4 parts, polyoxyethylene sorbitan monostearate 2.5 parts, polyoxyethylene oleyl ether sodium phosphate 2.5 parts, ketoprofen 3 parts, methyl paraoxybenzoate 0.1 part,
0.1 parts of propyl paroxybenzoate and 4 parts of propylene glycol were added and dissolved by heating at 80 ° C. 77.4 parts of water was added under strong stirring to emulsify, stirred for 1 hour, and cooled to 40 ° C.
The pH was adjusted by adding 2.4 parts of triisopropanolamine. A white uniform ketoprofen-containing cream having a pH value of 6.1 was obtained.

Comparative Example 4 A cream was prepared in the same manner as in Example 2 except that 5 parts of ethanol was added instead of the propylene glycol in the cream prepared in Example 2.

Example 3 1.5 parts of Carbopol 940, 2 parts of glycerin distearate, 3 parts of isopropyl myristate, 2 parts of glycerin monocaprylate, 2 parts of polyoxyethylene sorbitan monooleate, 2.5 parts of sodium polyoxyethylene stearyl ether phosphate, ketoprofen 3 parts, propyl paraoxybenzoate 0.2 part, 1,3-butylene glycol 5 parts and propyl paraben 0.2 parts were added, and the mixture was heated and stirred.

76.1 parts of water was added under strong stirring, emulsified, stirred for 1 hour, cooled to 40 ° C., and 2.3 parts of triethanolamine and 0.2 parts of peppermint oil were added. A white uniform ketoprofen-containing cream having a pH value of 6.2 was obtained.

Comparative Example 5 A cream was produced in the same manner as in Example 3 except that the amount of glycerin distearate in the cream prepared in Example 3 was changed to 10 parts and the amount of water was changed to 66.1 parts. .

Comparative Example 6 A cream was prepared in the same manner as in Example 3 except that 4.5 parts of polyoxyethylene stearyl ether was used instead of 2 parts of the emulsifier polyoxyethylene sorbitan monooleate and 2.5 parts of sodium polyoxyethylene stearyl phosphate. However, a uniform cream was not obtained due to poor emulsification.

Example 4 0.51 parts of Carbopol 941, 3 parts of diisopropyl adipate, 1 part of glycerin distearate, 4 parts of glycerin monocaproic acid, 10 parts of polyglycerin, 2.5 parts of polyoxyethylene sorbitan monostearate, 2.5 parts of polyoxyethylene stearyl ether phosphorus 2.5 parts of sodium citrate, 3 parts of ketoprofen, 0.2 parts of propyl paraoxybenzoate and 0.2 parts of propylparaben were added and heated and stirred. Water 7
0.4 part was added under strong stirring, emulsified, stirred for 1 hour, cooled to 40 ° C., and triisopropanolamine 2.5
Parts, 0.2 parts of l-menthol. A white uniform ketoprofen-containing cream having a pH value of 6.0 was obtained.

Test Method 6 Skin Irritation Test Using four types of Example 1, Example 2, Comparative Example 4, and Japan Petroleum Vaseline, they were stuck on the upper back of 25 healthy males using mini-patches for 48 hours. The degree of skin rash 2 hours and 24 hours after peeling was determined. The results are shown in Table 2, and the criteria are shown below Table 2.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 47/32 A61K 47/32 N (56) References JP-A-61-238723 (JP, A)

Claims (1)

(57) [Claims] 1. An anti-inflammatory agent comprising ketoprofen, mono- and / or di-fatty acid glycerin, polyhydric alcohol, carboxyvinyl polymer, water-soluble base substance, emulsifier and water, and having a pH of 4.5 or more and less than 6.3. Analgesic cream.