OA12175A - Pharmaceutical composition for intramuscular injection containing loxoprofen. - Google Patents

Abstract

Disclosed is a formulation for intramuscular injection containingloxoprofen or a pharmaceutically acceptable salt thereof, having an excellent anti-inflammatory analgesic effect, as an active ingredient.

Description

1 012175

PHARMACEUTICAL COMPOSITION FOR INTRAMUSCULAR INJECTIONCONTAINING LOXOPROFEN

TECHNICAL FIELD 5

The présent invention relates to a novel pharmaceutical formulation containingloxoprofen. In particular, the invention relates to the formulation for intramuscularinjection containing loxoprofen or a pharmaceutically acceptable sait thereof, which has anexcellent anti-inflammatory analgésie effect, as the active ingrédient. 10

BACKGROUND ART

Loxoprofen (chemical name: 2-[4-(2-oxocyclopentyl)phenyl]propionic acid) is anonsteroidal anti-inflammatory drug (NSAID) of propionic acid type and is represented by 15 the following formula:

The above drug is usually used in the form of a sodium sait, that is, as loxoprofen sodium. 20 Loxoprofen sodium is effective for the treatment of rheumatoid arthritis, déformant arthritis, lumbosacral strain, adhesive capsulitis and shoulder-arm-necksyndrome. The drug is also known to be effective for relief of post-operative or post-traumatic pains, or for pain relief after tooth extraction. Currently, it is widely used in anoral tablet. 25

The above drug causes relatively less gastroenteric disorders than any other 2 012175 propionic acid-type NSAIDs, but still causes such side effects as gastroenteric disordersand peptic ulcer upon a long-term administration. Therefore, several studies hâve beenrecently carried out to develop transdermal formulations thereof such as sustained releaseadhesive préparations [PCT/JP1997/02936, Korean Patent Application No 98-41351(October 1, 1998), US Patent No. 4,740,374 (April 26, 1988), PCT/WO95/16440 (June 22,1995), Korean Patent Application No. 96-38430 (September 5, 1996)]. Such transdermalformulations hâve the advantage that they can alleviate side effects or uneasiness fromadministration of oral formulations for patients having difficulty in oral absorption orrequiring a long-term administration. However, the above formulations must alsocomprise polymers in the same manner as the previously developed adhesive préparationsand thus, may cause skin éruptions due to long-term adhesion or skin allergies such asitching, etc. They also cause other side efifect such as discomfort in motions of patients.Further, even though the absorption rate of a drug through the skin can be controlled, ittakes a long time to obtain the desired therapeutic effect due to différence in thepercutaneous absorption rate or absorption amount, depending on a part of pain andphysical constitution of each individual. Thus, the transdermal formulations hâve adrawback that they cannot be used in such emergent cases as suffering from severe pains.

Loxoprofen sodium has a different reaction mechanism from ketoprofen andibuprofen, generally known propionic acid-type NSAIDs. It has an excellent anti-inflammatory analgésie effect by the inhibitory action on the biosynthesis of prostaglandin,a causative agent of inflammation and pain. That is, this drug is a pro-drug, which isconverted into a trans-OFI métabolite, i.e. 2-[para-(trans-2-hydroxycyclopentyl)phenyljpropionic acid in vivo through the metabolism by a ketone reductase upon oraladministration. The above métabolite exhibits an excellent anti-inflammatory analgésieeffect by the inhibitory action on cyclooxygenase, a prostaglandin synthetase [Matsuda etal., Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp263-266 (1983)]. Theketone reductase is mainlv distributed in liver or kidney [Tanaka et al., Japanese Journal ofInflammation, Vol. 3, No. 2, Spring, ppl51-155 (1983)]. The enzyme metabolizesloxoprofen sodium into the trans-OII métabolite to exhibit the strong anti-inflammatory 3 U i 21 7 5 analgésie effect. This enzyme is also known to exist on the surface of the skin to exhibitthe équivalent pharmacological effect [US Patent No. 4,740,374 (April 26, 1988)]. Forthe above reason, oral formulations such as tablets containing loxoprofen or apharmaceutically acceptable sait thereof as an active ingrédient are widely commercialized(Loxonin or Loxfen). Also. external formulations such as adhesive préparations andpatches hâve been recently studied. By contrast, no intramuscular injection of this drughas been reported.

As previously described, it is difficult to administer oral formulations ofloxoprofen, which hâve been developed hitherto, in serious cases with diffïculty in the oralabsorption or cases with gastroenteric disorders. However, patches under extensivestudies hâve not yet been developed completely. Also, the transdermal formulation ofloxoprofen must contain many auxiliary agents such as pénétration enhancing agents andthus, may cause side effects such as skin éruptions. Moreover, they may cause suchdiscomforts as restricting motions due to the long-term adhesion onto a particular part ofthe body. Particularly, since inflammation or pain is likely to occur in a joint, patches forpercutaneous absorption are likely to hâve many problems in continuously providing thedesired pharmacological effects, for example, because they are easily detached from theskin by motions of a joint.

Therefore, it has been needed to develop a novel formulation of loxoprofen, whichcan also be applied to patients with diffïculty in the oral absorption and can solve ail thedrawbacks due to the transdermal administration.

DISCLOSURE OF THE INVENTION

The présent inventors performed extensive studies to develop a novel formulationof loxoprofen. As a resuit, the inventors found that loxoprofen sodium can provide anexcellent anti-inflammatory analgésie effect not only on the skin but also in the musclethrough the conversion into the trans-011 métabolite by the ketone reductase. Based on 4 012175 the above, the inventors identified that an intramuscular injection of loxoprofen is alsoapplicable to patients having difficulty in the oral absorption. Moreover, it was found thatas compared with the oral formulations, it has an équivalent or higher anti-inflammatoryanalgésie effect even in smaller quantities and has a fast action without any side effect in 5 the oral formulations. Accordingly, the following présent invention was completed.

The présent invention relates to a pharmaceutical composition for intramuscularinjection containing loxoprofen of the following formula:

10 , or a pharmaceutically acceptable sait thereof as the active ingrédient.

In a préférable embodiment, the pharmaceutically acceptable sait of loxoprofen isloxoprofen sodium. 15 Hereinafter, the présent invention will be explained in more detail. As described

above, loxoprofen or a pharmaceutically acceptable sait thereof is absorbed into thegastrointestinal tract in inactivated forms upon oral administration. Then, it is convertedinto trans-OH métabolites by action of ketone reductases in the liver or kidney to providean excellent anti-inflammatory analgésie effect. It is also converted into trans-OH 20 métabolites by action of ketone reductases on the skin to show the same effect. However,the présent inventors identified that in the muscle, they are also convertible into trans-OHmétabolites by ketone reductases to hâve the similar effect, particularly, an équivalent orhigher effect even in 1/2 to 2/3 of the tablet quantities. In addition, it is generally the firstrequiremenl for treating patients suffering from pains to obtain an anti-inflammatory 25 analgésie effect. The présent intramuscular injection also provides the fast actionsatisfying the above requirement. 5 012175

The invention provides an intramuscularly injectable formulation of loxoprofen,which can solve side effects of oral formulations such as tablets, e.g. limitation in use foi-patients having difficulty in the oral absorption or having gastroenteric disorders uponlong-term administration. The formulation simultaneously solves side effects offormulations for external use, e.g. discomfort in use, skin allergies and the like.Particularly, it can be conveniently used for patients in need of the fast pharmacologicaleffect.

The formulation of the présent invention may be properly prescribed. In order tokeep the storage stability, an acidic aqueous solution or a buffer such as a phosphate buffer,which is injectable, may be used to adjust its pH thereby to give the injection excellentphysical and Chemical stability.

More specifically, the présent formulation may be prepared by dissolvingloxoprofen or a pharmaceutically acceptable sait in the water for injection in combinationwith a stabilizing agent or a solubilizing aid and sterilizing the obtained solution, forexample, at a high température under vacuum or by aseptie filtration. The water forinjection may be the distilled water or a buffer, for example, a phosphate buffer or asodium dihydrogen phosphate (NaJfPChj-citric acid buffer having the pH in the range of 3.5 to 7.5. The phosphate may be in the form of sodium or potassium sait, or anhydrousor hydrate, and the citric acid may be in the form of anhydrous or hydrate. Thestabilizing agent, which can be used in the présent invention, may be sodium pyrosulfite,sodium bisulfite (NaHSOj), sodium metabisulfite (NaiSjCh), or ethylene diaminetetraacetic acid. The solubilizing aid may be a base such as sodium hydroxide (NaOH),sodium bicarbonate (NallCOj), sodium carbonate (Na2COj) and potassium hydroxide(KOII), or an acid such as hydrochloric acid (HCl) or acetic acid (CffCOOII).

The formulation of the présent invention is preferably a solution having the pH inrange of 3.5 to 7.5. or a powder prepared by sterilization and freeze-drying. Theconcentration of the active ingrédient is preferably in the range of 2 to 20%. 6 012175

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a comparative distribution curve of the drug plasma concentrations of5 loxoprofen between tablet and intramuscular injection.

BEST MODE FOR CARRYING OUT THE INVENTION

This invention will be better understood from the following examples.10 However, one skilled in the art will readily appreciate the spécifie materials and resultsdescribed are merely illustrative of, and are not intended to, nor should be intended to, limit the invention as described more fully in the daims which follows thereafter.

Préparation of Injectable Solution 15

Exainple 1:

Loxoprofen sodium and sodium pyrosulfite were dissolved in the distilled waterfor injection. The solution was sterilized at a high température under vacuum and filled 20 into a 1 ml ampule to give an intramuscular injection (Table 1).

Table 1 : Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.2%(w/v) d.w. for injection ad 1 ml

Example 2:

Loxoprofen sodium and sodium pyrosulfite were dissolved in the distilled waterfor injection. Thereto was added dilute hydrochloric acid to adjust the pH to 6. The 7 Üi 2175 resulting solution was sterilized at a high température under vacuum, or by aseptiefiltration, and filled into a 1 ml ampule to give an intramuscular injection (Table 2).

Table 2: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.1%(w/v) d.w. for injection ad 1 ml Dilute hydrochloric acid q.s. (pH 6)

Example 3:

Loxoprofen sodium and sodium pyrosulfite were dissolved in the distilled waterfor injection. Thereto was added dilute hydrochloric acid to adjust the pH to 5. The 10 resulting solution was sterilized at a high température under vacuum, or by aseptiefiltration, and filled into a 1 ml ampule to give an intramuscular injection (Table 3).

Table 3: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.1%(w/v) d.w. for injection ad 1 ml Dilute hydrochloric acid q.s. (pH 5) 15 Example 4:

Loxoprofen sodium and sodium metabisulfite were dissolved in the distilled waterfor injection. Thereto was added dilute hydrochloric acid to adjust the pH to 4. Theresulting solution was sterilized at a high température under vacuum, or by aseptie 20 filtration, and filled into a 1 ml ampule to give an intramuscular injection ( fable 4).

Table 4: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) 8 012175

Sodium metabisulfite (Na2S2O5) 0.2%(w/v) d.w. for injection ad 1 ml Dilute hydrochloric acid q.s. (pH 4)

Example 5:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in the5 distilled water for injection to préparé a phosphate buffer solution of pH 6.5. To theprepared buffer solution were dissolved loxoprofen sodium and sodium pyrosulfite. Theresulting solution was sterilized at a high température under vacuum, or by aseptie filtration, and filled into a 1 ml ampule to give an intramuscular injection (Table 5). 10 Table 5: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfïte 0.2%(w/v) Potassium dihydrogen phosphate (KH2PO4) 0.68%(w/v) Sodium hydroxide (NaOH) 0.06%(w/v) d.w. for injection ad 1 ml

Example 6:

Sodium dihydrogen phosphate dodecahydrate and citric acid were dissolved in the15 distilled water for injection to préparé a sodium dihydrogen phosphate-citric acid buffersolution of pH 5.4. To the prepared buffer solution were dissolved loxoprofen sodiumand sodium pyrosulfïte. The resulting solution was sterilized at a high température undervacuum, or by aseptie filtration, and filled into a 1 ml ampule to give an intramuscular injection (Table 6).

Table 6: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfïte 0.2%(w/v) Sodium dihydrogen phosphatedodecahydrate (NaibPO^^fhO) 1.45%(w/v) Citric acid 0.53%(w/v) 9 012175 d.w. for injection

Ad 1 ml

Example 7:

Potassium dihydrogen phosphate and anhydrous sodium monohydrogen phosphate5 were dissolved in the distilled water for injection to préparé phosphate buffer solution ofpH 6.8. To the prepared buffer solution were dissolved loxoprofen sodium and sodiumpyrosulfite. The resulting solution was sterilized at a high température under vacuum, and filled into a 1 ml ampule to give an intramuscular injection (Table 7). 10 Table 7: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.2%(w/v) Potassium dihydrogen phosphate (KH2PO4) 0.34%(w/v) Anhydrous sodium monohydrogen phosphate (Na2HPO4) 0.34%(w/v) d.w. for injection Ad 1 ml

Example 8:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in the15 distilled water for injection to préparé a phosphate buffer solution of pH 7.0. To theprepared buffer solution were dissolved loxoprofen sodium and sodium pyrosulfite. Theresulting solution was sterilized at a high température under vacuum, and filled into a 1 ml ampule to give an intramuscular injection (Table 8). 20 Table 8: Composition of the 1 ml intramuscular injection of loxoprofen ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.2%(w/v) Potassium dihydrogen phosphate (KJI2PO4) 0.68%(w/v) Sodium hydroxide (NaOI-1) 0.12%(w/v) d.w. for injection ad 1 ml 10 012175

Example 9:

Potassium dihydrogen phosphate and sodium hydroxide were dissolved in thedistilled water for injection to préparé a phosphate buffer solution of pH 7.4. To the 5 prepared buffer solution were dissolved loxoprofen sodium and sodium pyrosulfite. Theresulting solution was sterilized at a high température under vacuum, and filled into a 1 mlampule to give an intramuscular injection (Table 9).

Table 9: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.4%(w/v) Potassium dihydrogen phosphate (KH2PO4) 0.68%(w/v) Sodium hydroxide (NaOH) 0.16%(w/v) d.w. for injection ad 1 ml 10

Example 10:

Loxoprofen sodium, sodium pyrosulfite and mannitol were dissolved in thedistilled water for injection. The solution was sterilized at a high température under 15 vacuum, and filled into a 1 ml ampule to give an intramuscular injection (Table 10).

Table 10: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.4%(w/v) Mannitol 5.0%(w/v) d.w. for injection ad 1 ml

Préparation of Injectable Powder 20

Example 11:

Loxoprofen sodium and mannitol were dissolved in the distilled water for injection. 11 012175

The solution was aseptically filtered and then, introduced into a vial. The vial was freeze-dried to préparé a dry powdered product. Before the use, to the vial was added 1 ml ofthe distilled water, which was packaged separately from the vial, and stirred to thecomplété dissolution to give an intramuscular injection (Table 11).

Table 11: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.4%(w/v) Mannitol 20.0%(w/v) d.w. for injection ad 1 ml

Example 12: 10 Potassium dihydrogen phosphate and sodium hydroxide were dissolved in the distilled water for injection to préparé a phosphate buffer solution of pH 6.5. To theprepared buffer solution were completely dissolved mannitol, loxoprofen sodium andsodium pyrosulfite. The resulting solution was aseptically filtered and introduced into avial. The vial was freeze-dried to préparé a dry powdered product. Before the use, to 15 the vial was added 1 ml of the distilled water, which was packaged separately from the vial,and stirred to the complété dissolution to give an intramuscular injection (Table 12).

Table 12: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen sodium 6.81%(w/v) Sodium pyrosulfite 0.4%(w/v) Potassium dihydrogen phosphate (KH2PO4) 20.0%(w/v) Sodium hydroxide (NaOH) 0.06%(w/v) Mannitol 25.0%(w/v) d.w. for injection ad 1 ml 20 Example 13:

Loxoprofen and sodium bicarbonate were dissolved in the distilled water to 12 012175 préparé a solution of 1 ml. To this solution was added sodium pyrosulfite and the mixturewas stirred to the complété dissolution. The resulting solution was aseptically filtered andintroduced into a vial. The vial was freeze-dried to préparé a dry powdered product.Before the use, to the vial was added 1 ml of the distilled water, which was packaged 5 separately from the vial, and stirred to the complété dissolution to give an intramuscularinjection (Table 13).

Table 13: Composition of the 1 ml intramuscular injection bf loxoprofen

Ingrédients Contents Loxoprofen 6.25%(w/v) Sodium pyrosulfite 0.4%(w/v) Sodium bicarbonate (NaHCCh) 2.13%(w/v) d.w. for injection ad 1 ml 10 Example 14:

Loxoprofen and sodium hydroxide were dissolved in the distilled water to préparéa solution of 1 ml. To this solution was added sodium pyrosulfite and the mixture wasstirred to the complété dissolution. The resulting solution was aseptically filtered and 15 introduced into a vial. The vial was freeze-dried to préparé a dry powdered product.Before the use, to the vial was added 1 ml of the distilled water, which was packagedseparately from the vial. The mixture was stirred to the complété dissolution to give anintramuscular injection (Table 13). 20 Table 14: Composition of the 1 ml intramuscular injection of loxoprofen

Ingrédients Contents Loxoprofen 6.25%(w/v) Sodium pyrosulfite 0.4%(w/v) Sodium hydroxide (NaOH) 2.13%(w/v) d.w. for injection ad 1 ml

Experiment 1: Comparison of the drug plasma concentrations of loxoprofen betweentablet and intramuscular injection in rats 13

Oi 2175

The plasma concentration of loxoprofen in the intramuscular injection obtainedfrom Example 1 was evaluated and compared with the commercially available loxoprofentablet (Loxonin: control) in male SD rats of 6 weeks old free from spécifie pathogens. 5

In the control group, the formulation was orally administered to the rats with asingle dose of 10 mg/kg. In the experimental group, the formulation was intramuscularlyinjected to the rats with a single dose of 5 mg/kg. The blood gathered from the rats at 2, 5,10, 20, 30, 60, 120 and 180 minutes after the administration and pretreated. Then, the 10 drug plasma concentrations were analyzed. The following results are the plasmaconcentration of loxoprofen (pg/ml) vs. time (min).

Table 15: Comparison of the drug plasma concentrations of loxoprofen between tablet andintramuscular injection

Time (min) Drug plasma concentration (pg/ml) ofintramuscular injection Drug plasma concentration (pg/ml) oftablet 2 4.0 4.1 5 4.5 5.5 10 5.6 5.8 20 6.5 7.4 60 5.4 6.5 120 4.1 5.0 180 2.8 3.7

As shown in the above Table 15, because the intramuscular injection wasadministered at the amount of 50% of the tablet, the drug plasma concentration thereof wasshown to be slightly lower than that of the tablet. llowever, the curves of the drug plasmaconcentration change between the experimental and the control group were shown to be 20 similar (Fig. I)

Experiment 2: Stability lest of intramuscular injection

Samples were (aken from the intramuscular injection of loxoprofen obtained from 14 012175

Example 1 stored at the room température, 50 °C and 60 °C, for 1, 3 and 4 weeks,respectively. Subsequently, the drug content and variation in the pH were measured.The results are shown in the follovving Table 16. 5 Table 16a: Variation in the drug content of loxoprofen intramuscular injection

Storage température 0 week 1 week 3 weeks 4 weeks R.T. 100.1% 99.8% 99.7% 99.9% 50 °C 99.6% 98.6% 99.5% 99.8% 60 °C 99.6% 100.1% 99.3% 98.9%

Table 16b: Variation in the pH of loxoprofen'intramuscular injection

Storage température 0 week 1 week 3 weeks 4 weeks R.T. 6.46 6.43 6.43 6.42 50 °C 6.44 6.44 6.44 6.44 60 °C 6.44 6.44 6.44 6.45

As shown in the above Table 16, both of the drug content and the pH in the10 loxoprofen intramuscular injection were stably maintained without significant variation.

Experiment 3: Comparison of foot edemas of loxoprofen between tablet andintramuscular injection in rats 15 1) Experimental animal: Male SD rats over 6 weeks old free from spécifie pathogens 2) Test material and administration dosage: An edema inducing agent, 1%carageenan lambda type IV (Sigma Co.), was subcutaneously injected into the bottom of 20 the paw in the rat to induce the foot edema. Loxoprofen sodium was formulated into 5rng/2 ml and 10 mg/10 ml solutions for an intramuscular injection using phosphate bufferaccording to the method in Example 5. The obtained formulations were intramuscularlyinjected wilh the dose of 5 mg/2 ml/kg, and orally administered with the dose of 10mg/ml/kg. respectively. 25 15 012175 3) Test method and calculation formula: A standard point was marked in the jointrégion of the ankle in the left hind paw of the rat and then, the volume of the foot beforethe administration was measured by plethysmometer (Hugo Sacks & Coulbourn). Testformulations were intramuscularly injected or orally administered to the rats. After 20 5 minutes, 1% carageenan was subcutaneously injected to the left hind paw of the rats withthe dose of 0.1 ml per animal. After 2 hours and 30 minutes, the volume of the foot wasmeasured, and the edema rate and the inhibition rate of edema were calculated by thefollowing formulae: 10 Edema rate (%) = [(foot edema after injection of the edema inducing agent - foot edema before injection of the edema inducing agent) / foot edema before injection of theedema inducing agent]x 100

Inhibition rate of edema (%) = 100 - [average edema rate of the test material- 15 administered group / average edema rate of the non treatment groupx 100] 4) Evaluation: The signifïcance of the différence in an edema inhibition rate of theexperimental group and the control group was verified according to ANOVA. It wasconcluded that the edema was inhibited in the level of p<0.05. 20 5) Rate of edema and inhibition rate of edema: The results are shown in thefollowing Table 17.

Table 17: Comparison of foot edemas after the administration of loxoprofen between tablet25 and intramuscular injection

Experimental group Administration route Dose perbody weight # ofrats Edema rate(%) Inhibition rateof edema (%) Control Non treatment - 4 133.2±8.3 - Injection Intramuscular injection 5 mg/kg 4 36.0±18.8* 73.0 Tablet Oral administration 10 mg/kg 4 31.7+19.0* 76.2 16 012175 *: P<0.05 vs. control group (The edema rate was expressed in MeaniStandard Déviation)

As shown in the ahove Table 17, in case of the intramuscular injection of 5 loxoprofen sodium with the dose of 5 mg/kg, the inhibition rate of edema was 73.0%. Onthe other hand, in case of the oral administration of loxoprofen sodium with the dose of 10mg/kg, the inhibition rate of edema was 76.2%. Accordingly, the équivalent inhibitionrate could be obtained by an intramuscular injection of only 50% dose of the drugcompared with the oral administration. 10

Experiment 4: Comparison of analgésie effects of loxoprofen between tablet andintramuscular injection in rats 1) Experimental animal: Male ICR mice of 5 weeks old free from spécifie 15 pathogens 2) Test material and administration dosage: Loxoprofen sodium was formulatedinto solutions of 5 mg/2 ml and 10 mg/10 ml using the phosphate buffer according to themethod in Example 5. The solutions were intramuscularly injected with a dose of 5 mg/2 20 ml/kg, and orally administered with a dose of 10 mg/10 ml/kg, respectively. At 20minutes after the administration, a pain inducing agent, 0.7% acetic acid in D.W., wasintraperitoneally injected with a dose of 10 ml/kg to induce pain. Then, the nurnber ofwrithing was measured from 5 minutes after inducing pain for 10 minutes. 25 3) Comparison of analgésie effects: The results are shown in the following Table 18.

Table 18: Comparison of analgésie effect of loxoprofen between tablet and intramuscularinjection

Experimental Administration Dose per body # of # of Inhibition rate of 17 012175 group route weight mice writhing pain (%) Control Non treatment - 18 35.6± 10.8 - Injection Intramuscular injection 5 mg/kg 13 16.5±10.4* 53.7 Tablet Oral administration 10 mg/kg 15 17.7± * 8.0 64.0 *: P<0.05 vs. control group (The number of writhing was expressed in Mean±Standard Déviation)

As shown in the above Table 18; in case of the intramuscular injection of 5 loxoprofen sodium with the dose of 5 mg/kg, the inhibition rate of pain was 53.7%. Onthe other hand, in case of the oral administration of loxoprofen sodium with the dose of 10mg/kg, the inhibition rate of edema was 64.0%. Accordingly, the dominant inhibition rateof pain could be obtained by an intramuscular injection of only 50% dose of the drugcompared with an oral administration. 10

INDUSTRIAL APPLICABILITY

The intramuscular injection of the présent invention can be applied to patientswith difficulty in oral absorption, and can also obtain an équivalent or higher anti- 15 inflammatory analgésie effect even in smaller quantities, compared with the oralformulations. Further, it can exhibit the fast action without side effects due to thepercutaneous absorption.

Claims (12)

18 012175 WHAT IS CLAIMED IS:

1. A pharmaceutical composition for intiamuscular injection containingloxoprofen of the following formula:

or a pharmaceutically acceptable sait thereof, as an active ingrédient.

2. The composition according to Claim 1, wherein the pharmaceuticallyacceptable sait of loxoprofen is loxoprofen sodium. 10

3. The composition according to Claim 1 prepared by the process comprising thesteps of dissolving loxoprofen or the pharmaceutically acceptable sait thereof in the waterfor injection in combination with a stabilizing agent or a solubilizing aid followed bysterilizing the obtained solution. 15

4. The composition according to Claim 3 sterilized by the treatment at a hightempérature under vacuum or by aseptie filtration.

5. The composition according to Claim 3, wherein the water for injection is the20 distilled water for injection or a buffer solution for injection.

6. The composition according to Claim 5, wherein the buffer solution for injectionis a phosphate buffer or a sodium dihydrogen phosphate (NafhPCUj-citric acid buffersolution having the pH in the range of 3.5 to 7.5. 25

7. The composition according to Claim 6, wherein the phosphate is in the form ofsodium or potassium sait, or of anhydrate or hydrate, and the citric acid is in the form of 19 012175 anhydrous or hydrate.

8. The composition according to Claim 3, wherein the stabilizing agent is selectedfrom the group consisting of sodium pyrosulfite, sodium bisulfite (NaHSO3), sodium 5 metabisulfite (Na2S2Û3) and ethylene diamine tetraacetic acid.

9. The composition according to Claim 3, wherein the solubilizing aid is selectedfrom the group consisting of sodium hydroxide (NaOH), sodium bicarbonate (NaHCO3),sodium carbonate (Na2CO3), potassium hydroxide (KOH), hydrochloric acid (HCl) and 10 acetic acid (CH3COOH).

10. The composition according to Claim 3, which is a solution having the pH inthe range of 3.5 to 7.5.

11. The composition according to Claim 3, which is a powder prepared by sterilization followed by freeze-drying.

12. The composition according to Claim 1, which contains 2 to 20% of the activeingrédient. 20