JP2682563B2 - Anti-inflammatory analgesic cream - Google Patents

Description

Description: TECHNICAL FIELD [0001] The present invention relates to an anti-inflammatory analgesic cream containing ketoprofen as an active ingredient, which improves absorption of ketoprofen and further stabilizes the cream. The present invention relates to a preparation excellent in usability and safety. [0002] Ketoprofen is a non-steroidal anti-inflammatory and analgesic agent having excellent anti-inflammatory and analgesic effects, particularly osteoarthritis, tendon / tendonitis / myalgia. -A drug that is widely used for the treatment of swelling and pain after trauma and surgery, and is used not only as an internal drug 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 increase the solubility of ketoprofen and, in turn, the absorbability, irritation derived from lower alcohols is expressed.
The current situation is that it is difficult to satisfy each of them. The inventors of the present invention have conducted extensive studies in search of an anti-inflammatory analgesic cream satisfying the above-mentioned needs, and as a result, have excellent absorption of ketoprofen, stability of cream, and feeling of use. The present invention has been completed by finding a ketopropene preparation having excellent safety. The present invention has as essential components (i) ketoprofen, (ii) mono-fatty acid glycerin and / or di-fatty acid glycerin, (ii)
i) polyhydric alcohol, (iv) carboxyvinyl polymer,
(V) A water-soluble basic substance, (vi) an emulsifier, and (vii) water, wherein the emulsifier is an anti-inflammatory analgesic cream which is a polyoxyethylene higher alcohol ether phosphate and / or a salt thereof. . In addition, if desired, an anti-inflammatory analgesic cream of the present invention can be expressed with a higher effect by optimally blending these components, by incorporating an absorption promoter, a preservative, an ultraviolet absorber, a fragrance, a coloring agent, and the like. obtain. That is, it is preferable that the content of (i) ketoprofen is 0.1 to 5 parts by weight based on 100 parts by weight. Ketoprofen has a small pharmacological effect in an amount of less than 0.1 parts by weight, and causes a problem such as irritation of ketoprofen itself in an amount of 5 parts by weight or more. (Ii) The corresponding fatty acid of mono-fatty acid glycerin and / or 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. More preferably, the fatty acid is stearic acid and / or isostearic acid, and further 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, further preferably 2 to 5 parts by weight, based on 100 parts by weight in total. When the amount is less than 1 part by weight, the absorbability of ketoprofen is insufficient, and when the amount is 10 parts by weight or more, the hardness is high and the elongation of the cream is 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 total amount is 100 parts by weight,
The compounding amount is preferably 1 to 30 parts by weight, more preferably 2 to 20 parts by weight, further preferably 3 to 15 parts by weight. 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 blending amount is 30 parts by weight or more, the cream will become sticky and the usability will deteriorate. In this range, the irritation is extremely low. (Iv) Carboxyvinyl polymer is a water-soluble vinyl polymer having a carboxyl group in the molecule, for example, Hibiswako 103, 10 manufactured by Wako Pure Chemical Industries, Ltd.
4 and 105 and Carbopol 934, 940 and 941 manufactured by Goodrich Chemical Company. The amount of carboxyvinyl polymer compounded is 100 parts by weight,
The amount can be 0.2 to 5 parts by weight, preferably 0.5 to 3 parts by weight, and more preferably 0.5 to 3 parts by weight. Examples of the water-soluble base substance (v) include triethanolamine, triisopropanolamine and the like, and a neutralizing amount can be added so that the pH becomes 4.5 to 6.5. Addition amount is 100 parts by weight,
0.5 to 10 parts by weight, preferably 1 to 5 parts by weight is preferred. The (vi) 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 the anionic surfactant, by type, carboxylate type, sulfonate type, sulfate ester type,
There are phosphoric acid ester salt types; nonionic surfactants include ether type, ether ester type, ester type, block copolymer type of ether and ester, and the like. Among them, preferable examples include polyoxyethylene higher alcohol ether phosphates and / or salts thereof, and polyoxyethylene sorbitan fatty acid esters. The total amount of emulsifier is 10
It can be 1 to 10 parts by weight, preferably 2 to 8 parts by weight, and more preferably 3 to 6 parts by weight, relative to 0 parts 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 composition components which can be optionally added and blended. In order to improve the absorbability of ketoprofen, three components of mono-fatty acid glycerin and / or di-fatty acid glycerin, polyhydric alcohol and carboxyvinyl polymer are indispensable. Will end up. 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). Examples of (a) absorption promoters that can be incorporated as desired include isopropyl adipate, isopropyl myristate, etc. described on page 224 of "Medical action and biomembrane" by Fujii, Terada and Nomura. It is preferable that the compounding amount is 0 to 10 parts by weight based on 100 parts by weight. (B) Examples of preservatives include benzoic acid and its sodium salt, methylparaben, ethylparaben, propylparaben, butylparaben, sorbitanic acid and its sodium salt, and the like, or a mixture thereof, and the total amount is 100 parts by weight. It is preferably 0 to 3 parts by weight. (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 manufactured, for example, as follows. Ketoprofen, glycerin fatty acid ester, emulsifier and other compounding ingredients 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. Then, the polyhydric alcohol is dissolved in hot water of 70 to 80 ° C., the mixture is added to the dispersion mixture, and the mixture is uniformly emulsified by a homomixer to obtain the polyhydric alcohol. 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. The anti-inflammatory and analgesic cream of the present invention obtained as described above has excellent absorbability and an excellent anti-inflammatory and analgesic effect when applied to the skin, and is also effective as a cream. It is a formulation that is satisfactory in terms of long-term storage stability, usability, and safety. The anti-inflammatory effect of the formulation is shown below in a pharmacological test; the safety in a patch stimulation test; the feeling of use in a sensory test;
Stability is demonstrated by accelerated stability testing. EXAMPLES (Reference Example) Synthesis Method of Fatty Acid Glycerin Synthesis of Glycerin Diisostearate (or Glycerin Distearate) Glycerin 1 was added to a flask equipped with a condenser with a test tube.
Moles, 2 moles of isostearic acid (or stearic acid), 0.8 g of potassium hydroxide, 220-230
The mixture was heated to ° C and reacted for 10 hours to obtain glyceryl diisostearate (or glyceryl distearate). Test Method 1 Drug Permeation Experiment Using Extracted Skin A Franz-type cell was used using abdominal shaved skin of hairless rats (purchased from Saitama Experimental Animal). Each sample is applied after fixing to a cell with the exfoliated skin stratum corneum side facing upward. After fixing the dermis side of the excised skin so that it is in close contact with the physiological saline filled in the receiver container, the amount of ketoprofen that has permeated the excised skin and moved into the physiological saline solution on the receiver side is measured by high performance liquid chromatography every 6 hours. Measured over. Table 1 shows the amount of permeation after 2 hours and 6 hours. Test Method 2 Carrageenin-Exterior Edema Suppressing Effect on Rat Paw Edema One group of 8 Wistar male rats (purchased from Shizukyo Co., Ltd.) weighing about 130 g was used without fasting. After measuring the left hind paw volume of the rat, a sample 100 was placed on the left hind paw.
mg was applied. After 4 hours, the unabsorbed residual sample was wiped with absorbent cotton containing lukewarm water, and 0.1 mL of a 1% carrageenin (inflammatory agent) physiological saline solution was injected subcutaneously into the footpad of the same area 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, in order to prevent the sample from being ingested orally, the animals were shackled during the application period and housed in individual cages. Test Method 3 Measurement of Carrageenin Inflammatory Paw Pain Threshold Increase Rate About 70 g of Wistar male rats (purchased from Shizukyo) were used in groups of 7, and a sample of 100 mg was applied to the left hind paw. After 4 hours, the unabsorbed test substance was wiped with absorbent cotton containing lukewarm water, and 0.1 mL of a 1% carrageenin physiological saline solution containing 10% kaolin was injected under the footpad of the same area. Three hours after the injection of the inflammatory agent, pressure stimulus was applied to the left hind paw using a balance-type pressure device, and the pain threshold was measured using the withdrawal reflex of the paw 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 Stability of Cream The appearance of the cream was examined by keeping it in a constant temperature bath at 50 ° C. for 1 month continuously. The notation is “stable …… ◎; separation …… ×
(Number of days separated) ". The presence or absence of ketoprofen crystals in the cream was examined continuously at -10 ° C for 1 month.
The display method is "No crystal precipitation ... ◎ Crystal precipitation ...
… × (Number of days when precipitation started) ”. The results are shown in Table 1. Test method 5 Examination of feeling of use and physical properties of cream Nobi ... Using a spread meter manufactured by Sogo Co., Ltd. (glass plate weight: 115 g), measurement was carried out in a thermostatic chamber at 23 ° C. and 50% RH. 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. After extending the glass plate, the extension distance of 10 seconds was subtracted from the extension distance of 1000 seconds to determine the extension. The larger the difference, the greater the spread. Hardness : Using a penetrometer, JIS K 222
It measured based on 0. At a measurement temperature of 23 ° C., the distance at which a 1/2 cone (weight: 225 g) penetrates in 5 seconds was displayed in mm. The higher the value, the softer it is. Stickiness: About 0.5 g of sample is placed on the skin and 10
It was reciprocated 10 times and rubbed in with the index finger so that the area would be mm x 50 mm. The finger was lightly touched, and the tackiness was examined (finger tack), and judged as follows. ◎ …… Refreshing feeling △ …… Slightly sticky feeling × …… Strong sticky feeling [0019] Next, the content of each drug is 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, sodium polyoxyethylene oleyl ether phosphate 2.5 parts, ketoprofen 3 parts and propyl paraoxybenzoate 0.2 parts were heated and dissolved at 80 ° C., 5 parts of propylene glycol was added and stirred for 10 minutes. 73.3 parts of water was added with vigorous stirring to emulsify and after stirring for 1 hour, the mixture was cooled to 40 ° C. and 2.5 parts of triethanolamine was added to adjust the pH. A white uniform ketoprofen-containing cream with a pH 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 removed from the cream prepared in Example 1. Comparative Examples 2 and 3 As in Comparative Example 1, propylene glycol or carbopol 9 was selected from among the creams prepared in Example 1.
Creams were prepared in the same manner as in Example 1 except for 40, and used as Comparative Examples 2 and 3. Example 2 Carbopol 941 1 part, diisopropyl adipate 3 parts, glycerin diisostearate 4 parts, polyoxyethylene sorbitan monostearate 2.5 parts, sodium polyoxyethylene oleyl ether phosphate 2.5
Parts, 3 parts of ketoprofen, 0.1 part of methyl paraoxybenzoate, 0.1 part of propyl paraoxybenzoate and 4 parts of propylene glycol were added and dissolved by heating at 80 ° C. 77.4 parts of water was added with vigorous stirring to emulsify, stirred for 1 hour and cooled to 40 ° C., and triisopropanolamine 2.
The pH was adjusted by adding 4 parts. A uniform white ketoprofen-containing cream with a pH 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 propylene glycol in the cream prepared in Example 2. Example 3 Carbopol 940 1.5 parts, glycerin distearate 2 parts, isopropyl myristate 3 parts, glycerin monocaprylate 2 parts, polyoxyethylene sorbitan monooleate 2 parts, polyoxyethylene stearyl ether phosphate 2.5 parts sodium, 3 parts ketoprofen,
0.2 parts of propyl paraoxybenzoate and 5 parts of 1,3-butylene glycol were added and stirred with heating. Water 76.1
Parts under strong stirring, emulsify and stir for 1 hour, then 40 ° C
After cooling, 2.3 parts of triethanolamine and 0.2 part of peppermint oil were added. A white, uniform ketoprofen-containing cream with a pH of 6.2 was obtained. COMPARATIVE EXAMPLE 5 The procedure of Example 3 was repeated 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. A cream was produced. Comparative Example 6 The procedure of Example 3 was repeated, except that 2 parts of polyoxyethylene sorbitan monooleate and 2.5 parts of sodium polyoxyethylene stearyl phosphate were replaced with 4.5 parts of polyoxyethylene stearyl ether. A cream was produced in the same manner as in Example 3, but a uniform cream could not be obtained due to poor emulsification. Example 4 Carbopol 941 0.5 part, diisopropyl adipate 3 parts, glycerin distearate 1 part, glycerin monocaproic acid 4 parts, polyglycerin 10 parts, polyoxyethylene sorbitan monostearate 2.5 parts , 2.5 parts of sodium polyoxyethylene stearyl ether phosphate, 3 parts of ketoprofen, and 0.2 parts of propyl paraoxybenzoate were added and stirred with heating. 70.4 parts of water was added under vigorous stirring to emulsify, stirred for 1 hour, cooled to 40 ° C., and 2.5 parts of triisopropanolamine and 0.2 part of 1-menthol were added. A white, uniform ketoprofen-containing cream having a pH value of 6.0 was obtained. Test Method 6 Skin Irritation Test Using four kinds of Example 1, Example 2, Comparative Example 4 and Vaseline from Japanese Pharmacopoeia, a total of 48 healthy men's upper backs were mini-patched.
I pasted it on time. Each skin rash was evaluated 2 hours and 24 hours after peeling. The results are shown in Table 2, and the criteria are shown below Table 2. [Table 1] [Table 2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 47/24 A61K 47/24 N ADA ADAH 47/32 47/32 N (56) References 61-238723 (JP, A)

Claims (1)

(57) [Claims] Ketoprofen, mono-fatty acid glycerin and / or di-fatty acid glycerin, polyhydric alcohol, carboxyvinyl polymer, water-soluble base substance, emulsifier and an anti-inflammatory analgesic cream characterized by containing water, wherein the emulsifier,
An anti-inflammatory analgesic cream which is a polyoxyethylene higher alcohol ether phosphate and / or a salt thereof.