JPH0135805B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anti-inflammatory analgesic gel containing ketoprofen as an active ingredient. Ketoprofen has the formula () It is a phenylpropionic acid derivative represented by It is a drug that is widely used in the treatment of inflammatory diseases in various medical fields. Conventionally, non-steroidal anti-inflammatory analgesics have generally been administered orally in the form of capsules, tablets, etc., and have shown excellent clinical results. However, on the other hand, side effects such as gastrointestinal, hepatic, and renal damage due to continuous oral administration of these drugs have become a problem, and efforts have been made to develop suppositories and other formulations to reduce such side effects. However, no satisfactory results have been obtained yet. In particular, it is generally known that non-steroidal anti-inflammatory analgesics have extremely poor transdermal absorption compared to other anti-inflammatory analgesics, and although there are some examples of them being used as external agents, these None of the absorption effects are satisfactory. Furthermore, there are very few external preparations that are sufficiently useful in terms of local efficacy and safety. An example of an anti-inflammatory analgesic ointment containing indomethacin was developed as a therapeutic agent for inflammatory diseases with the aim of reducing side effects such as gastrointestinal disorders when applied topically. 53−81616
As seen in the No. 1 patent publication, this example also has poor transdermal absorption due to poor drug release from the ointment base (gel base), and has side effects such as skin irritation, as well as gastrointestinal disorders. It has not yet been completely overcome, and there are many clinical problems in terms of therapeutic efficacy.
It has not been possible to overcome the traditional drawbacks. For the reasons detailed above, there is currently a demand for the development of external anti-inflammatory analgesics that have excellent transdermal absorption, excellent medicinal efficacy, and even higher safety. Therefore, the present inventors conducted extensive research in search of a topical anti-inflammatory analgesic that could meet the above requirements, and found that the gel of the present invention, which is characterized by containing ketoprofen, is superior to other gels such as indomethacin-containing gel. It has been found that the transdermal absorption and anti-inflammatory effect are superior to other formulations, and the safety is higher.
Furthermore, in terms of formulation, indomethacin is unstable to alkalis, has poor solubility in gel bases, and tends to precipitate crystals, whereas ketoprofen is resistant to gel bases. The present invention was completed by discovering that the drug has excellent stability and solubility, is compatible with the gel base of the present invention, and has an excellent usability. The gel agent of the present invention is a mixture of ketoprofen, glycols, lower alcohol, water, or a mixture of lower alcohol and water, and a gelling agent, and if desired, a solubilizer and a nonionic surfactant are added thereto. Manufactured by gelation. Note that a neutralizing agent may be appropriately added depending on the gelling agent. More specifically, the glycols used in the present invention are preferably propylene glycol, butylene glycol, etc., and the lower alcohols are preferably ethanol, isopropyl alcohol, etc. still,
Lower alcohols are usually used mixed with water, but due to other ingredients, they may not be mixed at all, and in this case, water is mixed alone. Further, it is preferable to mix these contents so that glycol is 40% by weight or less, lower alcohol is 60% by weight or less, and water is 55% by weight or less. Next, examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, alginate propylene glycol ester, and the like. The gelling agent is preferably blended so that the final concentration is 0.5 to 5% by weight. Incidentally, examples of the organic amine that neutralizes the carboxyvinyl polymer include triethanolamine, diisopropanolamine, and the like. In addition, when using this neutralizing agent, an amount is used that adjusts the pH to around neutrality, that is, pH 5 to 7, more preferably pH 5.5 to 6.5, and a preferable amount is 0.1 to 1.
It is better to use it in weight percentage. Examples of the dissolving agent include propylene carbonate, diethyl sebacate, diisopropyladipate, crotamiton, and the like. This solubilizer is preferably blended in an amount sufficient to dissolve ketoprofen. Furthermore, nonionic surfactants include sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene sorbitan monooleate, and monolauric acid. Preferably, polyoxyethylene sorbitan, polyoxyethylene nonyl phenyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether or a mixture thereof is blended. Ketoprofen, the active ingredient of the present invention, is 0.5
A sufficient effect can be expected at ~5% by weight. The ketoprofen gel of the present invention can be prepared by, for example, (A) adding a gelling agent to water to swell it, while (B) dissolving ketoprofen with a dissolving agent, and then dissolving it in a mixture of glycols and lower alcohols, and then ( It can be obtained by adding B) to (A), adding an amine, and gelling it. Incidentally, the gel of the present invention can be obtained even if the order of blending the compounds is slightly changed in the above method. The gel of the present invention produced as described above is stable even when stored for a long period of time, and when applied to the skin, it provides excellent pain relief and anti-inflammatory treatment as shown in the experimental examples below. It is effective and highly safe. In particular, compared to gel preparations that use indomethacin as the active ingredient, as shown in the experimental examples below, the absorption rate is extremely high, the edema suppression rate is excellent, and there are fewer side effects such as redness and rash, making it highly safe. It is something that has a nature. The transdermal absorption effect of the gel of the present invention is as follows:
The anti-inflammatory effect and safety test will be demonstrated through pharmacological experiments. Experimental Example 1 Transdermal Absorption Test Five healthy adult males were used as subjects, and 1.4 cm x 1.4 cm sections were made with adhesive tape at eight locations on the skin of the flexor side of the forearm. Next, according to the method of Lindsay C. et al., a microsyringe was filled with a gel of the same base containing 1% each of ketoprofen and indomethacin, and 20μ of the gel (containing 190μg of drug) was administered and directly attached to the adhesive tape. It was fixed with. At 0 and 4 hours after administration, the adhesive tape was removed and the sample was inserted into a 25 ml volumetric flask.
Further, the drug remaining at the administration site was collected by pressing a funnel against the administration site, injecting a small amount of methanol through the funnel leg, and washing the funnel several times. The recovered methanol was adjusted to a constant volume of 25 ml, and 2 ml of ketoprofen was diluted with 2 ml of methanol and then measured using a double beam spectrophotometer UV-200 (Double beam spectrophotometer UV-200).
using a spectrophotometer (manufactured by Shimadzu Corporation)
Absorbance was measured at 225 mμ and 246 mμ wavelengths. or,
Indomethacin was made into a constant volume of 25 ml, and its absorbance was measured at a wavelength of 320 mμ. For quantitative determination, a calibration curve created from the absorbance of various known concentrations of the drug was used. The absorption rate was calculated using the following formula. Absorption amount (%) = 100 x (1 - amount recovered 4 hours after administration/amount recovered 0 hours after administration) The test results are shown in Table 1 below.

[Table] Each value is the average value of 5 subjects. Experimental Example 2 Carrageenin - Topical anti-inflammatory effect on rat skin edema Male Wistar rats weighing 90-110g (4 weeks old)
Evaclaim [Product name: Tokyo Tanabe Pharmaceutical Co., Ltd.]
After removing the hair with a product manufactured by J.D. Co., Ltd., I left it overnight and used it. 1% carrageenan (Pycnin A, manufactured by Pasco International Company) - Physiological saline for injection and physiological saline were injected intradermally at 0.1 ml/site each in a dorsal symmetrical manner, and the former was tested. A patch test adhesive plaster (Small size, manufactured by Torii Pharmaceutical Co., Ltd.) adsorbed with 0.1 ml of each compound was immediately applied. After 2.5 hours, 0.5 ml/100 g of 1% Pontamine Sky Blue (PSB)-physiological saline solution was injected through the tail vein, and after another 30 minutes, the animals were exsanguinated to death. Peel the skin and immediately measure the thickness of the intradermal injection site with a dial.
thickness gauge manufactured by Ozaki Seisakusho Co., Ltd.: measurement pressure 40g]
The edema rate was determined using the following formula. Edema rate (%) = Thickness of carrageenin injection site - Thickness of physiological saline injection site / Thickness of physiological saline injection site In addition, the product of the major axis and the minor axis of the pigment exudation area was determined to be the pigment exudation area, and Harada et al. (Harada, M.,
Takeuchi, M. Fukao, T. & Katagiri, K.: J.
Pharm.Pharmacol 23 , 218, 1971) was used to extract Pontamine Sky Blue, and the amount of leached pigment was determined by measuring with a spectrophotometer. The test results are shown in Table 2.

【table】

[Table] Experimental Example 3 Anti-inflammatory effect of topical application on rat footpad edema due to bone fracture Male Wistar rats weighing around 130g (5 weeks old)
A group of 8 animals was used. 100 mg of the test compound was carefully rubbed into the left paw, and the application site was wrapped with saran wrap to prevent the rat from licking it. In addition, there is a disposable beaker (DB-1) on the head.
for Automatic Blood Cell Counter：TOA
(manufactured by Medical Electrouics Co., Ltd.) and fixed with rubber. After 3 hours, the rat was anesthetized with ether, and the leg region to which the test compound was applied was pinched using forceps equipped with a rubber tube to induce a linear fracture in the metatarsal bone. Immediately thereafter, 100 mg of the test compound was applied to the same site again and the same treatment was performed. Judgment was made 3 hours after the fracture, and the edema rate was calculated by measuring the foot volume before and 3 hours after the fracture using Fujihira's method (Eiichi Fujihira: Applied Pharmacology 5, 119-, 1971).
Statistical processing was performed using student-test (Kimichi Sugimoto: Illustrated Medical Statistics: Igaku Shoin 1968). The test results are shown in Table 3.

【table】

[Table] It was applied at intervals.
** indicates a significant difference at P<0.01.
Experimental Example 4 Damage to gastric mucosa in rats Male Wistar rats weighing approximately 200 g were given free access to water and fasted for 24 hours, after which the test compound was administered. The test compound was applied by applying a patch test plaster containing 0.1 ml of the same gel to the back of a rat whose head had been shaved with an electric razor, and by suspending ketoprofen and indomethacin bulk powder in 0.5% tragacanth gum physiological saline. Administered orally. Six hours after administration, the animals were sacrificed, the stomach was removed, an incision was made along the large bay, and the presence or absence of ulcers on the gastric mucosa was visually observed.
The ulcer incidence was calculated using the following formula. Ulcer incidence (%) = Number of animals with ulcers/Number of animals subjected to experiment x 100 The results are shown in Table 4.

[Table] Experimental example 5 Male and female ddY mice weighing 19-26g and weight 102-
One group of male and female Wistar rats each weighing 130g.
It was used as 10 animals. The maximum amount of the test compound (gel containing 3% ketoprofen) of 15,000 mg/Kg was applied to the backs of both species after hair removal using electric hair clippers, and mortality was examined after 14 days. The test results are shown in Table 5.

[Table] Experimental Example 6 Patch test on healthy men A patch test was conducted on 22 healthy men according to the method of Kawamura et al . That is, a patch test adhesive plaster containing 0.1 ml of the test compound was applied to the inside of the subject's upper arm for 24 hours. 30 minutes and 24 hours after peeling, skin findings at the patched area were visually evaluated according to the criteria below.

【table】 The test results are shown in Table 6.

[Table] Shows that.
The results of the above pharmacological experiments revealed that the gel of the present invention has excellent skin absorption, is very effective medicinally, and is also highly safe. The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples only. In the following description, parts mean parts by weight. Example 1 Carboxyvinyl polymer [Carbopol 940
(manufactured by Gutsudoritsuchi Chemical Co.)] 1.5 parts was swollen in 20 parts of water. On the other hand, 10 parts of propylene carbonate and 35 parts of propylene glycol were mixed, and 1 part of ketoprofen was dissolved therein. Next, 2 parts of hydroxypropylcellulose dissolved in 20 parts of ethanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing this with a mixture of propylene carbonate and propylene glycol in which the ketoprofen was dissolved,
A solution of 0.2 parts of triethanolamine dissolved in 8.5 parts of water was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 2 Carboxyvinyl polymer [Hibis Wako
104: manufactured by Wako Pure Chemical Industries, Ltd.] were swollen in 20 parts of water. Meanwhile, 15 parts of propylene carbonate and 20 parts of propylene glycol were mixed, and 3 parts of ketoprofen was added to the mixture.
part was dissolved. Next, 2 parts of hydroxypropyl cellulose dissolved in 30 parts of ethanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the above-mentioned mixture of propylene carbonate and propylene glycol in which ketoprofen was dissolved, a solution of 0.2 parts of triethanolamine dissolved in 7.8 parts of water was added, and the mixture was thoroughly stirred until the whole was homogeneous to provide anti-inflammatory and pain relief. A gel was obtained. Example 3 1.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 20 parts of water. On the other hand, 10 parts of propylene carbonate and 35 parts of propylene glycol were mixed, and 0.5 part of ketoprofen was dissolved therein.
Next, add 1.5 parts of hydroxypropyl cellulose to 25 parts of water.
The mixture was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing a mixture of propylene carbonate and propylene glycol in which the ketoprofen was dissolved, diisopropanolamine was added.
A solution of 0.5 parts dissolved in 6.3 parts of water was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory analgesic gel. Example 4 2.5 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 20 parts of water. On the other hand, mix 15 parts of propylene carbonate, 10 parts of propylene glycol, and 20 parts of ethanol, and add 5 parts of ketoprofen.
part was dissolved. Next, 2 parts of hydroxypropyl cellulose dissolved in 20 parts of ethanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the mixture of propylene carbonate, propylene glycol, and ethanol in which the ketoprofen was dissolved, 0.3 parts of triethanolamine dissolved in 5.2 parts of water was added, and the mixture was thoroughly stirred until the whole was homogeneous. An anti-inflammatory analgesic gel was obtained. The reference examples shown below were used as comparative gels of the present invention in the transdermal absorption and pharmacological experiments described above. Reference Example 1 1.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 20 parts of water. Separately, 10 parts of propylene carbonate and 35 parts of propylene glycol were mixed, and 1 part of indomethacin was dissolved therein. Hereinafter, an anti-inflammatory analgesic gel was obtained in exactly the same manner as in Example 1. Example 5 2 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 36 parts of water. On the other hand, 2 parts of diisopropyladipate, propylene glycol
10 parts of ethanol and 40 parts of ethanol were mixed, and 3 parts of ketoprofen and 1 part of hydroxypropyl cellulose were added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of diisopropanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 6 2 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 32 parts of water. Separately, 1.5 parts of diethyl sebacate, 20 parts of propylene glycol, and 35 parts of ethanol were mixed, and 2 parts of ketoprofen and 2 parts of hydroxypropyl cellulose were added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 0.5 parts of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 7 Two parts of carboxyvinyl polymer (same as in Example 1) were swollen in 30.5 parts of water. Separately, 2 parts of diisopropyl adipate, 15 parts of 1,3-butylene glycol, and 40 parts of ethanol were mixed, and 3 parts of ketoprofen and 1.5 parts of hydroxypropyl cellulose were added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of diisopropanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 8 2 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 31.5 parts of water. Meanwhile, 5 parts of diisopropyl adipate, 20 parts of 1,3-butylene glycol, 0.5 parts of polyoxyethylene (9) lauryl ether, and 30 parts of ethanol were mixed, and 3 parts of ketoprofen and 2 parts of hydroxypropyl cellulose were added thereto, and the mixture was stirred. and dissolved. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 9 1 part of carboxyvinyl polymer (same as in Example 1) was swollen in 39 parts of water. On the other hand, 3 parts of diisopropyladipate, propylene glycol
15 parts of ethanol and 35 parts of ethanol were mixed, and 1 part of ketoprofen was added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of diisopropanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 10 Two parts of carboxyvinyl polymer (same as in Example 1) were swollen in 30 parts of water. Separately, 2 parts of diisopropyl adipate, 5 parts of propylene glycol, and 50 parts of ethanol were mixed, and 3 parts of ketoprofen and 2 parts of hydroxypropyl cellulose were added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of diisopropanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 11 Two parts of carboxyvinyl polymer (same as in Example 1) were swollen in 10 parts of water and 29 parts of 1,3-butylene glycol. On the other hand, propylene carbonate 10
1 part and 40 parts of ethanol were mixed, 3 parts of ketoprofen was added thereto, and the mixture was stirred and dissolved. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 1 part of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 12 0.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 41.8 parts of water. On the other hand, 2 parts of diisopropyl adipate, 10 parts of propylene glycol, and 40 parts of ethanol were mixed, and 0.5 part of ketoprofen was added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. Next, a solution of 0.2 parts of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Example 13 1.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 36 parts of water. On the other hand, 2 parts of ketoprofen was added to 45 parts of ethanol and 10 parts of propylene glycol, and the mixture was stirred and dissolved. This was then added to the water-swollen carboxyvinyl polymer described above and stirred until complete hydration. Next, a solution of 0.5 parts of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Reference Example 2 1 part of carboxyvinyl polymer (same as in Example 1) was swollen in 45.7 parts of water. Separately, 2 parts of diisopropyl adipate, 10 parts of propylene glycol, and 35 parts of ethanol were mixed, and 0.1 part of ketoprofen and 1 part of hydroxypropyl cellulose were added thereto and dissolved by stirring. This was then added to the water-swollen carboxyvinyl polymer described above and stirred until complete hydration. Next, a solution of 0.2 parts of triethanolamine dissolved in 5 parts of water was added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel. Reference Example 3 3 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 14 parts of water. On the other hand, 5 parts of diisopropyl adipate, propylene glycol
10 parts of ketoprofen and 2 parts of hydroxypropylcellulose were added to the mixture, and the mixture was stirred and dissolved. This was then added to the water-swollen carboxyvinyl polymer described above and stirred until complete hydration. Next, a solution of 1 part of diisopropanolamine dissolved in 5 parts of water was added to this, and the mixture was thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel.

Claims (1)

[Scope of Claims] 1. An anti-inflammatory and analgesic gel containing ketoprofen as an active ingredient, glycols, lower alcohols and/or water as a gel base, and a gelling agent. 2. The anti-inflammatory and analgesic agent according to claim 1, which contains ketoprofen as an active ingredient, glycols, lower alcohols and/or water as a gel base, a gelling agent, a neutralizing agent, a solubilizing agent, and a nonionic surfactant. Gel agent.