MXPA94002112A - Anti-inflammatory, analgesic and transdermal gel. - Google Patents

Abstract

The present invention discloses transdermal gels including (1) a non-steroidal anti-inflammatory drug of propionic acid derivatives, as effective components, (2) poloxamer, (3) one, or more selected agents starting from lower alcohol, propylene glycol, polyethylene glycol and glycerin, (4) one or more selected agents starting from fatty acids, fatty alcohols, and menthol (5) water or a buffer solution. These gels form thin and flexible films, which are easy to wash with water. They possess prolonged anti-inflammatory and analgesic activities, and excellent physiochemical stability with lesser systemic secondary effects and gastric irritation.

Description

. / f > GF.L TRANSDBRAMICO ANTIINFLAMATORIO AND ANALGESICO The gentlemen SANG-CHEOL CHI, HYUN-KWANG TAN, HEUNG-WON CHUN, Chinese nationality the first two and North American and the third, residing respectively in 203-401 Taeyoung APT, Bono-dong, Ansan, Kyunggi-Do; 1506-12, Seocho 3 dong, Seocho-u, Seoul, both in the Republic of Korea, and the third in 420 Sandstone D. , city of AThens, State of Georgia, United States of North America, inventors, cede, sell and transfer to IL-DONG PHARM. CO. , LTD., Korean company, domiciled at 60, Yan jae-dong, Seocho-ku, Seoul, Republic of Korea, all rights to the invention described below: SUMMARY OF THE INVENTION Transdermal gels including (1) an orio or steroidal anti-inflammatory drug of propionic acid derivatives, as effective components, (2) poloxamer (3) one or more agents selected from lower alcohol, propylene glycol, polyethylene glycol, and glycerin, (4) one or more agents selected from fatty acids, fatty alcohols, and mentho (5) water or a buffer solution. The gels form thin and flexible films, which can be easily washed with water. They have long-lasting anti-inflammatory and analgesic activities, and an excellent physico-chemical stability with fewer systemic side effects and gastric irritation. * Background of the Invention Technical Background * The present invention relates to a transdermal anti-inflammatory and analgesic gel containing a non-steroidal anti-inflammatory drug of propionic acid derivatives, as an effective ingredient. In particular, the present invention relates to a novel transdermal iodine and analgesic transdermal gel which is water soluble, and which provides antiinflammatory and analgesic activities comparable to oral administration, while significantly reducing systemic and side effects. Gastrointestinal irritation after oral administration of the drug.

The Previous Technique Typical examples of the non-steroidal antiinflammatory drug of propionic acid derivatives include ketoprofen, ibuprofen, f-lurbiprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofé, oxaprozin, * pranoprofen, suprofén, to inoprofé, butibufén and fenbufén, etcetera. It has powerful anti-inflammatory and analgesic activities, and is widely used for the treatment of rheumatic arthritis and its related conditions. Conventionally, these drugs have been administered orally in the form of solid preparations, such as tablets and capsules. However, it has combined systemic side effects, or gastrointestinal irritation at once 'of its oral administration. In order to reduce these side effects, these drugs have been formulated as transdermal preparations based on the fact that the skin permeability of these nonsteroidal antiinflammatory drugs is known to be relatively higher than that of other antiinflammatory drugs. steroidal For example, JP 58-39616, JP 58-83622, JP 58-103311, JP 61-238723 and USP 4,393,076 and 4,534,980, describe the formulation of non-steroidal anti-inflammatory drugs of propionic acid derivatives in tradermic preparations, generally an ointment. or a cream. They claim that the systemic side effects and gastrointestinal irritation of these drugs were significantly reduced, while satisfactory therapeutic effects were obtained. In these patents, they typically used carboxyvinyl polymer or hydroxypropylmethylcellulose as a gel base in the formulation of transdermal drug preparations.

* However, the skin permeations of the drugs from their preparations were not sufficient to achieve the pharmacological effects comparable to the oral administration of the drugs, due to the low percutaneous absorption of the drugs from the preparations, and therefore, a large amount of the preparation must be applied to achieve a desired efficacy.

* As a result of extensive research seeking to ameliorate the drawbacks of existing patents and products, the present inventors have succeeded in establishing a novel transdermal gel containing a nonsteroidal antiinflammatory drug of propionic acid derivatives. The gel is soluble in water, has a high permeation index in the skin, and therefore, excellent anti-inflammatory and analgesic activities, comparable to its oral administration. It also showed lower systemic side effects and gastrointestinal irritation, and good physicochemical stability.

Summary of the Invention The present invention provides an anti-inflammatory and analgesic Lransdermic gel comprising, by weight, 0.5 to 5 percent non-spheroidal aniinflammatory drug of a propionic acid derivative as an effective ingredient; from 10 to 30 percent poloxamer as a gel forming agent; from 0 to 30 percent of one or more agents selected from a lower alcohol, propylene glycol, polyethylene glycol, and glycerin; from 0 to 10 percent of one or more agents selected from fatty acids, fatty alcohols, and menthol; and you have totaled 100 percent with water or with a regulatory solution.

Detailed description of the invention The transdermal gels of the present invention can be prepared by dissolving a mixture that includes an anti-inflammatory drug orio or steroidal of propionic acid derivatives, such as ketoprofen, fibripeprobe, ibuprofen, naproxen, fenoprofe, benoxaprofé, indoprofen, pirprofen, carprofen , oxaprozin, pranoprofen, suprofen, li? iinoprofé, butibufen and fenbufen, etc .; poloxamer; and one or more agents selected from lower alcohol, glycerin, propylene glycol and polyethylene glycol; one or more enhancing agents selected from fatty acids, fatty alcohols, and rae tol; and if necessary one or more different agents, including a preservative, a ß-flavorant, in water or in a buffer solution. More specifically, the lower alcohol used in the present invention may be ethanol and isopropyl alcohol, and the poloxamer derivatives may be poloxamer 407 and poloxamer 338, poloxamer 237 and others. The concentrated aqueous poloxamer solution, used as a gel-forming agent of the present invention, is a clear liquid of low viscosity at the refrigerator temperature or lower, but becomes a clear, solid gel upon heating to room temperature or of the body. The polymer also possesses several properties that make it particularly suitable for use in the formulation of transdermal dosage forms. These include low toxicity and skin irritation, excellent compatibility with other chemicals, high solubilizing capacity for different conditions, and good drug release characteristics. The polyethylene glycol can be polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 and others. The fatty acids can be lauric acid, oleic acid, capric acid, myristic acid, and others, and the fatty alcohols can be lauryl alcohol, oleyl alcohol, and others.

In the present invention, the pH of the gel can be from 4 to 8, which is usual for the gel-forming agent * conventional, but it is desirable to use a buffer solution having a pH value around the pKa value of each active compound. The preservative may be benzoic acid, sodium benzoate, methyl p-hydroxybenzoate, ethyl p-idroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, or a mixture thereof. The f * gel compositions of the present invention desirably include 0.5 to 5 percent non-steroidal anti-inflammatory drug of propionic acid derivative; from 10 to 30 percent poloxamer; and from 0 to 30 percent lower alcohol or polyethylene glycol or propylene glycol or glycerin; 0 to 10 percent fatty acid or fatty alcohol or menthol. When the gel of the present invention is applied to the skin, it forms a thin, flexible film from which the drug is released slowly and continuously, resulting in prolonged antiinflammatory and analgesic activities lasting one day. Propylene glycol, polyethylene glycol, and glycerin, act as a humectant, as well as a cosolvent. Fatty acid or fatty alcohol or menthol, act as a penetration enhancer.

- The present transdermal gels can be prepared simply as follows: the drug and the poloxamer are heated to a temperature higher than 90 ° C to obtain a homogeneous liquid mixture, and then the mixture is cooled to 40-60 ° C. Separately, Water or a buffer solution is prepared in which the other additives have dissolved, and is added to the previous liquid mixture. When cooled to room temperature, or in the refrigerator, the gel forms. Transdermal gels produced from anti-inflammatory or steroidal drug of propionic acid derivatives are water soluble, transparent with a good texture, and exhibit excellent anti-inflammatory and analgesic activity, with less gastrointestinal irritation, as shown in the following Experiments. Hereinafter, the present invention will be described in more detail with reference to the following examples, but it is not considered to be limited thereto. Through all the examples, all percentages are by weight.

Example 1 Quetoprofen 3% Poloxamer 407 15% Polyethylene glycol 3% Ethanol 18.5% Menta1 0.3% methyl p-hydroxybenzoate 0.17% propyl p-hydroxybenzoate 0.2% Regulatory solution with a pH of 4.5 60.01% 3 grams of ketoprofen and 15 grams of poloxamer 407 were heated at 105 ° C for 10 minutes to obtain a liquefied mixture, and then cooled to 60 ° C. Separately, 0.17 grams of methyl p-hydroxybenzoate, 0.02 grams of propyl p-hydroxybenzoate, 0.3 grams of menthol in 18.5 grams of ethanol were dissolved, and 3 grams of polyethylene glycol 300 were mixed with 60.01 grams of a buffer solution. with a pH of 4.5. After the alcohol solution was mixed with the above mixture at 60 ° C, the aqueous solution was added to the final mixture at 60 ° C, to obtain a gel of which oprofen.

Example 2 Quetoprofen 3% Poloxamer 407 17% Polyethylene glycol 4000 5% Ethanol 20% Lauric acid 5% Water 50% 3 grams of ketoprofen and 17 grams of poloxamer 407 were heated at 105 ° C for 10 minutes to obtain a liquefied mixture , and then cooled to 60 ° C. Separately, 5 grams of lauric acid were dissolved in the mixture of 5 grams of polyethylene glycol 4000, and 20 grams of ethanol, which was mixed in the above liquefied mixture at 60 ° C Finally, 50 grams of water were added under vigorous agitation, to obtain a ketoprofen gel.

# Example 3 Quetoprofen 1% Poloxamer 407 20% Regulatory solution with a pH of 4.5 79% One gram of ketoprofen and 20 grams of poloxamer 407 at 105 ° C were heated for 10 minutes to obtain a liquefied mixture. After cooling to room temperature, 79 grams of a buffer solution with a pH of 4.5 was added to the liquefied mixture under stirring, and was kept in a refrigerator overnight to obtain a ketoprofen gel.

Example 4 Ibuprofen 1% Poloxamer 407 20% Propylene glycol 10% Ethanol 20% NaCl 0.2% Water 48.8% One gram of ibuprofen and 20 grams of poloxamer 407 were heated at 110 ° C for 15 minutes to obtain a liquefied mixture, and cooled to 60 ° C. A mixture of 10 grams of propylene glycol, 20 grams, was separately prepared. of ethanol, 48.8 grams of water, and 0.2 grams of sodium chloride, and added to the previous liquefied mixture at 60 ° C, to obtain an ibuprofen gel.

Example 5 Ibuprofen 3% Poloxamer 407 15% Polyethylene glycol 300 10% Ethanol 20% Lauryl alcohol 5% Water 47% 3 grams of ibuprofen and 15 grams of poloxamer 407 were heated at 110 ° C for 15 minutes to obtain a liquefied mixture, and then cooled to 60 ° C. Separately, 5 grams of lauryl alcohol were dissolved in the mixture of 10 grams of polyethylene glycol 300 and 20 grams of ethanol, which was added to the previous liquefied mixture at 60 ° C. , 47 grams of water were added under vigorous agitation, to obtain an ibuprofen gel.

Example 6 Ibuprofen 3% Poloxamer 237 30% Polyethylene glycol 300 5% E anol 10% Regulatory solution with a pH of 52% Three grams of flurbiprofen and 30 grams of poloxamer 237 were heated at 110 ° C for 10 minutes, to obtain a liquefied mixture, and cooled to 60 ° C. To this mixture was added 5 grams of polyethylene glycol 300, 10 grams of ethanol, and 52 grams of a buffer solution with a pH of 4, at 60 ° C, to obtain an ibuprofen gel.

Example 7 Flurbiprofen 3% Poloxamer 407 17.5% Propylene glycol 10% Ethanol 20% Lauric acid 5% Regulating solution with a pH of 44.5% Three grams of flurbiprofen and 17.5 grams of poloxamer 407 were heated at 115 ° C for 10 minutes, to obtain a liquefied mixture, and then cooled to 60 ° C. Separately, 5 grams of lauric acid was dissolved in the mixture of 10 mg. grams of propylene glycol and 20 grams of ethanol, which was added to the previous liquified mixture at 60 ° C. Finally, 44.5 grams of a buffer solution of pH 4 was added under vigorous stirring to obtain a flurbiprofen gel .

Example 8 Naproxen 5% Poloxamer 407 20% Polyethylene glycol 5% Ethanol 20% Regulatory solution with a pH of 50% 5 grams of naproxen and 20 grams of poloxamer 407 were heated at 160 ° C for 10 minutes to obtain a mixture liquefied, and cooled to 60 ° C. Separately, 20 grams of ethanol and 5 grams of polyethylene glycol 300 were mixed in 50 grams of a buffer solution with a pH of 4.0 and added to the previous liquified mixture at 60 °. C to obtain a naproxen gel.

Example 9 Oxaprozin 1% Poloxamer 407 20% Propylene glycol 10% Ethanol 10% Menthol 0.5% Na and 20 grams of poloxamer 407 at 160 ° C for 10 minutes, to obtain a liquefied mixture, and cooled to 60 ° C. Separately, 0.5 grams of menthol was dissolved in 10 grams of eta, and mixed with the mixture. Finally, a solution of 58.5 grams of water and 10 grams of propylene glycol in the mixture at 60 ° C was added to obtain an oxaprozin gel. ^ 3. Example 1Q Pirprofen 2% Poloxamer 407 20% Glycerin 5% Isopropyl alcohol 20% Water 53% Two grams of pirprofen and 20 grams of poloxamer 407 were heated at 105 ° C for 10 minutes, to obtain a liquefied mixture, and cooled to 60 ° C. Separately, 20 grams of isopropyl alcohol and 5 grams of glycerin were mixed in 53 grams of water, and added to the previous liquefied mixture, to obtain pirprofen gel.

Example 11 Alminoprofen 1% Poloxamer 407 25% Propylene glycol 15% Ethanol 5% Water 54% One gram of alminoprofen and 25 grams of poloxamer 407 were heated at 110 ° C for 10 minutes to obtain. p 'iz the liquefied, and cooled to 60 ° C. Separately, 5 grams of ethanol and 15 grams of glycol of r pilono in 54 grams of water were mixed, and added to the mixture Previous liquid at 60 ° C, to obtain an alminoprofen gel.

Example 12 Butybufen 1% Poloxamer 407 20% * Polyethylene glycol COO 5% Isopropyl alcohol 15% One gram and butibufen and 20 grams of poloxamer 407 were heated at 90 ° C for 10 minutes, to obtain a liquefied mixture, and SH cooled to 40 ° C. Separately, 15 grams of isopropyl alcohol and 5 grams of glycol were mixed. 200 polyethylene in 59 grams of water, and added to the previous liquefied mixture at 40 ° C to obtain a butibuffee gel. The anti-inflammatory and analgesic transdermal gels of the present invention prepared as above exhibited excellent Carrotocological activities with less gastric irritation and showed an S t? Xi-t physicochemical stability, as shown in the following Experiments.

Experiment 1 Anti-inflammatory activity on carrageen-induced leg edema in rats. Male Sprague-Dawley rats weighing approximately 200 grams were used as the test animals. Three hours before the carrageenan injection, each gel of Example 1, 4, and 7, was applied on the left leg of the rats in the dose of 50 milligrams. Then, 0.1 milliliter of 1% carrageenan in physiological saline was injected into the armerite subplan leg. Immediately and three hours after the injection of carrageenan, the volume of the paw was measured using a plethysmometer (Ugo Basile Co., Italy) , and the percentage of swelling of the paw and the percentage of inhibition of the formation of the edema were calculated as follows.

Volume of the paw to the volume three hours after the initial injection of carrageenan of the leg% of swelling x 100 initial volume of the leg% of hipchamiento of the group treated with drug x 100% of the control group The results are presented in Table 1 TABLE 1 Ho Group of Rats% of% swelling inhibition Control 7? .2 + 19 Example 1 (ketoprofen gel.). 6 + 6.2 *** 66.8 Example 7 (flurbi- oropéri gel) 30.1 + 8.8 ** 61. ü * - Average value + _ Standard des iación <• - * Significantly different; comparing with the control ÍP 'i) .05) invention, exhibited a significant decrease in the percentage of swelling of the paw, compared to the control. The percentage of inhibition of the formation of edema by means of the gels, was in the scale from 58 to 66 percent that is the maximum inhibition, 60 percent, that can be obtained with this model.

Experiment 2 Anti-inflammatory activity on inhibition of adjuvant-induced arthritis in rats: Sprague-Dawley male rats were anesthetized by weighing approximately 250 grams lightly, and an emulsion (6 milligrams / milliliter) of Mycobacterium butyricide was inoculated into subplantar mineral oil in the left foot of the rats. rats Each gel of Examples 1, 4 and 7 was applied to the inoculated paw at the dose of 50 milligrams, once a day, from day 12 to day 20 after injection. On day 21 after injection, the paw volume was measured according to the method of Experiment 1, to determine the edema formation of the paw injected with the adjuvant. The results are presented in the following Table 2. < * TABLE 2 Group No. of Swelling Rats * Control 10 2.30 + 0.37 Example 1 (ketoprofen gel) lu 0.79 ¿0 AB-fr-v Example 4 (ibuprofen gel) 10 0.95 + 0.31 + * Example 7 (flurbiprofen gel) 10 1.14 + 0.35 * * * - Average value +. Standard deviation t * Significantly different compared to the control As shown in Table 2, the Lranchermic gels according to the present invention had excellent anti-inflammatory activity, since they decreased the paw edema induced by the subplantar injection of the adjuvant, by more than 50 percent, comparing with The control group.

EXERCISE 3 Percutaneous Absorption '- Four male Sprague-Dawley rats weighing 200 grams ± 20 grams were used to evaluate the percutaneous absorption of ketoprofen from the gel of Example 1. Prior to the application of the gel, the hair was carefully removed in the area of the ventral skin of the. rat with an electric razor. 50 milligrams of the gel were uniformly applied over the area of approximately 2 centimeters by 3 centimeters, rubbing lightly. At predetermined time intervals, 250 microliters of blood was collected in a microcentrifuge tube that contained heparin to obtain a plasma sample. The concentration of ketoprofen in the plasma of the rat was quantified with High Performance Liquid Chromatography. The results are presented in the following Table 3.

* Average value < - Standard deviation It is known that the maximum concentration of ketoprofen after oral administration to rats occurs at i) .25-0.5 hours after the dose. After the transdermal application of the gel of Example I, however, the absorption of ketoprofen was so low that the maximum concentration of the drug was at 6 hours after the dose, as can be seen in Table 3. And also, maintained the concentration of ketoprofen in plasma on the plain relatively several hours after transdermal application, even when it was much lower than after oral administration of the drug.

Experience 4 Formation of gastric ulcer: Male Sprague-Dawley rats weighing about 200 grams were used as the test animals. Food was removed from the rats for 24 hours before dosing, while water was allowed freely through the whole experiment. Each gel of Examples 1, 4, and 7, was applied lightly, in the dose of 50 milligrams / kilogram, on the dorsal skin of 2 centimeters by 3 centimeters where the hair was removed. As a reference, the rats in the control group were administered ketoprofen orally as a suspension in physiological saline in the dose of 10 milligrams kilogram. Six hours after administration, the rats were sacrificed and the ulcer formation in the stomach was scored as follows: 0"normal, 1: reddening mucosa, 2: one to four small ulcers (less than 2 millimeters in diameter) , 3: more than four ueñas ulcers or a large ulcer (greater than 2 millimeters "in diameter), 4 '. more than one large ulcer. The rating of two higher ones was considered as ulcer formation. The results are presented in the following Table 4.

TABLE 4 As can be seen in Table 3, when * formulated non-spheroidal antiinflammatory drugs of propionic acid derivatives in gels according to the present invention, and were administered transdermally, gastric ulcer formation was much lower, even at doses of 5 times that of oral administration. Ulcer formation was also observed after percutaneous administration of the gels, indicating that a significant amount of the drug permeated the skin and was absorbed into the skin. * blood circulation.

Experiment 5 Stability test: The gels of Examples 1, 4, and 7. were stored at 4 ° C, 25 ° C, and 40 ° C. After six months the samples were examined whether the initial texture of each gel was maintained or not. The color change was visually tested against a white background, and small amounts of the gels were subjected to microscopic examination to identify any rectalisation of the drug. The amount of the drug in the gel was quantified using High Performance Liquid Chromatography, and the results are presented in the following Table 5.

TABLE 5 As Table 4 is shown, any change in appearance or recrystallization in the gel was observed, and little change in the amount of drug in the gel was detected, compared to the initial amount, indicating an excellent physicochemical stability of the gel.

Claims (4)

NEW DK THE INVENTION Having described the above invention, it is considered as a novelty, and therefore, the content of the following is claimed as property: CLAIMS

1. An anti-inflammatory and analgesic transdermal gel, which includes, by weight, 0.5% to 5% of a non-steroidal anti-inflammatory drug of propionic acid derivatives as an effective ingredient; from 10 to 30 percent, of poloxamer as a gel forcing agent; from 0 to 30 percent of one or more agents selected from a lower alcohol, propylene glycol or, polyethylene glycol, and glyceryl; from 0 to 10 percent of one or more agents selected from fatty acids, fatty alcohols, and rae tol; and total up to 100 percent with water or with a regulatory solution.

2. The transdermal gel according to claim 1, characterized in that the agent further includes one or more agents selected from preservatives and flavorings.

3. The transdermal gel according to claim 1, characterized in that the non-steroidal anti-inflammatory drug of acid derivatives * propionic, is one or more drugs selected from the group consisting of ketoprofen, ibuprofen, flurbiprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alrainoprofen, butibufen and fenbufen,

4. The gel transdermal according to claim 1, characterized in that the pH of the gel is controlled to the value around the pKa of the drug used. * IN WITNESS WHEREOVER, I have signed the above description and Novelty of the Invention, as attorney of IL-DONG PHARM. CO., LTD, in the city of Mexico, D.E., on the 23rd day of March, 1994. IL-DONG PHARM CO. , LTD. / o Samuel Dorantes R