PHARMACEUTICAL COMPOSITION FOR INTRAMUSCULAR INJECTION CONTAINING LOXOPROPHENE \ FIELD OF THE INVENTION The present invention relates to a new pharmaceutical formulation containing loxoprofen. In particular, the invention relates to the formulation of the intramuscular injection containing the loxoprofen or a pharmaceutically acceptable salt thereof, which has an excellent anti-inflammatory analgesic effect, as an active ingredient. BACKGROUND OF THE INVENTION Loxoprofen (chemical name: 2- [4- (2-oxocyclopentyl) phenyl] propionic acid) is a non-spheroidal drug
(NSAID, for its acronym in English) anti-inflammatory of the propionic acid type and is represented by the following formula:
The above drug is normally used in the form of a sodium salt, that is, as loxoprofen sodium. Sodium loxoprofen is effective for the treatment of rheumatoid arthritis, deforming arthritis, lumbosacral sprains, adhesive capsulitis and shoulder-arm-neck syndrome. The drug is also known to be effective for the relief of post-operative or post-traumatic pain, or for the relief of pain after the extraction of a tooth. Currently, it is widely used in the form of an oral tablet. The drugs mentioned above cause relatively less gastroenteric disorders than any other NSAIDs, such as propionic acid, but still cause such side effects as gastroenteric disorders and peptic ulcer during a long-term administration. Accordingly, several studies have recently been carried out to develop transdermal formulations thereof such as sustained release in adhesive preparations [PCT / JP1997 / 02936, Korean Patent Application No. 98-41351 (October 1, 1998), S Patent No. 4,740,374 (April 26, 1988), PCT / O95 / 16440 (June 22, 1995), Korean Patent Application No. 96-38430 (September 5, 1996)]. Such transdermal formulations have the advantage that they can alleviate the side effects or discomforts from the administration of oral formulations for patients who have difficulty in oral absorption or who require a long-term administration. However, the above formulations should also comprise polymers in the same manner as the previously developed adhesive preparations and then so, can cause skin-surface rashes due to long-term adhesion or skin allergies such as itching, etc. They also cause another side effect such as discomfort in patient movements. Furthermore, although the absorption rate of a drug through the skin can be controlled, this takes a long period of time to obtain the desired therapeutic effect due to the difference in the rate of percutaneous absorption or amount of absorption, depending on a part of pain and the physical constitution of each individual. Thus, transdermal formulations have a disadvantage that they can not be used in such emergent cases as suffering from severe pains. Sodium loxoprofen has a different reaction mechanism from ketoprofen and ibuprofen, generally known as NSAIDs of the propionic acid type. It has an excellent anti-inflammatory analgesic effect due to the inhibitory action in the biosynthesis of prostaglandin, causative agent of inflammation and pain. That is, this drug is a pro-drug that is converted into a trans-OH metabolite, ie 2- [para- (trans-2-hydroxycyclopentyl) phenyl] propionic acid in vivo through metabolism by a ketone reductase in oral administration. The above metabolite exhibits an excellent anti-inflammatory analgesic effect by the inhibitory action on cyclooxygenase, a prostaglandin synthetase [Matsuda et al., Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp263-266 (1983)] . Ketone reductase is mainly distributed in liver or kidney [Tanaka et al., Japanese Journal of Inflammation, Vol. 3, No. 2, Spring, ppl51-155 (1983)]. The enzyme metabolizes loxoprofen sodium in the trans-OH metabolite to exhibit the strong anti-inflammatory analgesic effect. This enzyme is also known to exist on the surface of the skin to exhibit the equivalent pharmacological effect [U S Patent No. 4,740,374 (April 26, 1988)]. For the above reason, oral formulations such as loxoprofen containing tablets or a pharmaceutically acceptable salt as an active ingredient is widely marketed (Loxonin or Loxfen). Also, external formulations such as adhesive preparations and patches have recently been studied. In contrast, no intramuscular injection of this drug has been reported. As previously described, it is difficult to administer oral loxoprofen formulations, which have been developed up to now, in serious cases with difficulty in oral absorption or cases with gastroenteric disorders. However, patches under extensive studies have not yet been fully developed. Also, the transdermal loxoprofen formulations must contain many auxiliary agents such as agents to increase penetration and thus, may cause side effects such as skin rashes. Moreover, they can cause such discomforts as restriction in movements due to long-term adherence to a particular part of the body. Particularly, since inflammation or pain is likely to occur in a joint, patches for percutaneous absorption are likely to have many problems continuously providing the desired pharmacological effects, for example, because they are easily detached from the skin by movements of the skin. the joint Therefore, it is necessary to develop a new formulation of loxoprofen that can also be applied to patients with difficulty in oral absorption and can solve all the disadvantages due to transdermal administration. DESCRIPTION OF THE INVENTION The present inventors conducted extensive studies to develop a new formulation of loxoprofen. As a result, the inventors found that sodium loxoprofen can provide an excellent anti-inflammatory analgesic effect not only on the skin but also in the muscle through conversion to the trans-OH metabolite by ketone reductase. Based on the above, the inventors identified that an intramuscular injection of loxoprofen is also applicable to patients who have difficulty in oral absorption. Moreover, it was found that compared to oral formulations, it has an equivalent or superior anti-inflammatory analgesic effect even in smaller amounts and has a rapid action without any side effects in oral formulations. Accordingly, the following present invention was completed. The present invention relates to a pharmaceutical composition for intramuscular injection containing loxoprofen of the following formula:
, or a pharmaceutically acceptable salt thereof as an active ingredient. In a preferred embodiment, the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium. Next, the present invention will be explained in more detail. As described above, loxoprofen or a pharmaceutically acceptable salt thereof is absorbed in the gastrointestinal tract in inactivated forms on oral administration. Then, it is converted into trans-OH metabolites by the action of ketone reductases in the liver or kidney to provide an excellent anti-inflammatory analgesic effect. It is also converted into trans-OH metabolites by the action of ketones reductases on the skin to show the same effect. However, the present inventors identified that in the muscle, they are also convertible to transOH metabolites by ketone reductases to have the similar effect, particularly, an equivalent or even superior effect in 1/2 to 2/3 of the tablet amounts. In addition, it is generally the first requirement to treat patients suffering from pain to obtain an anti-inflammatory analgesic effect. The present intramuscular injection also provides fast action by satisfying the above requirement. The invention provides an intramuscularly injectable formulation of loxoprofen, which can resolve side effects of oral formulations such as tablets, for example limitation in use for patients having difficulty in oral absorption or gastroenteric disorders on long-term administration. The formulation simultaneously solves the side effects of formulations for external use, for example discomfort in use, skin allergies and the like. Particularly, it can be conveniently used for patients in need of rapid pharmacological effect. The formulation of the present invention can be properly prescribed. In order to maintain storage stability, an aqueous acidic solution or a buffer such as a phosphate buffer, which is injectable, can be used to adjust its pH accordingly to give the injection excellent physical and chemical stability. More specifically, the present formulation can be prepared by dissolving loxoprofen or a pharmaceutically acceptable salt in the water for injection in combination with stabilizing agent or a solubilized auxiliary and sterilizing the solution obtained, for example, at a high temperature under vacuum or by aseptic filtration. The water for injection may be distilled water or a buffer, for example, a phosphate buffer or a monobasic sodium phosphate-citric acid buffer (NaH2P04) -citric acid having the pH in the range of 3.5 to 7.5. The phosphate may be in the form of sodium or potassium salt, hydrated or anhydrous, and the citric acid may be in anhydrous or hydrated form. The stabilizing agent that can be used in the present invention can be sodium pyrosulfite, sodium bisulfite (NaHS03), sodium metabisulfite (Na2S203), or ethylenediaminetetraacetic acid. The solubilizing aid may be a base such as sodium hydroxide (NaOH), sodium bicarbonate (NaHCO 3), sodium carbonate (Na 2 CO 3) and potassium hydroxide (KOH), or an acid such as hydrochloric acid (HCl) or acetic acid ( CH3COOH). The formulation of the present invention is preferably a solution having the pH in the range of 3.5 to 7.5, or a powder prepared by sterilization and dehydrated by freezing. The concentration of the active ingredient is preferably in the range of 2 to 20%. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a curve of the comparative distribution of loxoprofen plasma drug concentrations between the tablet and intramuscular injection. THE BEST METHOD FOR CARRYING OUT THE INVENTION This invention will be better understood from the following examples. However, a person skilled in the art will readily appreciate the specific materials and results described are merely illustrative of, and are not intended, nor should be thought of as, limit the invention as more fully described in the claims which follow thereafter.
Preparation of the Injectable Solution Example 1: Sodium loxoprofen and sodium pyrosulfite were dissolved in distilled water for injection. The solution was sterilized at a high temperature under vacuum and filled with 1 ml ampule to give an intramuscular injection (Table
1) • Table 1: Composition of 1 ml of intramuscular injection of loxoprofen
Example 2: Sodium loxoprofen and sodium pyrosulfite were dissolved in distilled water for injection. To this was added dilute hydrochloric acid to adjust the pH to 6. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table 2). Table 2: Composition of 1 ml of intramuscular injection of loxoprofen
Example 3: Sodium loxoprofen and sodium pyrosulfite were dissolved in distilled water for injection. To this was added dilute hydrochloric acid to adjust the pH to 5. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table 3). Table 3: Composition of 1 ml of intramuscular injection of loxoprofen
Example 4: Sodium loxoprofen and sodium metabisulfite were dissolved in distilled water for injection. To this was added dilute hydrochloric acid to adjust the pH to 4. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table
4). Table 4: Composition of 1 ml of intramuscular injection of loxoprofen
Example 5: Potassium monobasic phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a buffer solution of pH 6.5. In the prepared buffer solution, sodium loxoprofen and sodium pyrosulfite were dissolved. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table 5). Table 5: Composition of 1 ml of intramuscular injection of loxoprofen
Example 6: Sodium monobasic phosphate decahydrate and citric acid were dissolved in distilled water for injection to prepare a buffer solution of citric acid-sodium monobasic phosphate pH 5.4. In the prepared buffer solution, sodium loxoprofen and sodium pyrosulfite were dissolved. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table 6). Table 6: Composition of 1 ml of intramuscular injection of loxoprofen
Example 7: Potassium monobasic phosphate and anhydrous sodium dibasic phosphate were dissolved in distilled water for injection to prepare a phosphate buffer solution of pH 6.8. In the prepared buffer solution, sodium loxoprofen and sodium pyrosulfite were dissolved. The resulting solution was sterilized at a high temperature under vacuum, or by aseptic filtration, and a 1 ml ampule was filled to give an intramuscular injection (Table 7). Table 7: Composition of 1 ml of intramuscular injection of loxoprofen
Example 8: Potassium monobasic phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a pH 7.0 phosphate buffer. In the prepared buffer solution, sodium loxoprofen and sodium pyrosulfite were dissolved. The resulting solution was sterilized at a high temperature under vacuum, and a 1 ml ampule was filled to give an intramuscular injection (Table 8). Table 8 Composition of 1 ml of intramuscular injection of loxoprofen
Example 9: Potassium monobasic phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer of pH 7.4. In the prepared buffer solution, sodium loxoprofen and sodium pyrosulfite were dissolved. The resulting solution was sterilized at a high temperature under vacuum, and a 1 ml ampule was filled to give an intramuscular injection (Table 9). Table 9: Composition of 1 ml of intramuscular injection of loxoprofen
Example 10: Sodium loxoprofen, sodium pyrosulfite and mannitol were dissolved in distilled water for injection. The solution was sterilized at a high temperature under vacuum, and a 1 ml ampule was filled to give an intramuscular injection (Table 10). Table 10: Composition of 1 ml of intramuscular injection of loxoprofen
Preparation of Injectable Powder Example 11: Sodium loxoprofen and mannitol were dissolved in distilled water for injection. The solution was aseptically filtered and then, it was introduced into a vial. The vial was dehydrated by freezing to prepare a dry powder product. Before use, 1 ml of distilled water was added to the vial which was packaged separately from the vial and mixed to complete the solution for an intramuscular injection (Table 11). Table 11: Composition of 1 ml of intramuscular injection of loxoprofen
Example 12: Potassium monobasic phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer of pH 6.5.
In the prepared buffer, mannitol, sodium loxoprofen and sodium pyrosulfite were completely dissolved. The resulting solution was aseptically filtered and introduced into a vial. The vial was dehydrated by freezing to prepare a dry powder product. Before use, 1 ml of distilled water is added to the vial, which was packed separately from the vial, and mixed for complete dissolution to give an intramuscular injection (Table 12). Table 12: Composition of 1 ml of intramuscular injection of loxoprofen
Example 13: Loxoprofen and sodium bicarbonate were dissolved in distilled water to prepare a 1 ml solution. To this solution was added sodium pyrosulfite and the mixture was stirred until its complete dissolution. The resulting solution was aseptically filtered and placed in a vial. The vial was dehydrated by freezing to prepare a dry powder product. Before use the vial is added with ul ml of distilled water that was packed separately from the vial, and mixed until complete dissolution for an intramuscular injection (Table 13). Table 13: Composition of 1 ml of intramuscular injection of loxoprofen
Example 14: Loxoprofen and sodium hydroxide were dissolved in distilled water to prepare a 1 ml solution. To this solution was added sodium pyrosulfite and the mixture was stirred until the dissolution was complete. The resulting solution was aseptically filtered and placed in a vial. The vial was dehydrated by freezing to prepare a dry powder product. Before use, 1 ml of distilled water, which was packed separately from the vial, is added to the vial. The mixture is stirred until complete dissolution to give an intramuscular injection (Table 13). Table 14: Composition of 1 ml of intramuscular injection of loxoprofen
Experiment 1: Comparison of plasma drug concentrations of loxoprofen between tablets and intramuscular injection in rats. The concentration of loxoprofen in plasma in the intramuscular injection obtained from Example 1 was evaluated and compared with the commercially available loxoprofen in tablets (Loxonin: control) in male 6-week-old SD rats free of specific pathogens. In the control group, the formulation was orally administered to the rats with a single dose of 10 mg / kg. In the experimental group, the formulation was injected intramuscularly to the rats with a single dose of 5 mg / kg. Blood was collected from rats at 2, 5, 10, 20, 30, 60, 120 and 180 minutes after administration and before treatment. Then, plasma drug concentrations were analyzed. The following results are the concentration of loxoprofen in plasma at (μg / ml) against time (in min).
Table 15: Comparison of loxoprofen drug concentrations in the plasma between the tablet and the intramuscular injection
As shown in Table 15 above, because the intramuscular injection was administered in the amount of 50% of the tablet, the drug concentration in plasma was shown to be slightly lower than that of the tablet. However, the plasma drug concentration curves change between the experimental concentration and the control group where it was shown to be similar (Fig. 1) Experiment 2: Intramuscular injection stability test Samples were taken from the intramuscular injection of loxoprofen obtained from Example 1 stored at room temperature, 50 ° C and 60 ° C, for 1, 3 and 4 weeks, respectively. As a consequence, the drug content and the variation in pH were measured. The results are shown in the following table 16. Table 16a: Variation in drug content of intramuscular injection of loxoprofen Table 16 b: Variation in pH of intramuscular injection of loxoprofen
As shown in the previous Table 16, both the drug content and the pH in the intramuscular injection of loxoprofen remained stable without significant variation. Experiment 3: Comparison of standing oedemas between loxoprofen tablet and intramuscular injection in rats 1) experimental animal: male SD rats about 6 weeks of age free of specific pathogens 2) test material and dosage administration: An edema-inducing agent , 1% carrageenan lambda type IV (Sigma Co.), was injected hypodermically into the plant of the rat paw to induce edema of the foot. Sodium loxoprofen was formulated in solutions of 5mg / 2ml and lOmg / lOml for an intramuscular injection using phosphate buffer according to the method in Example 5. The formulations obtained were injected intramuscularly at the dose of 5 mg / 2 ml / kg, and orally administered at the dose of 10 mg / ml / kg, respectively. 3) Test method and calculation formula: A normal (standard) point is marked in the ankle joint region the ankle region in the left posterior part of the rat leg and then, the volume of the foot before the administration was measured by the plethysmometer (Hugo Sacks &Coulbourn). The formulations of the test were injected intramuscularly or orally administered to the rats. After 20 minutes, 1% carrageenan was injected subcutaneously or hypodermically in the left posterior part of the rats' paw at the dose of 0.1 ml per animal. After 2 hours and 30 minutes, the volume of the foot was measured, and the rate of edema and the rate of edema inhibition was calculated by the following formula: Proportion of edema (%) = [(edema of the foot after injection of the edema-inducing agent - edema of the foot before the injection of the edema-inducing agent) / edema of the foot before the injection of the edema-inducing agent] xlOO Edema inhibition rate (%) = 100 - [average ratio of the edema of the test material administered to the group / the average proportion of the edema of the untreated group x 100] 4) Evaluation: The importance of the difference in the proportion of inhibition of the edema of the experimental group and the control group were verified according to with ANOVA. It was concluded that the edema was inhibited at the level of p < 0.05. 5) Proportion of edema and proportion of inhibition of edema: The results are shown in the following table 17. Table 17: Comparison of foot edema after administration of loxoprofen between tablets and intramuscular injection
*: P < 0.05 against the control group (The proportion of the edema was expressed in terms of +/- standard deviation) As shown in the previous table 17, in the case of the intramuscular injection of loxoprofen sodium with the dose of 5 mg / kg, the proportion of edema inhibition was 73.0%. On the other hand, in the case of oral administration of loxoprofen sodium at a dose of 10 mg / kg, the proportion of edema inhibition was 76.2%. Accordingly, the equivalent inhibition ratio could be obtained by an intramuscular injection of only 50% of the dose of the drug compared with oral administration. Experiment 4: Comparison of analgesic effects of loxoprofen between the tablet and intramuscular injection in rats 1) Experimental animal: Male ICR mice 5 weeks of age free of specific pathogens 2) Test material and dosage of administration: Loxoprofen sodium was formulated in solutions of 5 mg / 2 ml and 10 mg / 10 ml using the phosphate buffer according to the method in Example 5. The solutions were injected intramuscularly at a dose of 5 mg / 2 ml / kg, and orally administered at a dose of 10 mg / 10 ml / kg, respectively. At 20 minutes after administration, a pain-inducing agent, 0. 7% acetic acid in distilled water. , was injected intraperitoneally with a dose of 10 ml / kg to induce pain. Then, the number of writhings was moderate 5 minutes after inducing pain for 10 minutes. 3) Comparison of analgesic effects: The results are shown in the following table 18. Table 18: Comparison of the analgesic effect of loxoprofen between tablet and intramuscular injection
*: P < 0. 05 against the control group (The number of writhings was expressed in terms of +/- Standard Deviation) As shown in Table 18 above, in the case of intramuscular injection of loxoprofen sodium with the dose of 5 mg / kg, the proportion of pain inhibition was 53.7%. On the other hand, in the case of oral administration of loxoprofen sodium at a dose of 10 mg / kg, the proportion of edema inhibition was 64.0%. According to, the proportion of dominant pain inhibition could be obtained by an intramuscular injection of only 50% of the dose of the drug compared to an oral administration. FIELD OF INDUSTRIAL APPLICATION The intramuscular injection of the present invention can be applied to patients with difficulty in oral absorption, and it can also obtain an equivalent or greater anti-inflammatory analgesic effect even with smaller amounts, compared with oral formulations. In addition, it can exhibit rapid action without side effects due to percutaneous absorption.