KR20080039954A - Injection for intravenous drip - Google Patents

Abstract

A high-content injection for intravenous drip which is prepared by adding an acidic pH regulator to an aqueous suspension containing 4-(N-(4-morpholin-4-yl)butyl)carbamoylmethyl)-5,6,7, 8-tetrahydrophthalazin-1(2H)-one (Compound A) and dissolving it therein followed by, if necessary, adjusting the pH value by using a basic pH regulator. Because of being stable to light and heat, this injection is a highly useful preparation. It is preferable to adjust the pH value of the injection to 3 to 7. The concentration of the compound A is preferably from 50 mg/mL to 300 mg/mL and the viscosity of the injection is preferably from 1 mPa.s to 4 mPa.s.

Description

Injectable drops {INJECTION FOR INTRAVENOUS DRIP}

The present invention provides 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one and a pH adjuster. It relates to a high-dose injectable drug which is stable against heat and / or light.

4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one (hereinafter abbreviated as Compound A V)) may be a compound that is expected to be used as a prophylactic and / or therapeutic agent for cerebral infarction due to its poly-ADP-ribose) polymerase (hereinafter abbreviated as PARP) inhibitory activity.

Most of the patients who have fallen due to cerebral infarction are almost unconscious, and therefore, it is required to inject drugs quickly after infarction, and therefore, the therapeutic agent is required to be an injection.

In addition, in order to continuously administer a therapeutic agent to a patient in a clinical field, an injection for infusion is adjusted, but there is a need for an injection that contains a high concentration of the drug at a high convenience.

On the other hand, the solubility of the compound A in water was very low, and it was difficult to adjust the high content aqueous solution for making a drop injection.

Compound A has PARP inhibitory activity, so ischemic diseases (cerebral infarction, myocardial infarction, reperfusion injury, postoperative disorders, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebral sclerosis, arthritis, lung disorders, etc.), neurodegenerative diseases (cone) Exogenous system disorders, Parkinson's disease, Alzheimer's disease, muscular atrophy, lumbar spinal stenosis, etc., glaucoma, diabetes mellitus, diabetic complications, shock, head trauma, spinal cord injury, kidney failure, hyperalgesia It is disclosed that it is useful as a prophylactic and / or therapeutic agent for antiviral, blood flow disorders, etc., and also as an antiretroviral agent (HIV, etc.), an anticancer sensitizer or an immunosuppressive agent (International Publication No. WO 03/070707). Although there is description of the specific manufacturing method regarding a tablet or a lyophilizer, neither description nor suggestion regarding the high-dose injectable injection containing the said compound is mentioned.

Disclosure of the Invention

Problems to be Solved by the Invention

An object of the present invention is to improve the solubility of Compound A, a poorly water-soluble compound, and to provide a high-dose injectable drug which is stable against heat and light in long-term storage and easy to use in a medical field.

Means to solve the problem

The present inventors have diligently studied to solve the above problems, and found that the solubility of Compound A depends on the pH value, so that injections containing Compound A and an acidic pH adjuster and, if necessary, a basic pH adjuster are heated and The present invention has been found to be a drop injectable, easy to use in a medical field, which is stable to light, contains a high content of Compound A, and has a moderate viscosity.

That is, the present invention relates to the following high-dose injectable injections.

1.4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one and acidic pH regulator High dose injectables, containing a basic pH adjusting agent if necessary.

2. The high-dose injectable preparation according to item 1, wherein the injectable agent has a pH value of 3 to 7.

3. Parac. 1, wherein 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H)- A high content injectable injection, wherein the concentration of the ions is 50 mg / mL to 300 mg / mL.

4. The high-dose injectable agent according to item 1, wherein the acidic pH adjusting agent is at least one kind selected from organic acids and inorganic acids, and the basic pH adjusting agent is at least one kind selected from organic bases and inorganic bases.

5. The method according to item 4, wherein the acidic pH adjusting agent is at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric anhydride and glycine, and the basic pH adjusting agent is at least one selected from sodium hydroxide and sodium citrate. Injectable for content drop.

6. The injectable high-dose injection according to item 1, wherein the viscosity of the injection is 1 mPa · s to 4 mPa · s.

7. The high-dose injectable preparation according to item 1, which is filled in a container for injection.

8. The high-dose injectable preparation according to claim 7, which is formed by shading packaging.

9. The compound of claim 1, which is 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H)- A high content injectable injection, characterized in that the pH value is adjusted to 3 to 7 by adding a basic pH adjusting agent if necessary after dissolving by adding an acidic pH adjusting agent to the aqueous suspension of hot.

10. The method of paragraph 1, wherein the pH value of the injection is 4 and 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydro A high content injectable injection, characterized in that the concentration of thalazine-1 (2H) -one is 100 mg / mL to 300 mg / mL and the viscosity is 1 mPa · s to 4 mPa · s.

11. The method of paragraph 1, wherein the pH value of the injection is 6 and 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydro A high content injectable injection, characterized in that the concentration of thalazine-1 (2H) -one is 100 mg / mL to 300 mg / mL and the viscosity is 1 mPa · s to 4 mPa · s.

12. Hydrochloric acid in an aqueous suspension of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one And the pH value was adjusted to 4 and filled into an injection container, the viscosity being 1 mPa · s to 4 mPa · s, 4- (N- (4- (morpholin-4-yl) butyl) carba Moylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one has a concentration of 100 mg / mL to 300 mg / mL.

13. Hydrochloric acid in an aqueous suspension of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one The viscosity is 1 mPa * s-4 mPa * s formed by adding sodium hydroxide, adding sodium hydroxide, adjusting pH value to 6, and filling into a container for injection, and is 4- (N- (4- (morpholin- 4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one has a concentration of 100 mg / mL to 300 mg / mL Injections.

Implement the invention  Best form for

4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one (compound used in the present invention) A), i.e.

Compounds represented by are described in Example 28 (42) of WO 03/070707, which compounds can be prepared by known methods, for example, those described in WO 03/070707. Can be.

When water is added to a large amount of Compound A, it becomes cloudy. The pH value of the supernatant liquid of the aqueous suspension of Compound A is 9.4. The solubility of water in Compound A is remarkably increased by setting this pH value to about 7 or less, and especially by setting it to about 5 or less. Dissolves quickly in water. Therefore, the pH value of the dropwise injection of the present invention is preferably 7 or less.

The solubility of Compound A at various pH values was measured. For example, the following results were obtained.

<Measurement method>

Hydrochloric acid was added to the aqueous suspension of Compound A (about 250 mg / mL to 300 mg / mL) to pH 4, and after dissolving Compound A, an aqueous sodium hydroxide solution (0.05 or 1 mol / L) was added, and the respective pH values were adjusted. Adjusted. After preserving the prepared aqueous solution at 5 ° C. for 24 hours, the supernatant of the prepared solution was collected, filtered (pore size: 0.45 μm), and Compound A in the aqueous solution at each pH was quantified by high performance liquid chromatography. The results are shown in Table 1.

<Result>

pH 4 5 6 7 8 9 Quantification (mg / mL) 291.5 ^* 283.3 ^* 277.0 ^* 236.0 37.8 25.5

^* The aqueous solution of pH 4, 5, and 6 is considered to have a solubility of not less than the above-described quantitative value because no precipitation was observed after storage at 5 ° C. for 24 hours.

From the above results, when the pH value is 8 or more, the solubility of the compound A in water is low, but the solubility is remarkably improved by adjusting the pH value to 7 or less, and it is possible to prepare an aqueous solution containing a high concentration of the compound A. have.

pH value can be measured using a well-known method, for example, the pH measurement method described in the Japanese pharmacy room.

Although the addition amount of the pH adjuster in the injectable injectable preparation of this invention is not specifically limited, It is preferable to add the amount which the pH value of the injectable injectable agent will be in the range of about 3 to about 7.

Injectable injectable preparations of the present invention can be prepared by suspending Compound A in water as a solvent and adjusting the pH by adding a pH adjuster. Operation of addition or mixing is carried out in accordance with conventional pharmaceutical techniques.

When adjusting the pH of the injectable injection solution of the present invention, an acidic pH adjuster is added to the aqueous suspension of Compound A to dissolve Compound A, and if necessary, a basic pH adjuster is added to adjust the pH value of the aqueous solution to about 3 to about 7. It is desirable to. For example, an acidic pH adjuster is added to the aqueous suspension of Compound A to adjust the pH value to about 3 to about 7, or an acidic pH adjuster is added to the aqueous suspension of Compound A to quickly dissolve Compound A, followed by a basic pH adjuster. It is preferred to adjust the pH value to about 5 to about 7 by adding.

Compound A is not rapidly dissolved in water in the vicinity of neutrality (for example, pH 6 or more), and is rapidly dissolved in water by setting the pH value to about 5 or less, more preferably as the injectable injection agent of the present invention. A high content injection prepared by adjusting the pH value to about 4 with an acidic pH adjuster or a suspension of Compound A was dissolved in Compound A by adjusting the pH value to about 2 to about 5 with an acidic pH adjuster. And high content injections prepared by adjusting the pH value to about 6 with a basic pH adjuster. Considering administration to humans, the preferred pH range of the injectable solution is generally near neutral, which is advantageous in the latter method.

As the pH adjusting agent, any pH adjusting agent generally used in the preparation of injectable preparations can be used without particular limitation. As a pH adjuster, the pH adjuster etc. which are described, for example, in the "Pharmaceutical Additives Dictionary" published by Pharmacy Ilbo, 2005 (edited by Japan Pharmaceutical Additives Association) etc. are used. As a pH adjuster, an acidic pH adjuster or a basic pH adjuster can be mentioned. As the acidic pH adjusting agent, for example, organic acids such as citric acid, citric anhydride, succinic acid, tartaric acid, acetic acid, glacial acetic acid, lactic acid, sodium lactate and glycine, for example hydrochloric acid (including dilute hydrochloric acid), sulfuric acid, phosphoric acid, dihydrogen phosphate Inorganic acids such as potassium, sodium dihydrogen phosphate, sodium dihydrogen phosphate and sodium dihydrogen phosphate. As a basic pH adjuster, organic bases, such as sodium citrate, sodium acetate, anhydrous sodium acetate, triethanolamine, monoethanolamine, and meglumine, for example sodium hydroxide, sodium hydrogen phosphate, trisodium phosphate, dipotassium phosphate, Inorganic bases, such as anhydrous sodium monohydrogen phosphate, sodium carbonate, dry sodium carbonate, and sodium hydrogencarbonate, etc. are mentioned. These pH adjusting agents may be used alone, or may be used in combination of two or more thereof. In addition, you may use the said pH adjuster as a solution (for example, aqueous solution, alcohol solution, etc.).

In this invention, hydrochloric acid, sulfuric acid, phosphoric acid, citric anhydride, glycine, etc. are mentioned preferably as acidic pH adjuster, More preferably, hydrochloric acid is mentioned. Preferred examples of the basic pH regulator include sodium hydroxide and sodium citrate, and more preferably sodium hydroxide.

There is no restriction | limiting in particular in the density | concentration of an acidic pH adjuster and a basic pH adjuster, It can be set as the normal concentration of the pH adjuster used as a pharmaceutical additive.

Dropping injections of the present invention are stable against heat and light. Stability against heat and light can be determined, for example, as an indicator of residual rate. The residual ratio refers to the ratio of compound A after storage to compound A before storage. Injectable injectable preparations of the present invention, for example, of Compound A after preservation of an aqueous solution, after preservation of heat conditions (for example, at about 60 ° C. for about 1 month), or after exposure to light (for example, at 2500 ° C for about 20 days), The residual ratio is at least about 95% (about 95% to about 100%), preferably at least 98% (about 98% to about 100%). As a topical injection which is stable against heat and light, an aqueous solution having a compound A concentration of about 50 mg / mL or more and a pH value of about 3 to about 7 is preferable. Lowering the concentration of compound A lowers the stability to heat or light.

The residual ratio of Compound A in the injectable injection solution of the present invention is calculated based on the measurement result using a known analysis method (for example, high-performance liquid chromatography, gas chromatography, thin layer chromatography, etc.). In particular, it is preferable to measure using high-performance liquid chromatography. High-performance liquid chromatography is performed by a well-known method. Specifically, it can carry out by the method as described in the Example mentioned later. It is possible to calculate the residual ratio of compound A by measuring the peak area of compound A before storage and after storage using this method.

In addition, when the concentration of the compound A is increased, the viscosity of the aqueous solution also increases, making it difficult to handle in the medical field. For example, when a highly viscous liquid is used as an injectable injection, liquid is easily left in the container when the liquid is taken out of a container such as an ampoule and injected into an infusion bag, resulting in poor handling. Therefore, the viscosity of the high-dose injectable drug of the present invention is preferably about 1 to 4 mPa · s, which has good handling in the medical field. The high content injection of the present invention having a concentration of about 300 mg / mL or less has a viscosity of about 1 to about 4 mPa · s. Viscosity can be measured using a well-known method, for example, the viscosity measuring method described in Pharmacopoeia.

In the present invention, the high-dose injectable injection means an aqueous solution containing a high concentration of Compound A, for example, an aqueous solution having a concentration of Compound A of about 50 mg / mL or more, and the concentration of Compound A in view of stability and viscosity Preferably from about 50 to about 300 mg / mL, more preferably from about 100 to about 300 mg / mL.

In addition to the said pH adjuster, you may mix | blend the injection of this invention suitably with the other additive generally used for manufacture of a preparation for injection. As such an additive, for example, glucose, galactose, mannose, lactose, maltose, palatinose, trehalose, raffinose, eroloose, melitchose, 70v / v% N-hydroxyethyl lactamide aqueous solution, D Sorbitol, D-mannitol, DL-methionine, L-aspartic acid, L-alanine, L-arginine, L-glutamic acid, L-lysine, potassium L-glutamate, sodium sodium glutamate, L-cystine, L-histidine, L Methionine, N, N-dimethylacetamide, ascorbic acid, acetyltriptophan sodium, amineethylsulfonic acid, aminoacetic acid, gum arabic, gum arabic powder, alphathioglycerin, albumin, inositol, ethanol, ethyl urea, ethylene Diamine, Sodium Edetate, Sodium Edetate, Oleic Acid, Sodium Caprylate, Sodium Calmerose, Xylitol, Sodium Citrate, Glycerin, Calcium Gluconate, Sodium Gluconate, Magnesium Gluconate, Cr Atinine, Chlorobutanol, ethynolamide, succinic acid, sesame oil, sodium chondroitin sulfate, sodium salicylate, diethanolamine, diethylenetriamine pentaacetic acid, sesquioleate sorbitan, gelatin, gelatin hydrolyzate, sorbitan fatty acid ester , Soybean oil, thioglycolic acid, sodium thioglycolate, potassium thiocyanate, sodium thiosulfate, sodium thiosulfate, camellia oil, dextran 40, dextran 70, sodium desoxycholate, triethanolamine, sodium formaldehyde, sulfoxylate , Nicotinic acid amide, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, hydroxypropyl cellulose, castor oil, potassium pyrosulfite, sodium pyrosulfite, phenol, butylhydroxyanisole, propylene glycol Sodium heparin, benzyl alcohol, polyoxyethylene (160), polyoxypropylene (30) Recall, polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil 60, polysorbate 80, macrogol 400, macrogol 4000, meglumine, methane sulfo Sodium benzoate, monoethanolamine, monostearic acid aluminium, polyoxyethylene sorbitan monolaurate (20E.O.), peanut oil, sodium sulfite, sodium bisulfite, benzoic acid, sodium benzoate, benzyl benzoate, aluminum chloride, sodium chloride , Benzalkonium chloride, Benzetonium chloride, magnesium chloride, zinc chloride, zinc chloride solution, stannous chloride, ferric chloride, arginine hydrochloride, cystine hydrochloride, lysine hydrochloride, fructose, dry aluminum gel, dry sodium sulfite, dilute hydrochloric acid, Highly refined egg yolk lecithin, calcium oxide, zinc chloride, calcium bromide, sodium bromide, ammonium acetate, sodium acetate, zinc acetate, aluminum hydroxide, tablets Gelatin, refined soybean lecithin, refined soybean oil, refined white sugar, refined egg yolk lecithin, water for injection, calcium saccharide, lactic acid, ethyl lactate, sodium lactate, urea, concentrated glycerin, anhydrous ethanol, anhydrous sodium pyrophosphate, anhydrous Maleic acid, stannous anhydride, sodium anhydride, sulfuric acid, potassium aluminum sulfate, potassium sulfate, magnesium sulfate, and the like. These additives are generally formulated in proportions commonly used in injectable preparations. In addition, these additives may be used independently and may be used in combination of 2 or more type. It is easy for a person skilled in the art, and as described in Pharmacy Daily, published in 2005 by the Pharmaceutical Additives Dictionary (edited by the Japan Pharmaceutical Additives Association), these additives are, for example, stabilizers, surfactants, buffers depending on the purpose of use. And solubilizers, antioxidants, antifoaming agents, isotonic agents, emulsifiers, suspending agents, preservatives, analgesic agents, solubilizers, dissolution aids and the like.

The addition amount of the other additive in the composition of this invention is not specifically limited. In addition, other additives are added to the composition of the present invention as desired, and their addition is not essential.

The injectable injectable preparation of the present invention is filled into an injectable container and sterilized, and can be used as a high content injectable injectable preparation.

The amount of the injectable injectable agent of the present invention into the injectable container is not particularly limited, but is preferably, for example, about 0.5 mL to 10 mL, more preferably about 1 mL to about 10 mL. The content of Compound A per 1 unit (eg, 1 vial, 1 ampoule, etc.) for injection is not particularly limited, but is, for example, about 1 mg to about 5,000 mg, and more preferably about 100 mg to about 3,000 mg. The content of is mentioned.

Moreover, it can be set as the injection container which maintained sterility by the sterilization operation similar to a general injection container etc. in arbitrary processes in these processes. Further, if desired, filtration or the like may be performed with a dustproof filter (for example, 0.45 µm methyl cellulose membrane, 0.45 µm nylon 66 membrane, 0.45 µm polyvinylidene membrane, etc.) before filling into these containers. Specific sterilization methods used for sterilization include, for example, gas sterilization method, hot water sterilization method, hot water shower sterilization method, filter sterilization method, irradiation sterilization method (for example, electron beam sterilization method, ultraviolet sterilization method, γ-ray sterilization method, etc.) and autoclave sterilization (autoclave). ) Method, and the like. The filter sterilization method is, for example, after the preparation of the injectable injection solution of the present invention by the above method, for example, before filling into a suitable container such as an ampoule, vial, syringe, etc., for example, a disinfection filter (for example, 0.2 μm polyvinylidene dimple). Rode membrane, etc.). Gas sterilization is performed on injectable containers such as ampoules, vials and syringes before filling the injectable injectables of the present invention. Hot water immersion sterilization method, hot water shower sterilization method, irradiation sterilization method or high pressure steam sterilization method are prepared by the above method, for example, by applying the injectable injection solution of the present invention, for example, by filling into a suitable container such as an ampoule, a vial or a syringe. . High-pressure steam sterilization is preferably carried out for 5 to 30 minutes at 100 ° C to 125 ° C, for example. As a sterilization method in the present invention, for example, a filter sterilization method or a high pressure steam sterilization method is preferable.

In the present invention, the container for injection can be in any form as long as it is sealable and can maintain the sterility of the contents. In general, a vial or ampoule used for filling an injectable preparation or injection is preferable. Moreover, it can also be used as the syringe which filled the syringe with the inject | pouring injectable agent of this invention, and prefilled. The injection container may be made of any material. For example, a vial or an ampoule may be made of glass or plastic, or a prefilled syringe may be made of plastic. Moreover, combining these materials, for example, the glass container which coat | covered the inner surface with the plastic material, and the plastic container which coat | covered the inner surface with the glass material can also be used.

The glass material may be a glass material that can be used for a container for filling a medicine. In the case of using a glass container, the inner surface of the container may be coated with silicon or treated with silicon dioxide. The coating of silicone is made using a silicone-based coating agent (for example, dimethylsilicone oil, methylphenylsilicone oil, methylhydrogensilicone oil, etc.) and the like, and the thickness of the coating on the inner surface of such a container is preferably about 100 µm or less. By a known method such as a heat deposition method, a plasma enhanced chemical vapor deposition method, a plasma pulse chemical vapor deposition method, or the like so as to be about 15 µm to about 50 µm or less. The treatment of silicon dioxide is carried out by a known method, for example, a silicate treatment, a wave plasma chemical vapor phase treatment, or the like. In addition, glass containers (eg, silica coat ampoules, silica coat vials made by Shiotani glass, Fuji glass), type I plastic ampoules, type I plastic vials, etc. (made by Schott), etc. ) May be used.

The plastic material may be a plastic material usable in a container for filling a medicine, for example, polyethylene, polypropylene, polystyrene, polymethylpentene, polyester, polyamide, polycarbonate or cyclic olefin compound or crosslinked material. Polymer resins of cyclic hydrocarbon compounds and the like can be used without particular limitation.

When an ampoule is used as a container for injection, such an ampoule is filled by sealing the opening by filling the injectable injection agent of the present invention.

In the case of using a prefilled syringe as a container for injection, such a syringe fills the injectable injectable agent of the present invention, closes the tip portion for mounting the needle with a rubber or plastic part, and the plunger rod portion It is sealed by tightly sealing with a gasket or plunger rod made of rubber or plastic.

Preferred injectable containers used in the present invention include ampoules. In particular, a glass ampoule is preferable, and the light-shielding glass ampoule is especially preferable.

The injection container used in the present invention may be packaged with light shielding. As the light-shielding packaging, the above-mentioned injection container may be filled with a container which cuts light, that is, a shading container, or the light-shielding packaging described below may be provided in the injectable injection agent of the present invention filled in the injection container. do. Such a packaging can be used without particular limitation as long as it is a light-shielding packaging that is generally used. Specifically, a bag of a material which suppresses light permeability of a specific wavelength, a bag of a light shielding material such as plastic or aluminum, or a shrink wrap (for example, a shrink label) or a blister package using a light shielding plastic Can be used. By using these light-shielding packaging in combination, light-shielding property can be improved more.

[toxicity]

The toxicity of Compound A is very low and is safe enough for use as a medicament.

[Application to Malware]

Since compound A has PARP inhibitory activity, the injectable injectable preparation of the present invention containing compound A ischemic diseases (cerebral infarction, myocardial infarction, reperfusion injury, postoperative injury, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebral sclerosis, arthritis) , Pulmonary disorders), neurodegenerative disorders (conjugated extrapyramidal system), Parkinson's disease, Alzheimer's disease, muscular atrophy, lumbar spinal stenosis, etc., glaucoma, diabetes, diabetes complications, shock, head It is useful as a prophylactic and / or therapeutic agent for trauma, spinal cord injury, kidney failure, hyperalgesia, blood flow disorders, etc., and also as an antiretroviral agent (HIV, etc.), an anticancer sensitizer, or an immunosuppressive agent.

Injectable injectable preparations of the present invention may be used for 1) supplementing and / or enhancing the therapeutic effect of the injectables, 2) improving the dynamics and absorption of the injectables, reducing the dosage, and / or 3) reducing the side effects of the injectables. You may administer in combination with a drug as a combination.

Combinations of topical injectables with other agents of the present invention include simultaneous administration and timed administration. In addition, administration by the time difference may be administered by first administering the injectable injection of the present invention and then another drug, or by administering another drug first and subsequently by administering the injectable injection of the present invention. May be the same or different.

The other drug may be a low molecular compound, or may be a polymer protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. The dosage of the other medicament may be appropriately selected based on the dosage used clinically. Other drugs may be administered, for example, by combining any one kind or two or more kinds from the same kind and the different kind shown below in an appropriate ratio.

Examples of the other drugs include thrombolytic drugs (e.g., t-PA (t-PA, alteplase, tisokinase, nateplase, pamiteplase, montepla) Monteplase, desmoteplase, etc.), urokinase, prourokinase, nasaruplase, streptokinase, etc.), anticoagulants (e.g. For example, heparin (heparin sodium, heparin calcium, heparinoid, low molecular weight heparin (parnaparin, dalteparin, danaparoid, enoxaparin ( enoxaparin, nadroparin, bemiparin, leviparin, tinzaparin, etc.), activated blood coagulation inhibitors (fondaparinux, DX) -9065a, DU-176b, CS-3030, JTV-803, BMS-561389, BAY-59-7939, YM150, LY-517717, KFA-1982, KFA-1829, idraparinux , DPC-423, DPC-602, DPC-A52350, Otamixaban, HMR2096, FXV-673, RPR-130673, MCM16, MCM17, TC-10, RPR-256580, RPR-225430, RPR-247978, RPR-231352, RPR-209685, RPR-208944, RPR-208815, RPR-208707, RPR-208566, RPR-200095, RPR-130338, RPR-130737, RPR-132747, RPR-128515, RPR-120844, M- 55113, M-55190, M-55555, M-55529, MLN-1021, EGR-Xa, CI-1031, ZD-5227, AX-1826, ZK-813039, DE-00684, BIBT-986, BIBT-1011, BM-141248, PD-198961, PD-0313052, PD-313052, PMD-3112, PMD-3833, PMD-3805, PMD-3829, PMD-2612, PMD-2837, PMD-2566, SEL-2711, SSR- 122497A, SSR-126517, SSR-128428, SSR-128429, SSR-80670A, SSR-121903A, SSR-122429A, SSR-122574A, Org-42657, etc.), activating hemagglutination inhibitors (TTP-889, 224AE3) Etc.), vitamin K antagonists (such as warfarin), antithrombin drugs (argatroban, mesylic acid gabexate mesilate, mesylic acid nafamostat mesilate, simeragatran (ximelagatran), melagatran, dabigat ran, bivalirudin, lepirudin, hirudin, desirudin, SSR-182289A, SR-123781A, S-18326, AZD-0837, LB-30870, L- 375378, MCC-977, AT-1362, etc.), activated protein C preparations (dry concentrated human activated protein C), antithrombin III preparations, tissue factor pathway inhibitors, thrombomodulin preparations (ART-123 , MR-33, etc.), carboxypeptidase U inhibitors; thrombin-activatable fibrinolysis inhibitor (TAFI) (such as sodium citrate, AZD-9684, etc.), antiplatelets (e.g. aspirin, tilopidine, clopidogrel, dipyridamole, Cilostazol, ozagrel, prasugrel, ethyl icosapentate, veraprost, sarpogrelate, limaprost, GPIIb / IIIa receptor antagonists (abciximab, tirofiban, epitifibatide, YM028, etc.), AZD6140, etc., brain protection drugs (radical scavengers (edarabon, evserene (DR) 3305), etc.), astrocytic modulators (ONO-2506, etc.), N-methyl-D-aspartic acid (N-methyl-D-aspartate; NMDA) antagonists, α-amine-3-hydroxy-5-methyl Isoxazole-4-propionic acid (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) antagonist, nitric oxide synthase (NOS) inhibitor (L-NMMA, ONO-1714 ), Calcium antagonists, sodium channel antagonists, opioid antagonists, GABA agonists, neurotrophic factors, etc., anti brain edema drugs (glycerol, mannitol, etc.), plasma bulking agents (dextran 40, hydroxyethyl starch, albumin, penta) Starch (pentastarch, etc.), immunosuppressive drugs (cyclosporin, tacrolimus, azathioprine, methotrexite, cyclophosphamide, etc.), intercellular adhesion factor inhibitors, interleukin-8 antagonists, steroid drugs, etc. Can be.

In addition, other medicaments that complement and / or enhance the prophylactic and / or therapeutic effects of the injectable injectables of the present invention include those not only discovered to date but also subsequently discovered according to the mechanisms described above.

The dosage of Compound A varies depending on age, weight, symptoms, therapeutic effect, treatment time, etc., but usually 1 mg to 10 mg / kg / hour per adult is administered intravenously in the range of 1 hour to 24 hours per day. .

Of course, as described above, since the dosage varies according to various conditions, an amount smaller than the dosage may be sufficient, and in some cases, it may be necessary beyond the range.

As described above, according to the present invention, it is possible to improve the solubility of Compound A, which is a poorly soluble compound in water, and to provide a high-dose injectable drug which is stable against heat and light in long-term storage and easy to handle in the medical field.

Although an Example is given to the following and this invention is detailed, this invention is not limited to these.

Moreover, you may change in the range which does not deviate from the range of this invention.

In addition, in this invention, pH value is measured using pH meter (pH / ION METER F-24 Co., Ltd.), As a pH standard liquid, phthalic acid pH standard liquid (pH4.01), phosphate pH standard liquid (pH6) .86), borate pH standard solution (pH 9.18) was used.

Example 1: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (pH3)

Water for injection was added to Compound A (50 g) and stirred to make a suspension. The pH was adjusted to about 3 by addition of 1M hydrochloric acid and brought to 500 mL with water for injection. After making it into a uniform solution, it was filtered by suction with a stericup (material: polyvinylidene difluoride (PVDF), pore diameter: 0.2 μm, millipore), and sterilized by Teha Co., Ltd. in a 5 mL white background ampoule. ) Was charged in 5mL increments and dissolved in an ampoule waste container. The ampoule was autoclaved at 121 ° C. for 20 minutes under high pressure steam to prepare an injectable injection containing Compound A (100 mg / mL) having a pH of 3.

Example 2: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (pH4)

Water for injection was added to Compound A (60 g), followed by stirring to obtain a suspension. 1 M hydrochloric acid was added to adjust the pH to about 4 and brought to 600 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (100 mg / mL) injectable injection containing pH 4.

Example 3: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (pH5)

Water for injection was added to Compound A (50 g), followed by stirring to obtain a suspension. The pH was adjusted to about 5 by addition of 1M hydrochloric acid and brought to 500 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare an injectable injection containing Compound A (100 mg / mL) having a pH of 5.

Example 4: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (pH6)

Water for injection was added to Compound A (50 g), followed by stirring to obtain a suspension. 1 M hydrochloric acid was added to make the pH near 4, 1 M sodium hydroxide was added thereto to adjust the pH to about 6, and 500 mL was used with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (100 mg / mL) injectable injection containing pH 6.

Example 5: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (pH7)

Water for injection was added to Compound A (10 g), followed by stirring to obtain a suspension. 1 M hydrochloric acid was added to make the pH near 4, 1 M sodium hydroxide was added thereto to adjust the pH value to about 7, and to 100 mL using water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (100 mg / mL) injectable injection containing pH 7.

Example 6: Examination of stability by measurement of residual rate

Injectable injectable preparations prepared in Examples 1, 2, 3, and 4 were used as conditions 1: 40 ° C., 75% relative humidity for 1 month, and Condition 2: 1 month at 60 ° C. (except for injectable preparations prepared in Example 4) In the case of 1 month 13 days), or condition 3: 20 days (500 days in the case of the injectable injection preparation prepared in Example 4) in the light-exposure condition 2500 ㏓. The residual ratio of Compound A in the injectable injection at each pH after storage was measured to evaluate stability against heat or light.

<Measuring method of remaining rate>

1. Adjustment of Sample Solution

To 2 mL of the injectable drops prepared in Examples 1, 2, 3 and 4, water was added to make 50 mL. The solution was weighed in 5 mL portions, and sodium dodecyl sulfate solution (ion pair reagent-sodium dodecyl sulfate solution (2.88 g) was dissolved in water to make 1400 mL of a solution / acetonitrile mixture (7: 3). It was.

2. High Performance Liquid Chromatography (HPLC)

The reagent solution was subjected to high performance liquid chromatography under the following conditions.

Exam conditions

Detector: ultraviolet absorbance photometer (wavelength: 275 nm)

Column: Filled with a 5 µm octadecylsilylated silica gel for liquid chromatograph (for example YMC-pack ODS-A-302) in a stainless tube having an inner diameter of 4.6 mm and a length of 15 cm.

Column temperature: constant temperature around 25 ℃

Flow rate: 1.0 mL / min

Analysis time: 40 minutes

Injection volume: 20 μL

Mobile phase: A solution adjusted to pH 3.0 by adding phosphoric acid to a solution / acetonitrile mixture (7: 3) prepared by dissolving 2.88 g of ion pair reagent-sodium dodecyl sulfate in water to 1400 mL.

HPLC system: LC-2010C Shimatsu Corporation

3. Calculation of remaining rate

When the quantitative value after sterilization of the injectable injectable drug obtained by the absolute calibration curve method was 100%, the ratio of the quantitative value of the injectable injectable product after storage under heat or light-exposure condition was set as the residual rate (%). .

<Result>

Below, the residual ratio and pH value of the compound A in the inject | pouring agent for each pH of each pH after storing on thermal conditions or a light-exposure condition are shown.

Example 1 Example 2 Example 3 Example 4 Survival rate (%) pH value Survival rate (%) pH value Survival rate (%) pH value Survival rate (%) pH value After sterilization (Initial)  100.00  3.08  100.00  4.09  100.00  5.08  100.00  6.05 Condition 1  100.45  3.08  100.05  4.21  100.04  5.06   99.53  6.04 Condition 2  100.22  3.20  100.22  4.23   99.81  5.04  100.15  6.01 Condition 3   98.22  2.95   99.24  3.42   98.27  4.02   97.83  5.86

Topical injections of pH 3, 4, 5 and 6 do not affect the residual rate and pH value even if stored for 1 month or more under thermal conditions (conditions 1 and 2) and are chemically stable. In addition, under the conditions of 2,500 kPa light (condition 3), all of the four pH injections showed a slight decrease in the residual ratio and a decrease in the pH value, but had little effect.

From the above, it has been suggested that topical injections of all pHs can be stored for a long time.

Example 7: Examination of stability by measurement of change in properties, insoluble foreign matter and insoluble fine particles

Regarding the injectable injectable preparations prepared in Examples 1, 2, 3, 4 and 5, Condition 1: 40 ° C, 1 month at 75% RH, Condition 2: 1 month at 60 ° C (Examples 4 and 5 1 month 13 days for injectable injectables prepared in the US), or condition 3: 20 days at 2500 kPa in a bombing condition (19 days for injectable injectables prepared in Examples 4 and 5). The stability to heat or light was evaluated by the following items.

1. Appearance

Specifications: colorless to light yellow clear liquid

Topical injections of all pHs of pH 3, 4, 5, 6 and 7 were also clear solutions under the preservation conditions of conditions 1, 2 and 3.

2. Insoluble foreign substance

Specification: Clear and easily detectable insoluble foreign matter is not visible.

(1) In the laboratory, visually observe the preparation with a fluorescent lamp

Injectable injections of all pHs of pH 3, 4, 5, 6 and 7 also showed no increase of insoluble foreign matter under the preservation conditions of conditions 1, 2 and 3.

(2) visual observation using an ampoule observer

Injectable injections of all pHs of pH 3, 4, 5, 6 and 7 also did not show the appearance of flakes (eluate of glass) under the preservation conditions of conditions 1, 2 and 3.

There was no increase in insoluble foreign matter.

3. Insoluble particulate test

Specification: 10 µm or more: 6000 or less / container, 25 µm or more: 600 or less / container (container: 5 mL ampoule)

How to measure

Five ampoules of each solution were added to each of the dropwise injections for each pH in a clean container to obtain a test solution. Insoluble fine particle test method of injection 1st test: The test was carried out by the method by the light shielding type automatic fine particle measuring apparatus (Japanese pharmacy room). The test solution was gently agitated by hand to avoid bubble formation and foreign contamination, to uniform particles in the solution. 5 mL of the test solution was measured four times. The average number of particles was obtained except for the first measurement.

Injectable injectables at all pHs of pH 3, 4, 5, 6 and 7 also had insoluble particulates within the specification range under the preservation conditions of condition 1, 2 and condition 3.

The results of the above 1, 2 and 3 suggest that the injectable injection solution of the present invention is stable against heat and light, and long-term storage is possible.

Comparative Example 1: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (10 mg / mL)

Water for injection was added to Compound A (5 g) and stirred to make a suspension. 2.74M hydrochloric acid was added to pH4, 1M sodium hydroxide was added thereto to adjust the pH to about 6, and made 500 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (100 mg / mL) injectable injection containing pH 6.

Example 8: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (50 mg / mL)

Water for injection was added to Compound A (25 g) and stirred to make a suspension. 2.74M hydrochloric acid was added to pH4, 1M sodium hydroxide was added thereto to adjust the pH to about 6, and made 500 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under high pressure steam to prepare an injectable injection containing Compound A (50 mg / mL) having a pH of 6.

Example 9: application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (200 mg / mL)

Water for injection was added to Compound A (100 g) and stirred to make a suspension. 2.74M hydrochloric acid was added to pH4, 1M sodium hydroxide was added thereto to adjust the pH to about 6, and made 500 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (200 mg / mL) injectable injection containing pH 6.

Example 10 Application of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one Preparation of Injection (300 mg / mL)

Water for injection was added to Compound A (150 g) and stirred to make a suspension. 2.74M hydrochloric acid was added to pH4, 1M sodium hydroxide was added thereto to adjust the pH to about 6, and made 500 mL with water for injection. After the solution was made into a uniform solution, the resultant was filtered by suction with a stericup (material: PVDF, pore size: 0.2 μm, Millipore), and 5 mL white base ampoules were filled in 5 mL each using Teha and inoculated by an ampoule container. The ampoule was autoclaved at 121 ° C. for 20 minutes under autoclave to prepare a compound A (300 mg / mL) injectable injection containing pH 6.

Example 11 Examination of Stability by Residual Rate Measurement

Injectable injectable preparations prepared in Comparative Example 1, Examples 4, 8, 9 and 10 were subjected to condition 1: 40 ° C, 1 month at 75% relative humidity, condition 2: 1 month at 60 ° C, or condition 3: bombing condition 2500 It was preserve | saved under the conditions of 1 month (it is 22 days in the case of the injectable injectable preparation prepared in the comparative example 1). In the same manner as in Example 6, the residual ratio of Compound A in the dropwise injection of each pH after storage was measured to evaluate stability against heat or light.

<Result>

Below, the residual rate of the compound A in the injectable injection of each density | concentration after saving on thermal conditions or a light-exposure condition is shown.

  Residual rate (%) Comparative Example 1 (10 mg / mL) Example 8 (50 mg / mL) Example 4 (100 mg / mL)    Example 9 Example 10 (200 mg / mL) (300 mg / mL) After sterilization (Initial)     100.0     100.0     100.0     100.0    100.0 Condition 1     100.2     100.5      99.8     101.3    100.7 Condition 2     101.0     100.8     100.4     100.6    100.9 Condition 3      90.5      97.0      98.6      99.4     98.8

High dose injectables with concentrations of Compound A of 50, 100, 200 and 300 mg / mL, respectively, have no effect on the residual rate and are chemically stable even when stored for 1 month or more under thermal conditions (conditions 1 and 2). . In addition, under the conditions of 2,500 폭 light conditions (condition 3), the injection rate of all pH showed a slight decrease in the residual ratio, but there was almost no effect. On the other hand, the injectable injectable agent having a concentration of 10 mg / mL was stable under thermal conditions, but the residual ratio after storage under the conditions of light exposure was 95% or less and unstable with light.

It has been suggested from the above that the high-dose injection preparation of the present invention is stable against heat and light and can be stored for a long time.

Example 12: Viscosity Measurement

Viscosity measurement method The viscosity of the 300 mg / mL injectable injection compound of Compound A prepared in Example 10 in (2) Single Cylindrical Rotational Viscometer (Brookfield Viscometer) (Japan Pharmacy) was measured. It was about 3.6 mPa * s.

Therefore, it was suggested that the injectable injectable agent having a concentration of Compound A of 300 mg / mL or less is a viscosity that is easy to handle in the medical field.

The high-dose injectable injections of the present invention are useful for the prevention and / or treatment of cerebral infarction, etc. 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8- It is possible to provide tetrahydrophthalazine-1 (2H) -one to the clinic in a safe state without degrading the quality while maintaining a high residual rate, and also has a viscosity that is easy to handle in the medical field, and thus the availability as a pharmaceutical Very high.

Claims (13)

4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one and acidic pH regulator High dose injectables, if necessary, containing a basic pH adjusting agent. The high-dose injectable preparation according to claim 1, wherein the injectable agent has a pH value of 3 to 7. The method of claim 1, wherein 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one A high content injectable injection, wherein the concentration is 50 mg / mL to 300 mg / mL. The high-dose injectable preparation according to claim 1, wherein the acidic pH adjusting agent is at least one kind selected from organic acids and inorganic acids, and the basic pH adjusting agent is at least one kind selected from organic bases and inorganic bases. The high content point according to claim 4, wherein the acidic pH adjuster is at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric anhydride and glycine, and the basic pH adjuster is at least one selected from sodium hydroxide and sodium citrate. Applied injection. The injectable high-dose injectable according to claim 1, wherein the viscosity of the injectable is 1 mPa · s to 4 mPa · s. The injectable high-dose injectable agent according to claim 1, wherein the container for injection is filled. The high-dose injectable preparation according to claim 7, which is formed by shading packaging. The method of claim 1, wherein 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one A high content injectable injectable, characterized in that the pH value is adjusted to 3-7 by adding a basic pH adjusting agent if necessary after dissolving by adding an acidic pH adjusting agent to the aqueous suspension. The method of claim 1, wherein the pH value of the injection is 4, 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine A high-dose injectable injection, wherein the concentration of -1 (2H) -one is 100 mg / mL to 300 mg / mL and the viscosity is 1 mPa · s to 4 mPa · s. The method of claim 1, wherein the pH value of the injection is 6, 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine A high-dose injectable injection, wherein the concentration of -1 (2H) -one is 100 mg / mL to 300 mg / mL and the viscosity is 1 mPa · s to 4 mPa · s. Hydrochloric acid is added to an aqueous suspension of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one And the pH value is adjusted to 4 and filled into an injection container, the viscosity being 1 mPa · s to 4 mPa · s, 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl A 5,6,7,8-tetrahydrophthalazine-1 (2H) -one has a concentration of 100 mg / mL to 300 mg / mL. Hydrochloric acid is added to an aqueous suspension of 4- (N- (4- (morpholin-4-yl) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one After dissolving the solution, sodium hydroxide is added to adjust the pH value to 6 and filled into an injection container, and the viscosity is 1 mPa · s to 4 mPa · s, and 4- (N- (4- (morpholin-4- (I) butyl) carbamoylmethyl) -5,6,7,8-tetrahydrophthalazine-1 (2H) -one The concentration of the injectable for injection, characterized in that 100mg / mL to 300mg / mL.