TWI301413B - Pharmaceutical composition for intramuscular injection containing loxoprofen - Google Patents

Description

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1 1301413 A7 B7

V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) [Technical Field] The present invention relates to a novel pharmaceutical formulation containing epifenprofen, and in particular to an ibuprofen containing or pharmaceutically acceptable The salt is a prescription for an intramuscular injection of an active ingredient which has an excellent anti-inflammatory and analgesic effect. [Background of the Invention] Epoxyprofen (chemical name: 2-[4-(2-oxocyclopentyl)phenyl)propionic acid) is a propionic acid type non-steroidal anti-inflammatory drug (NSAID) having the following formula:

The above drugs are usually used in the form of a sodium salt, i.e., epoxyprofen. Sevoprofen sodium is quite effective in the treatment of rheumatoid arthritis, malformation arthritis, lumbosacral strain, mucositis, and shoulder-arm-neck syndrome. The drug is also known to be effective in reducing pain after surgery or after trauma, or reducing pain after tooth extraction. The drug is now widely used in the form of oral lozenges. Compared with any other propionic acid non-steroidal anti-inflammatory drugs, these drugs cause mild gastrointestinal disorders, but still cause side effects such as gastrointestinal disorders and peptic ulcers after long-term administration. Therefore, several studies have recently been conducted to develop a transdermal prescription such as a sustained release adhesive preparation [PCT/JP1 997/02936, Korean Patent Application No. 98-41351 (October 1998), U.S. Patent No. 4,740, No. 3 74 (April 26, 1998), PCT/WO95/16440 (1995 This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public) 91988 (please read the notes on the back and fill in the form) page)

Ministry of Economic Affairs, Intellectual Property and Production Bureau, I-Working Consumer Cooperatives Printed 1301413 Λ7 B7 V. Invention Description (1 2 ) June 22曰) Korean Patent Application No. 96-38430 (September 5, 1996). For patients who have difficulty in oral absorption or who require long-term medication, such transdermal formulations have the advantage of reducing the side effects or uneasiness caused by oral prescription. However, the above prescription also includes a polymer as in the previously developed adhesive preparation, and thus may cause skin rash due to long-term adhesion or skin allergies such as itching. These prescriptions can also cause other side effects, such as discomfort when the patient is exercising. In addition, although the rate of absorption of the drug through the skin can be controlled, the difference in the rate or amount of percutaneous absorption depends on the site of the pain and the physical structure of the individual, and it usually takes a long time to obtain the desired therapeutic effect. . Therefore, transdermal prescriptions cannot be used in emergency cases where severe pain occurs. Sodium cloprofen is different from the commonly known propionic acid type non-steroidal anti-inflammatory drugs such as ketoprofen and ibuprofen. Epoxyprofen sodium inhibits prostaglandin biosynthesis, inflammatory initiators and pain and thus has excellent anti-inflammatory and analgesic effects. That is, the drug is a prodrug, and after oral administration, it is converted into a trans-OH metabolite by the metabolism of ketoreductase in vivo, that is, 2-[p-(trans-2-hydroxycyclopentyl). Phenyl] propionic acid. The above metabolites have an inhibitory effect on the addition of a cyclooxygenase and a prostaglandin synthetase, and thus exhibit excellent anti-inflammatory and analgesic effects. [Matsuda et al., Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp 263-266 (1983)]. Ketoreductase is mainly distributed in the liver or kidney shout [Tanaka et al., Japanese Journal of Inflammation, Vol. 3, No. 2, Spring, pp 151-155 (1983)]. The enzyme metabolizes sodium bromide to an anti-OH metabolite and exhibits a strong anti-inflammatory and analgesic effect of this drug ______________^--------^---------^ (please Read the precautions on the back page and fill in this page. 1 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 2 91988 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints 1301413 ____B7 ___ V. Description of invention ( 3) Fruit. Such enzymes are also known to be present on the surface of the skin and exhibit the same efficacy [US Patent No. 4, 740, 3 74 (April 26, 1998)]. For the above reasons, the oral formulation is now widely commercialized (e.g., a key containing an active ingredient comprising epihalofen or its pharmaceutically acceptable salt) (Loxonin 〇r Loxfen). At the same time, external prescriptions such as adhesive preparations and patches have recently been studied. In contrast, intramuscular injections of this drug have not been reported. As described above, in cases with severe oral absorption difficulties and cases of gastrointestinal disorders, it is not suitable for oral administration of xyloxyprofen which has been developed to date. Patches have been extensively studied but have not yet been fully developed. At the same time, the transdermal formulation of epoxan must contain a number of adjuvants such as penetration enhancers and thus cause side effects such as skin rash. Moreover, since the prescription is adhered to a specific part of the living body for a long time, the action is restricted and it is uncomfortable. In particular, because of the possibility of inflammation or pain in the joint area, the patch for percutaneous absorption may cause many problems such as the patch being easily detached from the joint during the process of continuously providing the desired effect. . Therefore, there is a need to develop a novel ibuprofen prescription which can also be applied to patients who have difficulty in oral absorption and which can solve the shortcomings caused by all skin transfer medications. [Explanation of the Invention] The present inventors conducted extensive research to develop a novel epoxyprofen formulation. As a result, the present inventors have found that epoxyprofen is capable of converting to a ruthenium metabolite by a ketoreductase to exhibit an excellent anti-inflammatory analgesic effect not only on the skin but also on the muscle. Based on the above, the inventors determined that the intramuscular injection of epoprofen is also suitable for patients with difficulty in oral absorption. Applicable to China National Standard (CNS) A4 specification (2) 木 297 honggong) with wooden paper scales - Service 3 91988 f Please read the notes on the back and fill in this page again >

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1301413 A7 --- B7 _ ___ V. INSTRUCTIONS (4) Compared to prescriptions, even a smaller amount of such intramuscular injections can achieve the same or greater anti-inflammatory analgesic effect and a rapid effect without the side effects of oral prescription. Therefore, the present invention can be completed as follows. The present invention relates to a pharmaceutical composition comprising an intramuscular injection of an epoxyprofen or a pharmaceutically acceptable salt thereof as an active ingredient: m In a preferred embodiment, the epoxyprofen is pharmaceutically acceptable The salt accepted was epoxy riffin. The invention will be explained in more detail below. As described above, the oxyprofen or a pharmaceutically acceptable salt thereof is absorbed into the gastrointestinal tract in an inactive form after oral administration. It is then converted to an anti-OH metabolite by the action of a ketoreductase in the liver or kidney to provide an excellent anti-inflammatory analgesic effect. It can also be converted to anti-collar metabolites by the ketoreductase on the skin and shows the same effect. However, the inventors of the present invention can also convert it into anti--0H metabolites by the action of reductase, and exhibit the same effect, even using a dose of 1/2 to 2/3. Achieve the same or greater effect. In addition, immediate treatment is usually required first to alleviate the pain of the patient to achieve an anti-inflammatory analgesic effect. The intramuscular injection of the present invention also meets the above needs. The present invention provides a prescription for an intramuscular injection of ibuprofen, which is a side effect of an oral prescription of a key, for example, a sputum paper on a patient who has oral sputum (four) 〖 difficult or long-term medication after gastrointestinal disorders The scale applies to the Chinese National Standard (CNS) A4 specification (2〗 297 297 public)---- ^ 91988 -------------^--------^- --------^ (Please read the notes on the back and fill out this page) Ministry of Economic Affairs, Wisdom Finance' Production Bureau _ Workers' f Co., Ltd. Printed 4 1301413 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System 5, invention description (5) side can also solve the side effects of external prescriptions, such as the use of non-drip and skin allergies. In particular, the prescription is easy to use on patients who need rapid efficacy. The prescription of the present invention can be suitably opened. In order to maintain its storage stability, an injectable acidic aqueous solution or a buffer such as a phosphate buffer may be used to adjust its pH so that the injection has excellent physical and chemical stability. More specifically, the present invention may be prepared by dissolving the epoxyprofen or a pharmaceutically acceptable salt thereof in water for injection in combination with a stabilizer or a co-solvent, and then sterilizing the resulting solution via, for example, vacuum high temperature or aseptic drying. And prepared. The water for injection may be distilled water or a buffer (e.g., a phosphate buffer having a pH in the range of 3 5 to 7.5 or sodium dihydrogen phosphate (NaH 2 p 〇 4) - citric acid buffer). The phosphate may be in the form of an anhydrous or hydrated sodium or potassium salt, and the citric acid may be in the form of an anhydrous or hydrated form. The stabilizer used in the present invention may be sodium pyrosulfite, sodium sulfite (NaHS03), sodium metabisulfite (Na2S205) or ethylenediaminetetraacetic acid. The cosolvent may be a base such as sodium hydroxide (NaOH), sodium hydrogencarbonate (NaHC03), sodium carbonate (Na^O3), and potassium hydroxide (KOH), or may be an acid such as hydrogen acid (HC1) or acetic acid (CH3COOH). . The formulation of the present invention is preferably a solution having a pH in the range of 3.5 to 7.5 or a powder obtained by sterilization and freeze-drying. The concentration of the active ingredient is preferably in the range of 2 to 20%. [Simple description of the diagram] Figure 1 shows the epoxy in the lozenge and intramuscular injections (please read this on the back of the page). - Line - This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 91988 1301413

V. DESCRIPTION OF THE INVENTION (Comparative Distribution of Concentrations of the Ministry of Economic Affairs W-Production Bureau I-CPC Co., Ltd. 6) [Best Embodiments of the Invention] Although the following examples make the present invention more understandable, any Those skilled in the art should understand that the specific materials and results described herein are for illustrative purposes only and are not intended to limit the scope of the present invention. The appended claims (4) will more fully define the scope of protection of the present invention. Epoxyprofen and sodium metabisulfite were dissolved in the steamed water for injection. The solution was sterilized at a high temperature under vacuum and injected into the milliliter ampule and (iv) intramuscular injection (Table 1). Composition of 1 ml of intramuscular injection Example 2 Epoxyprofen sodium and sodium metabisulfite were dissolved in distilled water for injection, and dilute hydrogen acid was added thereto after the sonication to adjust {11 to 6 thereof. The obtained solution was sterilized at a high temperature of j or after sterile filtration, and then an intramuscular injection was obtained by injecting two or eight pens of ampoules (Table 2). Table paper scale applies to Chinese national standard T^NS) A4 specification (210 X 297 public 91988 ϋ nn ·ϋ n 1^1 nn ·ϋ I · nnnmn II a tfj_ I ί ·ϋ ϋ I nn I (please read the back first) Note: Please fill out this page again) 1301413 A7 B7 V. INSTRUCTIONS (7) TABLE 2: Composition of 1 ml intramuscular injection containing epoxyprofen _ Component content Epoxyprofen sodium 6.81% (w/v) _ Sodium metabisulfite 0.1% (w/v) Distilled water for injection ad 1 ml _ Dilute hydrochloric acid qs (pH 6) Child's application Example 3 Dissolve epoxyprofen and sodium metabisulfite in distilled water for injection. Dilute hydrochloric acid was added thereto to adjust the pH to 5. The obtained solution was sterilized at a vacuum high temperature or after sterile filtration, and then injected into 丨ml·% T to obtain an intramuscular injection (Table 3). —^ __ Epoxyprofen sodium 6.81% (w/v) __ sodium pyrosulfite. 1% (w/v) with distilled water ad 1 ml __ dilute hydrogen acid qs (pH 5) ------ ( Please read the precautions on the back and fill out this page.) Click---------Line 丨· I_|This Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Print 7 will be epoxyprofen sodium and Sodium metabisulfite is dissolved in distilled water for injection, and then dilute hydrogen acid is added thereto to adjust its pH to 4. The obtained solution is sterilized under vacuum temperature or aseptically filtered, and then injected into 1 ml of ampoule to obtain muscle. Intra-injection (Table 4). Light scale meaning (210 X 297 ) 91988 l3〇l4i3

--------------^--------^---------Line (Please read the notes on the back and fill out this page) 8 91988

1301413 Intramuscular injection was obtained in ampoules (Table 6). Table 6 · I% Oxygen>> Composition of 13⁄4 liter intramuscular injection of each fen. Sodium bisulfite sodium dihydrogenate·dodecyl sulfate (NaH2P〇4>12H2〇) citric acid 0.2% (w/v) 1.45% (w/v) 0.53% (w/v) Example 7 A sulphate buffer solution of pH 6.8 was prepared by dissolving dihydrogen phthalate and dissolving anhydrous diclofenac in water for injection. Epoxyprofen and pyrosulfuric acid were dissolved in the prepared buffer solution. The resulting solution was injected into a 1 ml female bottle at a vacuum high temperature to obtain an intramuscular injection (Table 7). Composition of Injectables Ingredient Content (Please read the notes on the back and fill out this page) 0 -------^---------Line! Ad 1 ml 9 Distilled water for injection Example 岂 Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare a phosphate buffer solution. Dissolve sodium xyloxifen sodium and sodium metabisulfite in a high temperature solution. 91988 nnnn I 1 n · ΐ3〇Γ413 5. Inventive Note (10) After A7 B7, inject it into a 1 ml ampoule to obtain Q Q.. Intra-injection (Table 8) Table 8 · Composition of 1 ml of muscle containing ibuprofen - Composition of the agent - Epoxyprofen sodium - Potassium hydrogen sulfite (kh2po4) Sodium hydroxide (NaOH) ^--- Steaming water content for injection is 6.81% (w/v) 0.2% (w/v) 〇.68% (w/v) 0.12% (w/v) ad 1 ml Reconstitution 9 Phosphoric acid II Hydrogen potassium and sodium hydroxide are dissolved in distilled water for injection to prepare a phosphate buffer solution of 1 ΡΗ 7.4. Sodium epoxyprofen and sodium metabisulfite were placed in the prepared buffer solution. The resulting solution was sterilized at a vacuum high temperature and then injected into 1 ml of ampoule to obtain an intramuscular injection (Table 9). --------------^ i — (Please read the phonetic transcription on the back? Please fill out this page again) · The Ministry of Economic Affairs Intellectual Property Office staff, consumer cooperatives printed 1 ml of epoxyprofen Composition of intramuscular injection

Content 6.81% (w/v) 0.4% (w/v) 0.68% (w/v) 16% (w/v) ad 1 ml i application of sodium oxaprofen, sodium metabisulfite and mannitol in the injection Steam the remaining water. After the solution was sterilized at a high temperature in a vacuum, it was further injected into 1 mA of an ampoule to obtain an intramuscular injection (Table 1). Line · This paper size standard (CNS) A4 specification (2) 〇x 297 public) 10 91988 A7 B7 1301413 V. Description of invention (u) ^10· Composition of 1 ml intramuscular injection containing epoxyprofen Ingredients Epoxyprofen sodium----___ Sodium metabisulfite mannitol injection distilled water content 6.81% (w/v) 〇.4% (w/v) 5.0% (w/v) ad 1 ml ΜΜΛΙ Oxyprofen sodium and mannitol are dissolved in a solution of distilled water for injection, sterile filtered, and introduced into a vial. The vial was lyophilized to prepare a dry powder product. Before use, 1 ml of distilled water separately packaged from the vial was added to the vial, and the mixture was stirred until completely dissolved to obtain an injectable injection (Table 11).

Will I (please read the phonetic on the back? Please fill out this page again) . --~---- ----- Ingredient content __^Epoxyprofen sodium 6.81% (w/v) ___ Sodium metabisulfite 0.4 %(w/v) ^_ mannitol 20.0% (w/v) _ distilled water for injection Ad 1 ml Child Shame> Example 12 Potassium dihydrogen phosphate and sodium hydroxide were dissolved in distilled water for injection to prepare PH 6.5 Phosphate buffer solution. Mannitol, sodium oxyprofen and sodium metabisulfite were completely dissolved in the prepared buffer solution. The resulting solution was sterile filtered and introduced into a vial. The vial is freeze-dried to prepare dry paper. The paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm). 91988 -I line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 11 Ι30Γ413

V. Description of the invention (U powder product. Use

, , , ~...w, 1 ml of the distilled package separately from the vial was added to the small crucible, and stirred until completely dissolved to obtain an intramuscular injection (Table 12). Composition of p-~1 i liter intramuscular injection ___ 戍分_ Epoxyprofen ^__ __Content: zz 6.81 %(w/v) ~ 0^4%(w/v) ~ --$ Potassium dihydrogen phosphate (κη, ρο4) 20.0% (w/v) _~-sodium hydroxide (NaOH) 0.06% (w/v), __ mannitol 25.0% (w/v) ^_ distilled water for injection ad 1 ml --------------装·1· f Please read the notes on the back and fill out this page.}L Example 1 3 Dissolve epoxyprofen and sodium bicarbonate Distilled water was used to prepare a 1 ml solution. Sodium metabisulfite was added to the solution and the mixture was stirred until completely dissolved. The resulting solution was sterile filtered and introduced into a vial. The vial was freeze dried to prepare a dry powder product. Before use, 1 ml of distilled water separately packaged from the vial was added to the vial and stirred until completely dissolved to obtain an intramuscular injection (Table 13). Department of Intellectual Property of the Ministry of Finance, Ministry of Commerce, Consumer Cooperatives, printed content of 6.25% (w/v) of xeroprofen sodium. 4% (w/v) sodium bicarbonate (NaHC03) 2.1 3% (w/v) injection Distilled water ad 1 ml This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 12 91988 1301413 V. Description of the invention (D Example 1 4 Dissolving epoxyprofen and sodium hydroxide in distilled water To prepare 1 ml of solution, sodium metabisulfite was added to the solution and the mixture was stirred until completely dissolved. The resulting solution was sterile filtered and introduced into a vial. The vial was cold bundle dried to prepare a dry powder product. The vial was separately packaged with 1 ml of distilled water and added to the vial, and the mixture was stirred until completely dissolved to obtain an intramuscular injection (Table 14). Test Example 1: Comparison of the rats were administered with a sterilizing agent and an intramuscular injection, respectively. The epox concentration was evaluated in plasma concentrations of the ibuprofen in the intramuscular injection obtained in Example 1 and compared with a commercially available epoxyprofen tablet (Loxonin: control), and both were used. Without specificity In the control group, the rats were orally administered with a dose of 1 mg/kg. In the test group, 5 mg/kg brothers < The dose was administered intramuscularly to the rats. The blood of the rats was collected at 2, 5, 10, 20, m ^ 〇, 60, 120, and 180 after administration, and pre-treated, each leaf, and then analyzed for epoxy. The concentration of rosin in plasma. The following is epoxy --------in the blood paddle: 痄 痄 This paper scale applies to China National Standard (CNS) A4 specification (21Qx 297 public) ~- — 丁< /辰反91988 back

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I I λ I Ministry of Economics, Ministry of Finance, Finance and Industry Bureau, Staff and Services Co-operatives, Printing 13 1301413

V. Description of the invention (η) (μg/ml) versus time (minutes). Concentration of Rofin in plasma Time (minutes) ^Αί3^) (μg/ml)

--- (Please read the note on the back and then fill out this page) As shown in Table 15 above, since only 50% of the dose of intramuscular injection is administered, its concentration in plasma shows a slighter than that of the tablet. low. However, the concentration change curves in the plasma of the test group and the control group were similar (Fig. 1). Test Example 2: Stability test of intramuscular injection The product obtained from the ibuprofen intramuscular injection obtained in Example 1 was stored at room temperature, 50 ° C and 60 ° C for 1, 3 and 4 weeks, respectively. Next, the drug content and pH change were measured. The results are shown in Table 16 below. Storage temperature 0 weeks 1 week 3 weeks 4 weeks Room temperature 100.1% 99.8% 99.7% 50°C 99.6% 98.6% 99.5% 99.8% 6(TC 99.6% 100.1% 99.3% 98.9% This paper scale applies to China National Standard (CNS) A4 specifications (210 x 297 public) 91988 Order: - Line 'Improvement of the Ministry of Economic Affairs This production bureau consumer cooperatives printed 14 1301413 A7 ________ B7 V. Description of invention (15) Table 16b · pH change of intramyocardial injection of epox Storage temperature 0 weeks 1 week 3 weeks 4 weeks Room temperature 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 (Please read the notes on the back and fill out this page) As shown in Table 16 above, The drug content and pH in the intramyocardial injection of ibuprofen remained stable without significant changes. Test Example 3: Comparison of the edema of the foot after administration of the epoxyprofen tablet and intramuscular injection to the rats 1) Test Animal: Six-week old male sr) rats without specific pathogens. - 丨 line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 2) Test substance and dosage: The edema inducer carageenan type IV (Sigma) was injected subcutaneously into the bottom of the rat's paw To induce foot edema. The sodium xefrolide was formulated into a 5 mg/2 ml and 10 mg/10 ml solution for intramuscular injection using a phosphate buffer solution according to the method of Example 5. The obtained prescriptions were intramuscularly injected at a dose of 5 mg / 2 ml / kg, respectively, and orally administered at a dose of 10 mg / ml / kg. 3) Test method and calculation formula: Mark the standard point on the joint portion of the left hind paw of the rat, and then measure the volume of the foot before administration by using a plethysmograph (Hug〇 Sacks & Coulbourn). The test prescription is administered to the rat intramuscularly or orally. After 20 minutes, a dose of 1% karanica per animal was injected subcutaneously into the left hind paw of the rat. After 2 hours and 30 minutes, the foot volume was measured and the edema rate and edema were calculated according to the following formula. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 15 91988

Γ30Γ413 V. Description of invention (16) Rate of edema: edema rate (〇/〇 = [(foot edema after injection of edema inducer - edema of foot before injection of edema inducer) / foot edema before injection of edema inducer h (10) edema inhibition Rate (%) = 100 - [Medication group _ average edema rate of test substance / average edema rate of non-untreated group X 100] 4) Evaluation: (4) ANOVA confirmed the importance of the difference in edema inhibition rate between the test group and the control group. As a result, the degree of edema was inhibited at p < 5) Edema rate and edema inhibition rate: The results are shown in the following list η. Table 17: Comparison of foot edema after administration of loxoprofen lozenges and intramuscular injections Test group - Lozenge route of administration Untreated intramuscular injection Oral dose per body weight. — 5 mg/kg 10 mg/ Kg rat number edema rate (%) 133.2 ± 8.3 * --------- 36 · 0 ± 18.8 * - one | _ _ 31.7 ± 19 · 0 * edema inhibition rate (%) relative to the control group ρ <;〇〇5 (The edema rate is expressed as mean ± standard deviation > As shown in Table 17 above, intramuscular injection of xylose sodium at a dose of 5 mg/kg has an edema inhibition rate of 73%. On the other hand, The oral edema is administered at a dose of 1 mg/kg, and the edema inhibition rate is 76.2%. Therefore, it is only necessary to administer 5 〇% of the drug dose of the intramuscular injection compared with the oral administration. The same inhibition rate was achieved.Test Example 4 ·Comparing the analgesic effect of xyloxyprofen after administration of tablets and intramuscular injections to rats. The paper size is applicable to China National Standard (CNS) A4 specification (2) 0 X 297 Love) 16 91988 1301413 V. Description of the invention (17 squirrels test animals: without specific pathogens Zhou Taixiong of ICR 2 small) amount of test substance administered μ: acetate buffer so that the method according to Example 5 of the formulated epoxy Luofen Na 5 mg / ml and 2 mg m ι〇 ml of solution. The resulting solution was administered intramuscularly at a dose of 5 mg / 2 ml / kg, respectively, and orally at a dose of 10 mg / 1 ml / kg. After 20 minutes of pitching, a pain inducing agent (0.7% acetic acid, combined with distilled water) was administered subcutaneously at a dose of ίο ml/kg to induce pain. The number of bridges was then measured after 5 minutes after induction of pain for 1 () minutes. 3) Comparison of analgesic effects: The results are shown in the following list μ. The analgesic effect test group of Luofen's analgesic effect test group is not treated - Ϊ The number of mice per body weight is 35.6 ± 10·8 —----- ! 5 ± 10.4: 17.7 士 8.0: Pain suppression rate (% 5 mg/kg 10 mg/kg vs. control p<〇.〇5 (peristalt number is expressed as mean ± standard deviation) Strictly as shown in Table 18 above, intramuscular injection of oxygen at a dose of 5 mg/kg In the case of sodium lapropion, the rate of pain inhibition is 53 7%. On the other hand, the inhibition rate was 64% in the case of oral administration of xyloxyphene sodium at a dose of W mg/kg. Therefore, compared with oral administration, only 50 〇 / ❻ of its drug dose of intramuscular injection can achieve significant pain suppression rate 0 [industrial application] scale applicable to China National Standard (CNS) A4 specification (210x 297 public) Love) 17 91988 (Please read the notes on the back and fill out this page again)

Ι30Γ413

V. INSTRUCTION DESCRIPTION OF THE INVENTION (I8) The intramuscular injection of the present invention can also be applied to patients who have difficulty in oral absorption, and can achieve the same or larger even with a smaller amount of the intramuscular injection of the present invention than the oral prescription. Anti-inflammatory and analgesic effects and the effects of rapid and no side effects, skin absorption caused by side effects. ----------------------Book---------^ (Please read the notes on the back and then fill out this page) Ministry of Economics Intellectual Property Bureau member Jiang Consumer Cooperative printed this paper scale applicable to China National Standard (CNS) A4 specification (210x297 mm) " ' ^ 18 91988

Claims (1)

1301413 A8 B8 C8 D8 Patent Application Range t 3 % oxygenated or its pharmaceutically acceptable salt is a pharmaceutical composition of one of the active components of the active ingredient, wherein the formula of the epoxyprofen is as follows: L. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of the epoxyprofen is an epoxyprofen steel. 3. A pharmaceutical composition according to the scope of the patent application, which is prepared by the following preparation method, which comprises dissolving epoxyprofen or a pharmaceutically acceptable salt thereof in water for injection and The step of combining a stabilizer or a builder and subsequently sterilizing the resulting solution. 4. The pharmaceutical composition of claim 3, which is sterilized by vacuum or sterile filtration treatment. •t·— 请Please read the notes on the back and fill out this page} 5. The pharmaceutical composition of claim 3, wherein the water for injection is distilled water for injection or a buffer solution for injection. 6. The pharmaceutical composition of claim 5, wherein the buffer/volume for injection is a sulphate buffer or sodium dihydrogenate (NaH2P〇) having a pH in the range of 3 · 5 to 7.5. 4) _ citric acid buffer solution. 7. A pharmaceutical composition according to claim 6 wherein the phosphate is in the form of an anhydrous or hydrated sodium or potassium salt and the citric acid is in the form of an anhydrous or hydrated form. 8. The pharmaceutical composition of claim 3, wherein the stabilizer is selected from the group consisting of sodium metabisulfite, sodium hydrogen sulfite (NaIiS〇3), and sodium metabisulfite. The paper scale applies to the Chinese National Standard (CNS) A4 specification (21) 〇χ 297 mm) 91988 Amendment 1301413 B8 C8 D8 (August 15, 1996) 6. The patent application scope (Na2S2〇5) and the group of ethylenediaminetetraacetic acid. 9. The pharmaceutical composition of claim 3 of the patent scope, wherein the cosolvent is selected from the group consisting of sodium oxychloride (Na〇H), sodium hydrogencarbonate (NaHC03), sodium carbonate (Na2C〇3), and potassium cesium hydroxide ( Groups of KOH), chloric acid (HC1), and acetic acid (CH3CO〇H). 10. The pharmaceutical composition of claim 3, which is a solution having a pH in the range of from 3.5 to 7.5. 11. A pharmaceutical composition as claimed in claim 3, which is a powder obtained by sterilization followed by cold bundle drying. 12. The pharmaceutical composition of claim 1 which contains 2 to 2% by weight of the active ingredient. (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).