HK1100529A - Quinolone-containing medicinal composition - Google Patents
Quinolone-containing medicinal composition Download PDFInfo
- Publication number
- HK1100529A HK1100529A HK07108384.0A HK07108384A HK1100529A HK 1100529 A HK1100529 A HK 1100529A HK 07108384 A HK07108384 A HK 07108384A HK 1100529 A HK1100529 A HK 1100529A
- Authority
- HK
- Hong Kong
- Prior art keywords
- solution
- compound
- added
- polyvalent metal
- preparation
- Prior art date
Links
Description
Technical Field
The present invention relates to a drug solution containing a quinolone compound, which alleviates disorders at a site of administration, particularly disorders in blood vessels, when a patient uses the drug solution containing a quinolone compound, and a method for alleviating disorders at a site of administration, particularly disorders in blood vessels, of a drug solution containing a quinolone compound.
Background
The quinolone compound has good drug effect as an antibacterial drug. However, when an aqueous injection solution containing a quinolone compound is injected intravascularly, the compound may cause a problem in blood vessels at the administration site as a part of side effects. As a method for reducing such a problem, a method is known in which a polyvalent metal compound, which is a compound of a metal such as magnesium, is added to an aqueous injection solution to form a chelate of a quinolone compound and a metal (ion).
That is, a pharmaceutical composition containing a quinolone carboxylic acid-metal ion-acid complex that can be administered by intravenous injection has been reported (see patent document 1). In addition, an aqueous pharmaceutical solution containing a mixture of a quinolone compound or a pharmaceutically acceptable salt thereof and a magnesium compound or a zinc compound with a cosolvent to improve the tolerance of an injection site has been reported (see patent document 2). In addition, a preparation for subcutaneous or intramuscular administration containing a carbostyril compound and magnesium ions and having suppressed local irritativeness has also been reported (see patent document 3).
However, these preparations must incorporate a larger amount of the polyvalent metal compound relative to the amount of the quinolone compound. For example, patent document 1 discloses incorporation of a polyvalent metal compound in an amount of 1.5 to 3 times by mole with respect to a carbostyril compound. In addition, in patent document 3, if the amount is not more than the equimolar amount, the effect tends to be reduced.
However, the metal (ion) itself has various physiological effects, and in order to suppress the development of the physiological effects, the amount of the metal (ion) to be mixed must be controlled. The conventional drug solutions containing a large amount of metal (ion) have a problem that the amount of the quinolone compound itself to be administered is limited in order to control the total amount of the metal (ion) to be administered. In the treatment of severe infectious diseases, a large amount of the carbostyril compound must be administered, but since the dose is limited, there is a possibility that a sufficient therapeutic effect cannot be obtained.
Further, a formulation capable of relatively reducing the amount of metal (ion) to be mixed has been reported (see patent document 2). The formulation is characterized by containing a cosolvent such as N-methylpyrrolidone or 2-pyrrolidone. However, this formulation is for subcutaneous injection, but none of the above co-solvents is generally available for intravascular administration of drug solutions.
Since a chelate is formed between a carbostyril compound and a metal ion, the pH of a drug solution of most preparations containing a carbostyril compound is close to neutral (patent documents 1 to 3), but from the viewpoint of chemical and physicochemical stability of the carbostyril compound, the pH of the drug solution is preferably adjusted to be weakly acidic, about 4. That is, the liquid properties of conventional preparations containing a quinolone compound are improved in the chelate-forming ability and are advantageous for the chelate-forming ability, but the near-neutral liquid properties are not sufficiently preferable from the viewpoint of stability of the quinolone compound.
Having the following formula (1):
the carbostyril compound (7- [3- (R) - (1-aminocyclopropyl) pyrrolidin-1-yl ] -1- [2- (S) -fluoro-1- (R) -cyclopropyl ] -1, 4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid) having the structure shown has excellent antibacterial activity, and particularly has excellent antibacterial activity against gram-positive bacteria resistant to drugs such as methicillin-resistant staphylococcus, penicillin-resistant pneumococcus, vancomycin-resistant enterococcus, and the like. In addition, it is expected to have high safety and a good therapeutic effect (see patent document 4). The quinolone compound is expected to have a good therapeutic effect against severe infections due to its antibacterial effect, and is usually administered in the form of a solution into such severe patients intravascularly. Therefore, it is desired to find a prescription for the drug solution containing the quinolone compound, which does not cause any trouble or can reduce trouble at the administration site even when administered intravascularly.
Patent document 1: japanese patent laid-open publication No. 5-502879
Patent document 2: japanese patent laid-open publication No. Hei 11-501331
Patent document 3: international publication No. WO 99/29322
Patent document 4: international publication No. WO 02/40478
Disclosure of The Invention
The object of the present invention is to provide a drug solution capable of intravascular administration, which can reduce local troubles even when a smaller amount of a polyvalent metal compound is incorporated into the drug solution, while ensuring an amount of a quinolone compound sufficient to exert a necessary therapeutic effect on infectious diseases.
The present inventors have conducted extensive studies to achieve the above object and have found that by adding a small amount of a polyvalent metal compound to a drug solution containing a specific quinolone compound, even when the liquid properties of the drug solution are weakly acidic, local troubles, particularly troubles with blood vessels, can be reduced, and have completed the present invention.
That is, the present invention provides a chemical solution comprising the following components (a) and (B):
(A) the following formula (1)
The compound represented by (A) or a salt thereof, and (B) a polyvalent metal compound, wherein the molar ratio of the component (B) to the component (A) (polyvalent metal/component (A)) is 0.01 to 0.7.
The present invention also provides a preparation for preparing the drug solution of the present invention, which contains the component (a) and a polyvalent metal compound; a set (set) for preparing the drug solution of the present invention by combining a preparation containing the component (a) and a solution for dissolving containing a polyvalent metal compound; a kit for preparing the drug solution of the present invention, which comprises a combination of a preparation containing the component (A) and a polyvalent metal compound and a dissolving solution; a kit for preparing the drug solution of the present invention, which comprises a combination of a solution preparation containing the component (A) and a solution preparation containing a polyvalent metal compound.
The present invention also provides a method for alleviating the trouble at the administration site of the component (a), which is characterized in that, when the compound represented by the formula (1), a salt thereof, or a hydrate thereof is administered, the polyvalent metal compound is present in a chemical solution containing the component (a) at a molar ratio (polyvalent metal/component (a)) of 0.01 to 0.7 relative to the component (a).
The use of the drug solution of the present invention can reduce the vascular disturbance of the carbostyril compound represented by the formula (1) even if the liquid properties thereof are weakly acidic. In addition, if the amount of the polyvalent metal compound is small in an amount of 0.01 to 0.7 times the molar ratio, the quinolone compound can be incorporated into the drug solution in an amount sufficient to expect a high therapeutic effect.
Best Mode for Carrying Out The Invention
The chemical solution of the present invention contains a compound represented by formula (1), a salt thereof, or a hydrate thereof (hereinafter referred to as compound (1)) as component (a) and a polyvalent metal compound as component (B) in specific amounts. In the compound (1), the hydrate form is not present in the drug solution, but is present only in the solid preparation.
The compound (1) and the polyvalent metal compound may be present together at the time of administration, and need not be present in the liquid medicine at the time of preparation. Examples of the drug solution preparation of the present invention include (i) a solution preparation in which the compound (1) and the polyvalent metal compound are dissolved and coexisted, (ii) a kit in which a solution preparation containing the compound (1) and a solution preparation containing the polyvalent metal compound are dissolved in combination, and (iii) a kit of a solution for dissolution in the case where a solid preparation containing the compound (1) is used as a kit. In the case of a preparation with a dissolving solution, the polyvalent metal compound may be contained in the dissolving solution; it may also be contained in a preparation containing the compound (1); it may be contained in a solution for dissolution or a preparation containing the compound (1) and then contained in a solution for dilution of a solution prepared with the solution for dissolution; the solvent may be contained only in the diluting solution instead of the dissolving solution. The preparation containing the compound (1) is not particularly limited as long as it is a solid preparation to be dissolved at the time of use, and a lyophilized preparation is preferred.
That is, the chemical solution of the present invention may be exemplified as follows.
Example 1: solution formulation
Examples thereof include (I) a solution preparation containing both the compound (1) and the polyvalent metal compound dissolved therein, and (II) a set of a solution preparation containing the compound (1) dissolved therein without containing the polyvalent metal compound and a solution preparation containing the polyvalent metal compound (corresponding to the above (I) and (II), respectively).
These solution preparations may be further added with a pH adjuster described later to adjust the pH of the drug solution to be weakly acidic around 4.
(I) In the case of (2), the solution is prepared as a solution in which the compound (1) and a polyvalent metal ion derived from a polyvalent metal compound coexist.
In the case of (II), the polyvalent metal compound is not contained in the preparation containing the compound (1), and a solution preparation is attached to the preparation so that the polyvalent metal compound is contained in the preparation. As the polyvalent metal ion-containing solution preparation, a commercially available infusion solution or the like containing the polyvalent metal ion used in the present invention can be used. Therefore, a solution preparation containing the compound (1) but not containing the polyvalent metal ion, which is premised on the use of the commercially available polyvalent metal ion-containing infusion solution, is also included in the embodiment of the present invention. In the case of (II), a diluting solution which may contain a polyvalent metal ion used in the present invention may be added. The solution for dilution containing a polyvalent metal ion may, for example, be a commercially available infusion solution.
Example 2: lyophilized preparation + solution for dissolution and/or solution for dilution (one or both of them contain polyvalent metal compound)
(iv) a preparation comprising a combination of a preparation containing the compound (1), preferably a lyophilized preparation (which may contain a pH adjuster as required), and a solution containing a polyvalent metal ion as a solution for dissolution and/or a solution for dilution for dissolving the lyophilized preparation (corresponding to the above-mentioned (iii)).
Optionally adding pH regulator into the solution for dissolving and/or diluting to make the medicinal liquid neutral.
In this case, the polyvalent metal compound is not contained in the lyophilized preparation containing the compound (1), but is contained in a solution for dissolving and/or a solution for diluting the lyophilized preparation. Further, as the dilution solution containing the polyvalent metal ion, a dedicated dilution solution may be used, and a commercially available infusion solution containing the polyvalent metal ion used in the present invention may be used. Therefore, a kit in which a lyophilized preparation containing the compound (1) and a solution for dissolution or a solution for dilution which is also used as a solution for dissolution are combined on the premise of using the commercially available infusion solution containing a polyvalent metal ion is also included in the embodiments of the present invention.
Example 3: lyophilized preparation containing polyvalent metal ion, and solution for dissolution and/or solution for dilution
A combination of a preparation containing the compound (1) and a polyvalent metal ion, preferably a lyophilized preparation and a solution for dissolution and/or a solution for dilution (corresponding to the above-mentioned (iii)).
A pH regulator may be added to the lyophilized preparation and/or the solution for dissolution, or even the solution for dilution, to make the medicinal liquid weakly acidic at about pH4.
In this case, the lyophilized preparation contains the compound (1) and a polyvalent metal ion. The drug solution of the present invention can be prepared by adding a solution for dissolution and/or a solution for dilution to a lyophilized preparation containing a polyvalent metal ion. As the diluent, a commercially available infusion solution, physiological saline, or the like can be used, except for a special diluent.
In addition, in administration, a solution prepared from the above preparation, solution for dissolution, or the like may be diluted with a usual infusion solution or the like. In this case, the diluted solution may be administered after dilution, or the compound (1) may be diluted immediately before entering the body by using a three-way stopcock or the like.
The polyvalent metal compound used in the present invention is not particularly limited as long as it is a compound which interacts with the compound (1) by coexisting with the compound (1) in the chemical solution. The interaction may be, for example, a metal chelate formed from the compound (1) and a polyvalent metal ion. The metal chelate compound may be an anionic component contained in the chemical solution.
In the present invention, the carbostyril compound and the polyvalent metal ion are dissolved and co-present and interact with each other upon administration. In the present technology, the amount of polyvalent metal required to exhibit the barrier-relieving effect is lower than the amount generally considered to be required for the formation of a metal chelate from the entire quinolone compound incorporated. Therefore, only a part of the carbostyril compound forms a metal chelate, and a reduction effect of the disorder can be obtained. That is, the interaction is not limited to the metal chelate, and may be an interaction that forms any other complex.
The polyvalent metal compound is preferably a magnesium compound or a calcium compound, particularly preferably a magnesium compound. The magnesium compound or the calcium compound may be used in the form of a salt of these metals with an acid or a halide or oxide of these metals.
Examples of the salt with an acid include a salt with an organic acid (for example, carboxylic acids such as gluconic acid and glucaric acid, sulfonic acids), and a salt with an inorganic acid (for example, sulfuric acid, hydrochloric acid, and hydrobromic acid). Specific examples of the salt of an organic acid include magnesium gluconate, calcium gluconate and calcium glucarate. Examples of the salt of an inorganic acid include magnesium sulfate and calcium sulfate. Examples of the halide or oxide of the metal include magnesium chloride, calcium bromide, and calcium oxide.
Among these polyvalent metal compounds, halides of magnesium or calcium are preferable, chlorides thereof are more preferable, and magnesium chloride is particularly preferable.
The molar ratio of the polyvalent metal compound to the compound (1) (polyvalent metal/component (A)) is 0.01 to 0.7, preferably 0.016 to 0.7, more preferably 0.2 to 0.7, particularly preferably 0.26 to 0.6, from the viewpoint of reducing local troubles and ensuring that the drug solution contains a sufficient amount of the compound (1) to be expected to have a high therapeutic effect.
The pH of the chemical solution of the present invention is preferably in the range of 2.5 to 6.9, more preferably 3.5 to 6.5, still more preferably 3.0 to 5.5, particularly preferably 3.5 to 4.5.
Additives for general preparations for intravascular administration, particularly for intravenous administration, such as pH adjusters, isotonic agents, solubilizing agents, analgesics, and the like, may be appropriately added to the preparation of the present invention. When the liquid medicine of the present invention has an additional dissolving solution, these additives may be added to either the preparation containing the compound (1) or the dissolving solution.
Examples of the pH adjuster include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, inorganic acid salts such as sodium hydrogen carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, potassium dihydrogen phosphate, sodium sulfite, sodium bisulfite, and sodium thiosulfate, organic acid salts such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, methanesulfonic acid, and thioglycolic acid, organic acid ester compounds such as ethyl lactate, organic acid salts such as sodium citrate, disodium citrate, sodium gluconate, calcium citrate, sodium lactate, sodium acetate, sodium pyrophosphate, sodium benzoate, sodium caprylate, and sodium thioglycolate, inorganic acid salts such as sodium hydroxide, and organic amine compounds such as monoethanolamine, diethanolamine, triethanolamine, ethylenediamine, meglumine, and tromethamine.
Examples of the isotonic agent include sugars or sugar alcohols such as sorbitol, mannitol, inositol, xylitol, erythritol, glucose, sucrose, purified white sugar, dextran, lactose, and maltose, and inorganic salts such as sodium chloride and sodium bromide.
Examples of the cosolvent include deoxycholic acid, polyoxyethylene hardened castor oil, polyoxyethylene-polyoxypropylene glycol, and polysorbate.
Examples of the analgesic agent include lidocaine and lidocaine hydrochloride.
The preparation of the drug solution of the present invention can be carried out according to a conventional method in the art. That is, there is no particular limitation as long as the compound (1) and the polyvalent metal ion can be dissolved in the chemical solution and both can be present. For example, it can be prepared as a solution preparation containing the compound (1) and a polyvalent metal ion, or as a combination of a plurality of solution preparations each containing the compound (1) and a polyvalent metal ion. Alternatively, a preparation containing the compound (1) may be prepared by freeze-drying or the like, and a solution for dissolution and/or a solution for dilution may be added to the preparation at the time of use to prepare a drug solution in the form of a kit. In the latter case, there may be mentioned a method of adding the polyvalent metal compound to the solution for dissolution and/or the solution for dilution in advance, and a method of adding the polyvalent metal compound to the preparation containing the compound (1) in advance.
The isotonic agent and the like are usually added when preparing a lyophilized preparation, but the lyophilized preparation containing the compound (1) of example 2 is preferably a preparation in which the isotonic agent and the like are not added but only the pH adjuster is added to the compound (1) in terms of stability. Further, the concentration of the compound (1) in the solution for preparing the lyophilized preparation is preferably 10mg/mL or more, more preferably 15mg/mL or more, particularly preferably 20mg/mL or more, from the viewpoint of caking property. In addition, the pH of the solution used for preparing the lyophilized preparation is preferably 5.5 or less, more preferably 5 or less, particularly preferably 2.5 to 4.5, from the viewpoint of solubility of the compound (1).
The preparation is shown below.
Example 1: solution formulation
The compound (1) and the polyvalent metal compound are dissolved by adding them to a solvent commonly used in the art. If necessary, a pH adjuster is added to adjust the pH. Other additives can be added according to the requirement, and the mixture is dissolved to form the preparation. When in use, the medicine is diluted properly to form a medicine liquid.
Alternatively, the compound (1) and the pH adjuster are added to a solvent to dissolve them. Adjusting pH, adding other additives, and dissolving to obtain preparation. Further, a polyvalent metal compound is added to a solvent to form a preparation. If necessary, the pH may be adjusted and other additives may be added. In application, the preparation is mixed and diluted to obtain medicinal liquid.
Example 2: lyophilized preparation + solution for dissolving containing polyvalent metal ion and/or solution for diluting containing polyvalent metal ion (containing metal in either or both)
Compound (1) and a pH adjuster are added to a solvent to dissolve them. The pH was adjusted as needed. Optionally adding other additives, dissolving, and freeze drying to obtain preparation. When in use, the polyvalent metal compound is redissolved by a solution containing the polyvalent metal compound, and the solution is diluted properly to form a liquid medicine.
Alternatively, the lyophilized preparation is dissolved in a solution for dissolving, and diluted with a diluent containing polyvalent metal ions to obtain a medicinal solution.
Alternatively, the solution containing the pH adjuster may be redissolved/diluted to obtain a neutral (pH) solution.
Example 3: freeze-dried preparation containing polyvalent metal ion and solution for dissolution
The compound (1) and the polyvalent metal compound are added to a solvent to dissolve them. The pH was adjusted as needed. Optionally adding other additives, dissolving, and freeze drying to obtain preparation. When in use, the medicine is redissolved and diluted properly to form a medicine liquid.
Alternatively, the acidic (pH) drug solution may be prepared by redissolving/diluting the solution with a pH adjuster.
The drug solution of the present invention can effectively alleviate troubles with the administration site of the drug solution, particularly, blood vessels.
When the drug solution of the present invention is used as a human pharmaceutical, the dose varies depending on the age, body weight, type of infectious bacteria, degree of infection, etc., and is 50mg to 1g, preferably 100mg to 800mg (based on the dose of the compound (1)) per day for an adult. In addition, when used in animals, the amount administered varies depending on the size of the animal to be treated, and the amount per day is 1 to 200mg, preferably 5 to 1000mg (based on the amount of the compound (1) administered) per 1kg of the body weight of the animal. The daily dose can be administered once a day, or 2-4 times.
Examples
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
7- [3- (R) - (1-Aminocyclopropyl) pyrrolidin-1-yl ] -1- [2- (S) -fluoro-1- (R) -cyclopropyl ] -1, 4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid was used as compound (1).
EXAMPLE 1 lyophilized preparation
To water for injection (25L) was added 1mol/L hydrochloric acid (1400 mL). Compound (1) (600g) was dissolved in the aqueous solution, and 1mol/L hydrochloric acid was added to adjust the pH to 3.4. To this solution, water for injection was added to adjust the content of compound (1) to 20 mg/mL. The solution was filled into containers 10mL each time, freeze-dried and sealed.
EXAMPLE 2 solution for dissolution (magnesium chloride solution)
Magnesium chloride (2.67g) was dissolved in water for injection, and water for injection was added thereto to make 500 mL.
EXAMPLE 3 solution in which the lyophilized preparation was redissolved and then diluted
The lyophilized preparation obtained in example 1 was redissolved with the magnesium chloride solution (10mL) obtained in example 2, and added to physiological saline (200mL) to be mixed.
EXAMPLE 4 solution for dissolution (magnesium chloride-mannitol solution)
Magnesium chloride (5.34g) and mannitol (10g) were dissolved in water for injection, and water for injection was added thereto to 1000 mL.
EXAMPLE 5 solution prepared by dissolving lyophilized preparation again and then diluting
The lyophilized preparation obtained in example 1 was redissolved with the magnesium chloride-mannitol solution (10mL) obtained in example 4, and added to physiological saline (200mL) for mixing.
EXAMPLE 6 solution for dissolution (magnesium chloride solution)
Magnesium chloride (3738mg) was dissolved in water for injection (630mL) and adjusted to 5.34mg/mL with water for injection. The aqueous solution was filtered through a membrane filter, and 10mL portions of the solution were filled into a container, which was sealed and terminally sterilized at 121 ℃ for 20 minutes.
EXAMPLE 7 solution for dissolution (magnesium chloride solution)
To water for injection (630mL) was added 1mol/L hydrochloric acid (2.2 mL). After dissolving magnesium chloride (3738mg), the pH was adjusted to 3.5 with 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide. Adjusted to 5.34mg/mL with water for injection. After filtering the solution through a membrane filter, 10mL portions of the solution were filled into a container, and the container was sealed and terminally sterilized at 121 ℃ for 20 minutes.
EXAMPLE 8 solution for dissolution (magnesium chloride-mannitol solution)
2.5g of magnesium chloride and 14.5g of mannitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-mannitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 9 solution for dissolution (magnesium chloride-mannitol solution)
1.5g of magnesium chloride and 16.5g of mannitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-mannitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 10 solution for dissolution (magnesium chloride-mannitol solution)
650mg of magnesium chloride and 18.5g of mannitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-mannitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 11 solution for dissolution (magnesium chloride-sorbitol solution)
2.5g of magnesium chloride and 14.5g of sorbitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-sorbitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 12 solution for dissolution (magnesium chloride-sorbitol solution)
1.5g of magnesium chloride and 16.5g of sorbitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-sorbitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 13 solution for dissolution (magnesium chloride-sorbitol solution)
650mg of magnesium chloride and 18.5g of sorbitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 2.5, 3.5 or 4.5 with hydrochloric acid. Water was added precisely to 500 mL. The magnesium chloride-sorbitol solution was filtered through a filter, and the solution was packed in a container in 10mL portions, sealed, and sterilized at 121 ℃ for 20 minutes.
EXAMPLE 14 dilution of lyophilized preparation after redissolution (magnesium chloride-mannitol solution)
2.5g of magnesium chloride and 14.5g of mannitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 3.5 with hydrochloric acid. Water was added precisely to 500mL and filtered through a filter. The lyophilized preparation obtained in example 1 was redissolved in 10mL of a filtered magnesium chloride-mannitol solution. After 2 lyophilized preparations obtained in example 1 were redissolved, 20mL of the redissolved solution was diluted to 100mL with physiological saline.
EXAMPLE 15 Diluent of lyophilized preparation (magnesium chloride-sorbitol solution)
2.5g of magnesium chloride and 14.5g of sorbitol were precisely weighed and dissolved in 450mL of water. The pH was adjusted to 3.5 with hydrochloric acid. Water was added precisely to 500mL and filtered through a filter. The lyophilized preparation obtained in example 1 was redissolved in 10mL of a filtered magnesium chloride-sorbitol solution. After 2 lyophilized preparations obtained in example 1 were redissolved, 20mL of the redissolved solution was diluted to 100mL with physiological saline.
EXAMPLE 16 dissolution solution (5% sorbitol solution containing magnesium chloride)
1.5g of magnesium chloride and 75g of sorbitol were precisely weighed, and water was precisely added to 1500 mL. The solution was filtered through a filter. The container was filled with 100mL of a 5% sorbitol solution containing magnesium chloride, sealed, and sterilized at 122 ℃ for 30 minutes.
EXAMPLE 17 dilution of lyophilized preparation after redissolution (5% sorbitol solution containing magnesium chloride)
20mL of a 5% sorbitol solution containing magnesium chloride was extracted from the preparation obtained in example 16, and 2 lyophilized preparations obtained in example 1 were re-dissolved in 10mL of a 5% sorbitol solution containing magnesium chloride, respectively. 20mL of the redissolved solution was returned to the formulation obtained in example 16.
EXAMPLE 18 redissolution of lyophilized preparation (magnesium chloride-mannitol solution)
0.3g of magnesium chloride and 3.3g of mannitol were precisely weighed and dissolved in 90mL of water. The pH was adjusted to 3.5 with hydrochloric acid. Water was added precisely to 100mL and filtered through a filter. The lyophilized preparation obtained in example 1 was redissolved in 10mL of a filtered magnesium chloride-mannitol solution. 10mL of the redissolved solution was diluted to 50mL with physiological saline.
EXAMPLE 19 dilution of lyophilized preparation after redissolution (magnesium chloride-sorbitol solution)
0.3g of magnesium chloride and 3.3g of sorbitol were precisely weighed and dissolved in 90mL of water. The pH was adjusted to 3.5 with hydrochloric acid. Water was added precisely to 100mL and filtered through a filter. The lyophilized preparation obtained in example 1 was redissolved in 10mL of a filtered magnesium chloride-sorbitol solution. 10mL of the redissolved solution was diluted to 50mL with physiological saline.
EXAMPLE 20 solution for dissolution (5% sorbitol solution containing magnesium chloride)
0.18g of magnesium chloride and 15g of sorbitol were precisely weighed, and water was precisely added to 300 mL. The solution was filtered through a filter. The container was filled with 50mL of a 5% sorbitol solution containing magnesium chloride, sealed, and sterilized at 122 ℃ for 30 minutes.
EXAMPLE 21 dilution of lyophilized preparation after redissolution (5% sorbitol solution containing magnesium chloride)
10mL of a 5% sorbitol solution containing magnesium chloride was extracted from the formulation obtained in example 20, and the lyophilized formulation obtained in example 1 was redissolved. The re-dissolved solution was returned to the formulation obtained in example 20.
[ preparation example 1]
D-sorbitol (6g) and magnesium chloride (1.05g) were dissolved in water for injection (100 mL). After 0.5mol/L hydrochloric acid (0.75mL) was added to the solution, compound (1) (3.0g) was dissolved. Then, 0.5mol/L hydrochloric acid was added to adjust the pH to 6.0, and then water for injection was added thereto to 150 mL.
[ preparation example 2]
40 parts of the solution of formulation example 1 and 60 parts of physiological saline were mixed to form a drug solution (concentration of compound (1): 8 mg/mL).
[ preparation example 3]
To compound (1) (200mg) were added a 10 w/v% aqueous mannitol solution (3.5mL) and a 2.5 w/v% aqueous magnesium chloride solution (2.8mL) to dissolve compound (1), followed by addition of water for injection (3.7 mL).
[ preparation example 4]
The solution of formulation example 3 (7mL) and physiological saline (10.5mL) were mixed.
[ preparation example 5]
The solution of preparation example 4 (6mL) and physiological saline (6mL) were mixed.
[ preparation example 6]
To compound (1) (200mg) were added a 10 w/v% aqueous mannitol solution (4mL) and a 2.5 w/v% aqueous magnesium chloride solution (2.12mL) to dissolve compound (1), followed by addition of water for injection (3.88 mL).
[ preparation example 7]
The solution of preparation example 6 (7mL) and physiological saline (10.5mL) were mixed.
[ preparation example 8]
The solution of preparation example 7 (6mL) and physiological saline (6mL) were mixed.
[ preparation example 9]
Water for injection (5mL) was added to the lyophilized preparation of example 1 for redissolution. To the solution were added 10 w/v% mannitol aqueous solution (2mL), 2.5 w/v% magnesium chloride aqueous solution (2.8mL) and water for injection (0.2 mL). The solution (7mL) was mixed with physiological saline (10.5 mL).
[ preparation example 10]
The solution of preparation example 9 (6mL) and physiological saline (6mL) were mixed.
[ preparation example 11]
Water for injection (5mL) was added to the lyophilized preparation of example 1 for redissolution. To this solution were added 10 w/v% mannitol aqueous solution (2.5mL), 2.5 w/v% magnesium chloride aqueous solution (2.12mL) and water for injection (0.38 mL).
[ preparation example 12]
The solution of preparation example 11 (7mL) and physiological saline (10.5mL) were mixed.
[ preparation example 13]
The solution of preparation example 12 (7mL) and physiological saline (6mL) were mixed.
[ preparation example 14]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, to this solution (23mL) were added 12.72 w/v% magnesium chloride aqueous solution (0.5mL), water for injection (0.5mL), 10 w/v% mannitol-containing physiological saline (8.4mL), and physiological saline (27.6mL) and mixed.
[ preparation example 15]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, 12.72 w/v% magnesium chloride aqueous solution (0.25mL), water for injection (0.25mL), 10 w/v% mannitol-containing physiological saline (4.2mL) and physiological saline (43.8mL) were added to 11.5mL (total amount after fine adjustment: 11.85mL) of the solution, and mixed, and the concentration of the compound (1) was fine adjusted.
[ preparation example 16]
To compound (1) (4.174g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 200 mL. Then, to this solution (46mL) were added 12.72 w/v% magnesium chloride aqueous solution (1mL), water for injection (1mL), physiological saline (16.8mL) containing 10 w/v% mannitol, and physiological saline (55.2mL) and mixed.
[ preparation example 17]
After adding physiological saline (40mL) to 40mL (total amount after fine adjustment: 40.46mL) of the solution of preparation example 16 and mixing, the concentration of compound (1) was fine-adjusted.
[ preparation example 18]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, to 23mL (total amount after fine adjustment: 23.58mL) of this solution were added 12.72 w/v% aqueous magnesium chloride solution (1.0mL), 10 w/v% mannitol-containing physiological saline (7.2mL) and physiological saline (28.8mL) and mixed, and the concentration of compound (1) was fine adjusted.
[ preparation example 19]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, to 11.5mL (total amount after a minute: 11.85mL) of this solution were added 12.72 w/v% aqueous magnesium chloride solution (0.5mL), 10 w/v% mannitol-containing physiological saline (3.6mL) and physiological saline (44.4mL) and mixed, and the compound was added
(1) The concentration of (c) was finely adjusted.
[ preparation example 20]
To compound (1) (4.174g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 200 mL. Then, to this solution (46mL) were added 12.72 w/v% magnesium chloride aqueous solution (2mL), 10 w/v% mannitol-containing physiological saline (14.4mL), and physiological saline (57.6mL) and mixed.
[ preparation example 21]
After adding physiological saline (40mL) to 40mL (total amount after fine adjustment: 40.46mL) of the solution of preparation example 20 and mixing, the concentration of compound (1) was fine-adjusted.
[ preparation example 22]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, to this solution (23mL) were added 33.6 w/v% magnesium chloride aqueous solution (1.0mL), 10 w/v% mannitol-containing physiological saline (2.4mL) and physiological saline (33.6mL) and mixed.
[ preparation example 23]
To compound (1) (3.168g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 151.8 mL. Then, 33.6 w/v% magnesium chloride aqueous solution (0.5mL), 10 w/v% mannitol-containing physiological saline (1.2mL) and physiological saline (46.8mL) were added to 11.5mL (11.85mL) and mixed.
[ preparation example 24]
To compound (1) (4.174g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 200 mL. Then, to this solution (34.5mL) were added 33.6 w/v% magnesium chloride aqueous solution (1.5mL), 10 w/v% mannitol-containing physiological saline (3.6mL) and physiological saline (50.4mL) and mixed.
[ preparation example 25]
Physiological saline (40mL) was added to the solution (40mL) of preparation example 24 and mixed.
[ preparation example 26]
To compound (1) (4.592g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 220 mL. Then, to this solution (51.75mL) were added 12.72 w/v% magnesium chloride aqueous solution (0.5625mL), water for injection (1.6875mL), 10 w/v% mannitol-containing physiological saline (19.98mL) and physiological saline (98.82mL) and mixed.
[ preparation example 27]
Physiological saline (56mL) was added to the solution (56mL) of preparation example 26 and mixed.
[ preparation example 28]
To compound (1) (4.383g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 210 mL. Then, to this solution (48.3mL) were added 13.25 w/v% magnesium chloride aqueous solution (0.504mL), water for injection (1.596mL), 10 w/v% mannitol-containing physiological saline (18.648mL), and physiological saline (92.232mL) and mixed.
[ preparation example 29]
Physiological saline (53mL) was added to the solution (53mL) of preparation example 28, and the mixture was mixed.
[ preparation example 30]
To compound (1) (5.009g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 240 mL. Then, to this solution (57.5mL) were added 13.25 w/v% magnesium chloride aqueous solution (0.6mL), water for injection (1.9mL), 10 w/v% mannitol-containing physiological saline (22.2mL) and physiological saline (109.8mL) and mixed.
[ preparation example 31]
Physiological saline (64mL) was added to the solution (64.5mL) of preparation example 30, and the mixture was mixed.
[ preparation example 32]
To compound (1) (4.592g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 220 mL. Then, to this solution (51.75mL) were added 12.72 w/v% magnesium chloride aqueous solution (1.125mL), water for injection (1.125mL), 10 w/v% mannitol-containing physiological saline (18.9mL) and physiological saline (99.9mL) and mixed.
[ preparation example 33]
Physiological saline (56mL) was added to the solution (56mL) of preparation example 32, and the mixture was mixed.
[ preparation example 34]
To compound (1) (4.383g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 210 mL. Then, to this solution (48.3mL) were added 13.25 w/v% magnesium chloride aqueous solution (1.008mL), water for injection (1.092mL), 10 w/v% mannitol-containing physiological saline (17.64mL) and physiological saline (93.24mL) and mixed.
[ preparation example 35]
Physiological saline (53mL) was added to the solution (53mL) of preparation example 34 and mixed.
[ preparation example 36]
To compound (1) (5.009g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 240 mL. Then, to this solution (57.5mL) were added 13.25 w/v% magnesium chloride aqueous solution (1.2mL), water for injection (1.3mL), 10 w/v% mannitol-containing physiological saline (21mL) and physiological saline (111mL) and mixed.
[ preparation example 37]
Physiological saline (64mL) was added to the solution (64mL) of preparation example 36 and mixed.
[ preparation example 38]
To compound (1) (4.592g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 220 mL. Then, to this solution (51.75mL) were added 12.72 w/v% magnesium chloride aqueous solution (2.25mL), 10 w/v% mannitol-containing physiological saline (16.2mL) and physiological saline (102.6mL) and mixed.
[ preparation example 39]
Physiological saline (56mL) was added to the solution (56mL) of preparation example 38, and the mixture was mixed.
[ preparation example 40]
To compound (1) (4.383g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 210 mL. Then, to 48.3mL (total amount after fine adjustment: 49mL) of this solution were added 13.25 w/v% magnesium chloride aqueous solution (2.016mL), water for injection (0.084mL), 10 w/v% mannitol-containing physiological saline (15.12mL) and physiological saline (95.76mL) and mixed, and the concentration of compound (1) was fine-adjusted.
[ preparation example 41]
Physiological saline (53mL) was added to the solution (53mL) of preparation example 40, and the mixture was mixed.
[ preparation example 42]
To compound (1) (5.009g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 240 mL. Then, to this solution (57.5mL) were added 13.25 w/v% magnesium chloride aqueous solution (2.4mL), water for injection (0.1mL), 10 w/v% mannitol-containing physiological saline (18mL), and physiological saline (114mL) and mixed.
[ preparation example 43]
Physiological saline (64mL) was added to the solution (64mL) of preparation example 42 and mixed.
[ COMPARATIVE EXAMPLE 1]
Sodium chloride (1.656g) was dissolved in water for injection (150 mL). After 0.5mol/L hydrochloric acid (22.425mL) was added to the solution, compound (1) (5.0g) was dissolved. Then, 0.5mol/L aqueous sodium hydroxide solution was added to adjust the pH to 4.5, and 250mL of water for injection was added thereto. 40 parts of this solution and 60 parts of physiological saline (concentration of compound (1): 8mg/mL) were mixed.
[ COMPARATIVE EXAMPLE 2]
To compound (1) (4.592g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 220 mL. Then, to this solution (51.75mL) were added water for injection (2.25mL), physiological saline (21.6mL) containing 10 w/v% mannitol, and physiological saline (97.2mL) and mixed (pH 4.5).
[ control example 3]
Physiological saline (56mL) was added to the solution (56mL) of comparative example 2, and the mixture was mixed (pH 4.7).
[ comparative example 4]
To compound (1) (4.383g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 210 mL. Then, to this solution (48.3mL) were added water for injection (2.1mL), physiological saline (20.16mL) containing 10 w/v% mannitol, and physiological saline (90.72mL) and mixed (pH 4.2).
[ COMPARATIVE EXAMPLE 5]
Physiological saline (53mL) was added to the solution (53mL) of comparative example 4, and the mixture was mixed (pH 4.5).
[ control example 6]
To compound (1) (5.009g), 0.06mol/L hydrochloric acid was added to dissolve the compound, and 0.06mol/L hydrochloric acid was further added to adjust the pH to 3.5. To this solution was added water for injection to 240 mL. Then, to this solution (57.5mL) were added water for injection (2.5mL), physiological saline (24mL) containing 10 w/v% mannitol, and physiological saline (108mL) and mixed (pH 4.0).
[ comparative example 7]
Physiological saline (64mL) was added to the solution (64mL) of comparative example 6, and the mixture was mixed (pH 4.3).
[ test example 1] (rat intravenous repeated administration test)
The drug solution of formulation example 2, the drug solution of control example 1 and physiological saline were intravenously administered to rats over 9 days (amount of drug solution administered: 10 mL/kg/day, administration rate: 1 mL/min), and animals were sacrificed on the second day of the last administration day to evaluate local disorders. The right tail vein was used in principle for administration, and the left tail vein was used when administration was impossible. The evaluation was performed using the sum of the number of times the drug could not be administered from the right tail vein and the score of the histological examination results (higher score indicates stronger disorder). The results are shown in Table 1.
[ test example 2] (Rabbit intravenous repeated administration test)
< method of intravenous repeated administration to rabbits >
The injection needle was inserted into the vein of the edge of the rabbit ear, and the part of the vein (site A) into which the needle had been inserted was grasped with a forceps. After injection of the drug solution (0.05mL), the vein 3cm from the site A to the central side was grasped with forceps. After the injection of the remaining drug solution (0.05mL), the needle was removed, and after 3 minutes, the forceps were released.
The chemical solution of preparation example 2, the chemical solution of control example 1 and physiological saline (amount of administered chemical solution: 0.1 mL/rabbit/day) were intravenously administered over 14 days according to the above-described repeated intravenous administration method for rabbits (1), and animals were sacrificed on the next day of the last administration day for evaluation. Assessment the score for the histological findings was used (higher score indicates stronger lesions). The results are shown in Table 1.
[ test example 3] (test for intramuscular Single administration in rabbits)
The liquid medicine of preparation example 2, the liquid medicine of control example 1 and physiological saline (amount of liquid medicine given: 1 mL/site) were each administered in a single dose in the lateral vastus of the thigh of a rabbit, and animals were sacrificed 2 days after the final administration for evaluation.
Evaluation was performed using the sum of the ratio of the serum CK value after administration to the serum CK value before administration and the score of the histological examination result (higher score indicates stronger disorder). The results are shown in Table 1.
Table 1 evaluation results of local disorders 1
| Test example 1 | Test example 2 | Test example 3 | |
| Preparation example 2 | 2.2 | 0 | 18.8 |
| Comparative example 1 | 8.4 | 2.0 | 25.2 |
| Physiological saline | 0.4 | 0 | 13.8 |
As is apparent from Table 1, in any of test examples 1 to 3, the medical solution of the present invention had lower barrier properties than the medical solution of comparative example 1, and was almost equal to physiological saline.
[ test example 4] (rat intravenous 2 weeks repeat administration test)
Formulation examples 27, 29, 31, 33, 35, 37, 39, 41, 43, 26, 28, 30, 32, 34, 36, 38, 40, 42 and control examples 2, 4, 6, 3, 5, 7 were administered 1 time per day into the tail vein of rats, and the administration was repeated 14 times (amount of liquid drug administered: 1 mL/kg/day, administration rate: 1 mL/min, 1 group of 5 animals). The administration site at the time of sacrifice was visually observed and examined histologically (7 specimens were prepared from the tail as the administration site for each 1, and the tissue change was scored. 0: no change, 1: mild, 2: moderate, 3: severe). The results are shown in Table 2. Values for histological examination represent mean values.
As is apparent from Table 2, it was confirmed that the drug solutions of the present invention (formulation examples 26, 28, and 30) containing magnesium chloride reduced the frequency of the above-mentioned symptoms (erosion (1 example in 5)) while the drug solutions (control examples 2, 4, and 6) at high concentrations (concentration of compound (1): 6.25mg/mL) resulted in erosion (2 examples in 5 examples), scabbing (1 example in 5 examples), and swelling (5 examples in 5 examples) at the administration site.
In particular, when the amount of magnesium chloride added is 0.828mg/mL or more, the above-mentioned symptoms are not observed at all.
The drug solution of the present invention showed a lower value than the control example in both necrosis and degeneration of the vascular wall and in all the tissue changes. In particular, the drug solution of the present invention at a low concentration (concentration of the compound (1): 3.125mg/mL) did not cause any necrosis or denaturation of the vascular wall at all.
Therefore, the drug solution of the present invention containing 0.01 to 0.7 times the molar ratio of magnesium can reduce the local vascular disorder of the compound (1) without depending on the pH of the drug solution.
TABLE 2 evaluation results of local disorders 2 (test example (4))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Medicinal liquid | Visual observation of the results | Organization survey result score-1*1 | Organization survey result score-2*2 |
| 3.125 | 0 | 0 | Comparative examples (3), (5) and (7) | Without change | 0.20 | 2.46 |
| 3.125 | 0.207 | 0.13 | Preparation examples (27) (29) (31) | Without change | 0 | 1.51 |
| 3.125 | 0.414 | 0.26 | Preparation examples (33) (35) (37) | Without change | 0 | 1.71 |
| 3.125 | 0.828 | 0.52 | Preparation examples (39) (41) (43) | Without change | 0 | 1.66 |
| 6.25 | 0 | 0 | Comparative examples (2) (4) (6) | Scaling of erosions (2 in 5 cases) (1 in 5 cases) swelling (5 in 5 cases) | 0.66 | 7.17 |
| 6.25 | 0.414 | 0.13 | Preparation examples (26) (28) (30) | Erosion (1 in 5 cases) | 0 | 1.83 |
| 6.25 | 0.828 | 0.26 | Preparation examples (32) (34) (36) | Without change | 0.03 | 1.97 |
| 6.25 | 1.66 | 0.52 | Preparation examples (38) (40) (42) | Without change | 0 | 1.43 |
Score 1-1: average of scores for necrosis and degeneration of vascular wall
Score 2-2: average of scores for all tissue changes
[ COMPARATIVE EXAMPLE 8]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to the solution (1mL) were added physiological saline (0.4mL) containing 10 w/v% mannitol and physiological saline (8.6mL) and mixed.
[ preparation example 44]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (1mL) were added 13.25% magnesium chloride aqueous solution (0.01mL), physiological saline (0.37mL) containing 10 w/v% mannitol, and physiological saline (8.62mL) and mixed.
[ preparation example 45]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (1mL) were added 13.25% magnesium chloride aqueous solution (0.02mL), physiological saline (0.35mL) containing 10 w/v% mannitol, and physiological saline (8.63mL) and mixed.
[ preparation example 46]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (1mL) were added 13.25% magnesium chloride aqueous solution (0.04mL), physiological saline (0.3mL) containing 10 w/v% mannitol, and physiological saline (8.66mL) and mixed.
[ test example 5] (test for intramuscular Single administration in rabbits)
The liquid medicines of preparation examples 44, 45 and 46, the liquid medicine of control example 8 and physiological saline were administered in a single dose in the lateral vas communis of the thigh of rabbits (amount of liquid medicine administered: lmL/site). Animals were sacrificed 2 days after administration, and sites of administration (extirpated latissimus muscle and surrounding lesions were scored visually for tissue changes.0: no change, 1: very mild, 2: mild, 3: moderate, 4: severe) and histological examination (muscle was collected, prepared into specimens, and tissue changes were scored for 0: no change, 1: very mild, 2: mild, 3: moderate, 4: severe). Further, the ratio of the serum CK value after administration to the serum CK value before administration was calculated. The results are shown in Table 3. The numerical values of the scores represent the mean values.
As is apparent from Table 3, the medical solution of the present invention to which magnesium chloride was added in an amount of 0.27mg/mL (molar ratio to the compound (1) was 0.26) or more exhibited a score lower than that of the comparative example as a result of visual observation and histological examination.
Table 3 evaluation results of local disorder (test example (5))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Medicinal liquid | Visual observation score-1 | Organization survey result score-2 |
| 0 | 0 | - | Physiological saline | 0.5 | 3.5 |
| 2 | 0 | 0 | Comparative example (8) | 3.0 | 6.8 |
| 2 | 0.13 | 0.13 | Preparation example (44) | 3.3 | 6.8 |
| 2 | 0.27 | 0.26 | Preparation example (45) | 1.8 | 6.0 |
| 2 | 0.53 | 0.52 | Preparation example (46) | 0.5 | 3.0 |
[ control example 9]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to the solution (43.75mL) were added physiological saline (17.5mL) containing 10 w/v% mannitol and physiological saline (78.75mL) and mixed.
[ preparation example 47]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to the solution (43.75mL) were added physiological saline (0.03125mL) containing 11.2% magnesium chloride, physiological saline (17.45625mL) containing 10 w/v% mannitol, and physiological saline (78.7625mL) and mixed.
[ preparation example 48]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to the solution (43.75mL) were added physiological saline (0.0625mL) containing 11.2% magnesium chloride, physiological saline (17.36875mL) containing 10 w/v% mannitol, and physiological saline (78.81875mL) and mixed.
[ preparation example 49]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (43.75mL) were added physiological saline (0.125mL) containing 11.2% magnesium chloride, physiological saline (17.2375mL) containing 10 w/v% mannitol, and physiological saline (78.8875mL) and mixed.
[ preparation example 50]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (43.75mL) were added physiological saline (0.25mL) containing 11.2% magnesium chloride, physiological saline (16.93125mL) containing 10 w/v% mannitol, and physiological saline (79.06875mL) and mixed.
[ preparation example 51]
0.06mol/L hydrochloric acid was added to the compound (1) to dissolve it, and then 0.06mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the concentration of compound (1) to 20 mg/mL. Then, to this solution (43.75mL) were added physiological saline (0.5mL) containing 11.2% magnesium chloride, physiological saline (16.31875mL) containing 10 w/v% mannitol, and physiological saline (79.43125mL) and mixed.
[ test example 6] (test for intravenous repeated administration to rat)
The drug solutions of formulation examples 47, 48, 49, 50 and 51, control example 9 and physiological saline were administered 1 time per day 1 time into the tail vein of rats, and 14 repeated administrations were carried out (amount of drug solution administered: 10 mL/kg/day, administration rate: 1 mL/min, 1 group of 5 animals). The site of administration at the time of sacrifice was visually observed and examined histologically (5 specimens were prepared from the tail of each 1 as the administration site, and the tissue change was scored higher. The results are shown in Table 4. Values for histological examination represent mean values.
As can be seen from table 4, the control example (control example 9) caused swelling (4 in 5 examples) and erythema (1 in 5 examples), but the above-mentioned symptoms were completely observed when the drug solutions of the present invention (formulation examples 48, 49, 50 and 51) to which magnesium chloride was added in an amount of 0.05mg/mL or more (molar ratio to compound (1) was 0.016) were used. The drug solution of the present invention showed a lower value than the control example in both necrosis and degeneration of the vascular wall and in all the tissue changes. In particular, the drug solution of the present invention containing 0.4mg/mL (molar ratio to the compound (1) is 0.13) of magnesium chloride does not cause any necrosis or denaturation of the vascular wall at all.
Table 4 evaluation results of local disorders (test example (6))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Medicinal liquid | Visual observation of the results | Organization survey result score-1*1 | Organization survey result score-2*2 |
| 0 | 0 | - | Physiological saline | Without change | 0 | 4.32 |
| 6.25 | 0 | 0 | Comparative example (9) | Erythema (1 in 5 cases) swelling (4 in 5 cases) | 1.00 | 10.80 |
| 6.25 | 0.025 | 0.008 | Preparation example (47) | Scab (1 in 5 cases) swelling (5 in 5 cases) | 0.64 | 9.40 |
| 6.25 | 0.05 | 0.016 | Preparation example (48) | Without change | 0.32 | 8.00 |
| 6.25 | 0.1 | 0.031 | Preparation example (49) | Without change | 0.52 | 8.32 |
| 6.25 | 0.2 | 0.063 | Preparation example (50) | Without change | 0.40 | 6.68 |
| 6.25 | 0.4 | 0.13 | Preparation example (51) | Without change | 0.00 | 5.72 |
Score 1-1: average of scores for necrosis and degeneration of vascular wall
Score 2-2: average of scores for all tissue changes
[ control example 10]
(1): to compound (1) (8.76g or 8.77g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 420 mL. Then, to this solution (132.25mL) were added water for injection (5.75mL), physiological saline (55.2mL) containing 10 w/v% mannitol, and physiological saline (248.4mL) and mixed.
(2): to compound (1) (7.30g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 350 mL. Then, to this solution (109.25mL) were added water for injection (4.75mL), physiological saline (45.6mL) containing 10 w/v% mannitol, and physiological saline (205.2mL) and mixed.
Comparative example 11
The solution of comparative example 10 and an equal amount of physiological saline were mixed.
[ preparation example 52]
(1): to compound (1) (8.76g or 8.77g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 420 mL. Then, to this solution (138mL) were added water for injection (4.5mL), a 12.72% aqueous solution of magnesium chloride (1.5mL), a physiological saline solution containing 10 w/v% mannitol (53.28mL) and a physiological saline solution (263.52mL) and mixed.
(2): to compound (1) (7.30g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 350 mL. Then, to this solution (115mL) were added water for injection (3.75mL), a 12.72% aqueous solution of magnesium chloride (1.25mL), a physiological saline solution containing 10 w/v% mannitol (44.4mL) and a physiological saline solution (219.6mL) and mixed.
[ preparation example 53]
The solution of preparation example 52 and an equal amount of physiological saline (160mL) were mixed.
[ preparation example 54]
(1): to compound (1) (8.76g or 8.77g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 420 mL. Then, to this solution (138mL) were added 12.72% magnesium chloride aqueous solution (6mL), physiological saline (43.2mL) containing 10 w/v% mannitol, and physiological saline (273.6mL) and mixed.
(2): to compound (1) (7.30g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 350 mL. Then, to this solution (115mL) were added a 12.72% magnesium chloride aqueous solution (5mL), a physiological saline solution (36.0mL) containing 10 w/v% mannitol, and a physiological saline solution (228.0mL) and mixed.
[ preparation example 55]
The solution of preparation example 54 and an equal amount of physiological saline (160mL) were mixed.
[ test example 7] (monkey intravenous 4 weeks repeat administration test)
The liquid drugs of preparation examples 52, 53, 54 and 55, control examples 10 and 11 and an aqueous solution of magnesium chloride (magnesium chloride concentration: 1.66mg/mL, pH4) were administered 1 time a day into the radial lateral cutaneous vein or saphenous vein of monkeys, respectively, for 28 repeated administrations (amount of liquid drug administered: 10 mL/kg/day, administration rate: 5 mL/min, 1 group of 2 animals). Histological examination of the administration site at the time of sacrifice was performed (1 limb 2 from the left and right limbs as the administration site, 8 total parts per 1 monkey were prepared and scored for tissue change, and a higher score indicates stronger disorder). The results are shown in Table 5. Values for histological examination represent mean values.
As is clear from Table 5, when a high concentration (concentration of the compound (1): 6.25mg/mL) of the drug solution was used for necrosis and degeneration of the vascular wall, the drug solutions of the present invention (preparation examples 52 and 54) to which magnesium chloride was added exhibited lower values than the control example (control example 10). In all the tissue changes, the drug solution of the present invention showed a value lower than that of the control example regardless of the concentration of the compound (1).
TABLE 5 evaluation results of local disorders (test example (7))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Medicinal liquid | Organization survey result score-1*1 | Organization survey result score-2*2 |
| 3.125 | 0 | 0 | Comparative example (11) | 0 | 2.14 |
| 3.125 | 0.21 | 0.13 | Preparation example (53) | 0 | 1.19 |
| 3.125 | 0.83 | 0.53 | Preparation example (55) | 0 | 1.50 |
| 6.25 | 0 | 0 | Comparative example (10) | 0.44 | 5.31 |
| 6.25 | 0.41 | 0.13 | Preparation example (52) | 0 | 3.25 |
| 6.25 | 1.66 | 0.53 | Preparation example (54) | 0 | 1.63 |
| 0 | 1. 66 | - | MgCl2Aqueous solution, pH4 | 0 | 1.38 |
Score 1-1: average of scores for necrosis and degeneration of vascular wall
Score 2-2: average of scores for all tissue changes
[ comparative example 12]
(1): to compound (1) (9.6g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 480 mL. Then, to the solution (50mL) were added physiological saline (20mL) containing 10 w/v% mannitol and physiological saline (90mL) and mixed.
(2): to compound (1) (6.8g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 340 mL. Then, to the solution (50mL) were added physiological saline (20mL) containing 10 w/v% mannitol and physiological saline (90mL) and mixed.
[ comparative example 13]
(1): to compound (1) (9.6g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 480 mL. Then, to the solution (50mL) were added physiological saline (20mL) containing 10 w/v% sorbitol and physiological saline (90mL) and mixed.
(2): to compound (1) (6.8g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 340 mL. Then, to the solution (50mL) were added physiological saline (20mL) containing 10 w/v% sorbitol and physiological saline (90mL) and mixed.
[ preparation example 56]
(1): to compound (1) (9.6g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mo1/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 480 mL. Then, to this solution (218.75mL) were added a 2.5% magnesium chloride aqueous solution (11.2mL), a physiological saline solution (81.594mL) containing 10 w/v% mannitol, and a physiological saline solution (388.456mL) and mixed.
(2): to compound (1) (6.8g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 340 mL. Then, to this solution (78.125mL) were added a 2.5% magnesium chloride aqueous solution (4mL), a physiological saline solution (29.141mL) containing 10 w/v% mannitol, and a physiological saline solution (138.734mL) and mixed.
[ preparation example 57]
(1): to compound (1) (9.6g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 480 mL. Then, to this solution (50mL) were added a 2.5% magnesium chloride aqueous solution (2.56mL), a physiological saline solution (18.65mL) containing 10 w/v% sorbitol, and a physiological saline solution (88.79mL) and mixed.
(2): to compound (1) (6.8g) was added 0.06mol/L hydrochloric acid to dissolve it, and then 0.06mol/L hydrochloric acid was added to adjust the pH to 3.5. To this solution was added water for injection to 340 mL. Then, to this solution (50mL) were added a 2.5% magnesium chloride aqueous solution (2.56mL), a physiological saline solution (18.65mL) containing 10 w/v% sorbitol, and a physiological saline solution (88.79mL) and mixed.
[ test example 8] (test for intravenous repeated administration to rat)
The drug solutions of preparation examples 56 and 57, control examples 12 and 13 and physiological saline adjusted to pH4 were administered 1 time a day into the tail vein of rats 1 time, and 14 repeated administrations were carried out (amount of drug solution administered: 10 mL/kg/day, administration rate: 1 mL/min, 1 group of 5 animals). The site of administration at sacrifice was examined anatomically and histologically (5 specimens were prepared from the tail of the site of administration for each 1, and the tissue change was scored higher, higher score indicating more severe disorder). The results are shown in tables 6 and 7. Values for histological examination represent mean values.
From table 6, it was confirmed that in the control examples (control examples 12 and 13), white spots, erythema, swelling, scabbing and erosion appeared at the administration site regardless of the kinds of the isotonic agents used, but when the liquid medicines of the present invention (preparation examples 55 and 56) to which magnesium chloride was added were used, swelling was confirmed in 1 of 5 examples, and no other symptoms were observed.
It is also confirmed from Table 7 that the drug solution of the present invention shows less than the values of the comparative examples in the necrosis and degeneration of the vascular wall and the total change of the tissue regardless of the kind of the isotonic agent used.
TABLE 6 evaluation of local disorder (visual observation) results (test example (8))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Isotonic agent | Medicinal liquid | Results of anatomical examination |
| 0 | 0 | 0 | - | Physiological saline, pH4 | Without change |
| 6.25 | 0 | 0 | Mannitol | Comparative example (12) | Erythema (1 in 5 cases) swelling (1 in 5 cases) scabbing (5 in 5 cases) erosion (2 in 5 cases) |
| 6.25 | 0.4 | 0.13 | Mannitol | Preparation example (56) | Without change |
| 6.25 | 0 | 0 | Sorbitol | Comparative example (13) | Erythema (1 in 5 cases) swelling (1 in 5 cases) scabbing (4 in 5 cases) scabbing (1 in 5 cases) erosion (1 in 5 cases) |
| 6.25 | 0.4 | 0.13 | Sorbitol | Preparation example (57) | Swelling (1 in 5 cases) |
TABLE 7 evaluation results of local disorders (test example (8))
| Concentration (mg/mL) of Compound (1) | MgCl2Concentration (mg/mL) | Adding MgCl in a molar ratio2Compound (1) | Isotonic agent | Medicinal liquid | Organization survey result score-1*1 | Organization survey result score-2*2 |
| 0 | 0 | 0 | - | Physiological saline, pH4 | 0 | 4.12 |
| 6.25 | 0 | 0 | Mannitol | Comparative example (12) | 0.60 | 12.32 |
| 6.25 | 0.4 | 0.13 | Mannitol | Preparation example (56) | 0.16 | 4.84 |
| 6.25 | 0 | 0 | Sorbitol | Comparative example (13) | 0.65 | 8.50 |
| 6.25 | 0.4 | 0.13 | Sorbitol | Preparation example (57) | 0.20 | 4.44 |
Score 1-1: average of scores for necrosis and degeneration of vascular wall
Score 2-2: average of scores for all tissue changes
The prescription of a lyophilized preparation containing the compound (1), particularly a lyophilized preparation containing no polyvalent metal which can be combined with the polyvalent metal-containing solution of the present application, was investigated.
[ lyophilized preparation 1]
To water for injection (800mL) was added 1mol/L hydrochloric acid (50 mL). Compound (1) (20g) was dissolved in the solution, and 0.1mol/L hydrochloric acid was added thereto to adjust the pH to 3.5. To this solution, water for injection was added to adjust the content of compound (1) to 20 mg/mL. The solution was filled into a container in 10mL portions, lyophilized according to the following procedure, and sealed.
i) The container filled with the compound (1) solution was placed in the shelf of a lyophilizer set at 5 c,
ii) the shelf temperature was continuously cooled to-40 ℃ at a cooling rate of 0.1 ℃/min.
iii) after the shelf temperature of-40 ℃ is kept for more than 3 hours,
iv) starting the reduced pressure treatment, setting the shelf temperature to-5 ℃ and keeping the shelf temperature for more than 3 hours.
v) setting the shelf temperature to 25 ℃ after the product temperature reaches above-5 ℃, and keeping the shelf temperature for more than 6 hours. During this time, the degree of vacuum was maintained at 1 Pa.
To the lyophilized preparation, 10mL of water for injection was added for dissolution. The re-dissolution took 236 seconds.
TABLE 8 preparation conditions of the lyophilized preparation
| Prescription | Proportion of Compound (1) [ mg/mL] | Amount of filling liquid [ mL] | Cooling temperature [ deg.C/min ]] | Primary drying | Secondary drying | ||
| Temperature [ deg.C ]] | Time [ hr] | Temperature [ deg.C ]] | Time [ hr] | ||||
| Freeze-dried preparation 1 | 20-0 | 10 | 0.1 | -5 | More than 30 | 25 | 6 or more |
[ detection of kindred substance and novel kindred substance ]
The lyophilized preparations prepared above were redissolved, and the presence or absence of a xenobiotic and the generation and amount of a new xenobiotic in the solution were measured. The edge-like substance is an impurity derived from a decomposition product of the compound (1), and the new edge-like substance is an impurity generated by a change in the compounding ratio with the additive.
The edge-like substances and the novel edge-like substances in 10. mu.L of the standard solution and the sample solution were measured under the HPLC conditions shown below. The results are shown in Table 9.
[ Standard solution ]
About 20mg of a standard of the compound (1) was weighed, and dissolved by adding the mobile phase B to obtain 50mL of a solution. The solution was filtered through a 0.45 μm filter, and the first 5mL of the filtrate was discarded, and the filtrate thereafter was used as a standard solution.
[ sample solution ]
The 1 ampoule was added with the same amount of water for injection as the filling liquid to redissolve. The solution was transferred to a 100mL volumetric flask and mobile phase B was accurately adjusted to 100 mL. This solution was weighed exactly 10mL, mobile phase B was added, and the solution was exactly 50 mL. The solution was filtered through a 0.45 μm filter, and the first 5mL of the filtrate was discarded, and the filtrate thereafter was used as a sample solution.
[10mM phosphate buffer ]
7.16g of disodium hydrogenphosphate 12 hydrate and 3.12g of sodium dihydrogenphosphate 2 hydrate were weighed, dissolved in 4L of water, and the solution was filtered through a 0.45 μm filter.
[ Mobile phase A ]
3L of 10mM phosphate buffer and 1L of acetonitrile were mixed.
[ Mobile phase B ]
1L of 10mM phosphate buffer and 3L of acetonitrile were mixed.
[ HPLC operating conditions ]
A detector: ultraviolet absorption photometer (292 nm wavelength)
Column: symmetry C18
Column temperature: 40 deg.C
Mobile phase: mobile phase a, mobile phase B and gradients thereof
Flow rate: about 1.0 mL/min
Solution injection amount: 10 μ L
Measuring time: 30 minutes
Automatic sampler washing liquid: water/acetonitrile (3: 7)
TABLE 9
| Prescription | Proportion of Compound (1) [ mg/mL] | Insoluble impurities1)60℃2W | Novel xenogenic substances | Total amount of kindred substances (% by area) | |
| Initial stage | 60℃2W | ||||
| Freeze-dried preparation 1 | 20 | - | Is free of | 0.85 | 1.32 |
| 1) Insoluble impurities | -: no + -: 10 less than full/container (50 μm to 100 μm) +: more than 10 per container (50-100 μm) |
As is clear from table 9, as a lyophilized preparation containing compound (1), a preparation having good properties can be prepared with a composition of compound (1) and an appropriate amount of a pH adjuster.
[ evaluation of the concentration of the drug solution for lyophilization ]
Liquid medicines having different concentrations of compound (1) were prepared according to the formulation example of lyophilized preparation 1, and lyophilized, and the concentration of compound (1) in the liquid medicine used for preparing the lyophilized preparation was examined. The results are shown in Table 10. From this table, it is clear that the content concentration of the compound (1) has an influence on the caking property of the lyophilized preparation.
That is, it was found that when the concentration of the compound (1) in the drug solution was 10mg/mL or more, the caking property as a lyophilized preparation was good.
TABLE 10 evaluation of agglomeration concentration of Compound (1) lyophilized preparation
| Concentration of Compound (1) in liquid medicine [ mg/mL] | Agglomeration of1) |
| 20mg/mL | 5/5 |
| 15mg/mL | 5/5 |
| 10mg/mL | 5/5 |
| 5mg/mL | 4/5 |
| 2.5mg/mL | 4/5 |
| 1.25mg/mL | 0/5 |
1) Number of clumps/number of samples
Therefore, the concentration of the compound (1) in the drug solution containing the compound (1) for preparing the lyophilized preparation of the compound (1) may be about 5mg/mL or more, preferably 10mg/mL or more, more preferably 15mg/mL or more, particularly preferably 20mg/mL or more.
[ evaluation of pH of lyophilized liquid medicine 1]
The change in solubility of the compound (1) based on the change in pH of the drug solution was repeatedly measured according to a conventional method. The results are shown in Table 11.
TABLE 11 solubility of Compound (1) in Water
| pH | When modulating | 1W |
| Solubility in water | ||
| 25℃ | ||
| pH3.5 | ≥20.1mg/mL | ≥20.1mg/mL |
| pH4.0 | ≥20.1mg/mL | 19.6mg/mL |
| pH4.5 | ≥20.1mg/mL | 20.1mg/mL |
| pH5.0 | - | 18.7mg/mL |
| pH5.5 | - | 4.8mg/mL |
| pH6.0 | - | 0.7mg/mL |
| 5℃ | ||
| pH3.5 | ≥20.1mg/mL | ≥19.6mg/mL |
| pH4.0 | ≥20.1mg/mL | 19.0mg/mL |
| pH4.5 | ≥20.0mg/mL | 18.8mg/mL |
| pH5.0 | - | 18.4mg/mL |
| pH5.5 | - | 5.4mg/mL |
| pH6.0 | - | 0.7mg/mL |
As is clear from table 11, if the liquid is a solution having a pH of about 5 or less, a liquid medicine having a concentration sufficient to cause agglomeration of the lyophilized preparation can be obtained. That is, the concentration of the compound (1) is preferably 10mg/mL or more, and the pH may be about 5 or less. In order to ensure a concentration of 20mg/mL or more, the pH may be set to 4.5 or less.
That is, the pH of the drug solution used for preparing the lyophilized preparation of compound (1) may be 5.5 or less, preferably 5 or less, more preferably 4.5 to 2.5.
[ evaluation of pH value of drug solution for lyophilization 2]
The stability of compound (1) was investigated by preparing a lyophilized preparation from drug solutions having different pH values according to the procedure of lyophilized preparation 1. The results are shown in Table 12.
Table 12 lyophilized formulation stability test results
| Name of sample | Content (wt.) | Xenogenic substances | |||
| Relative to the display amount% | Relative to the initial amount% | Total amount% | pH | Appearance of the product | |
| pH2.5 initial pH2.560 ℃ 1 WpH2.560 ℃ 2W | 95.396.091.9 | 100.0100.896.5 | 0.920.951.10 | 2.892.973.05 | Yellow and yellow |
| pH3.5 initial pH3.560 ℃ 1 WpH3.560 ℃ 2W | 96.596.096.2 | 100.099.499.7 | 0.930.961.17 | 3.733.813.86 | Yellow and yellow |
| pH4.5 initial pH4.560 ℃ 1 WpH4.560 ℃ 2W | 93.191.193.5 | 100.097.8100.5 | 0.931.131.31 | 4.474.514.53 | Yellow and yellow |
As is clear from table 12, the compound (1) exhibited sufficient stability in the lyophilized preparation prepared from the liquid drug solution containing the compound (1) and having ph2.5 to ph 4.5.
[ formulation example of lyophilized preparation of Compound (1) ]
The formulation examples of the lyophilized preparation of compound (1) obtained from the above-mentioned examination results are shown in table 13.
TABLE 13 Freeze-dried formulation recipe
| Purpose of use | Composition (I) | 1 ampoule middle (10mL) |
| Main agent | Compound (1) | 200mg |
| pH regulator | Hydrochloric acid | Moderate amount (pH2.5 to 4.5) |
| pH regulator | Sodium hydroxide | |
| (solvent) | (Water for injection) | (Total 10mL) |
Claims (23)
1. A liquid medicine characterized by comprising the following components (A) and (B): (A) the following formula (1)
The compound represented by (A), a salt or hydrate thereof, and (B) a polyvalent metal compound, wherein the molar ratio of the component (B) to the component (A) (polyvalent metal/component (A)) is O.01 to 0.7.
2. The chemical solution according to claim 1, wherein the polyvalent metal of the polyvalent metal compound is a metal capable of forming a metal complex with the component (A).
3. The medical solution according to claim 1 or 2, wherein the polyvalent metal compound is a magnesium compound or a calcium compound.
4. The medical solution according to claim 3, wherein the polyvalent metal compound is a magnesium compound.
5. The medical solution of claim 4 wherein the magnesium compound is magnesium chloride.
6. The liquid medicine according to any one of claims 1 to 5, wherein the pH is 2.5 to 6.9.
7. The drug solution according to any one of claims 1 to 6, which is a drug solution for intravascular administration.
8. A preparation comprising the component (A) for preparing the medicinal solution according to any one of claims 1 to 7 and a polyvalent metal compound.
9. A kit for preparing a drug solution according to any one of claims 1 to 7, wherein a preparation containing the component (A) and a solution for dissolving containing a polyvalent metal compound are combined.
10. A kit for preparing a drug solution according to any one of claims 1 to 7, wherein a preparation containing the component (A) and a polyvalent metal compound and a dissolving solution are combined.
11. The formulation or kit according to any one of claims 8 to 10, wherein the formulation comprising component (a) further comprises a pharmaceutical additive.
12. The formulation or kit of any one of claims 8 to 11, wherein the formulation comprising component (a) is a lyophilized formulation.
13. The kit according to any one of claims 8 to 12, further comprising a diluent which may contain a polyvalent metal compound.
14. A kit for preparing a drug solution according to any one of claims 1 to 7, wherein a solution preparation containing the component (A) and a solution preparation containing a polyvalent metal compound are combined.
15. The kit of claim 14, further comprising a diluent that may contain a polyvalent metal compound.
16. A method for alleviating the trouble of the component (A) at the site of administration, which comprises administering a compound represented by the following formula (1)
In the case of the compound represented by (a), a salt thereof, or a hydrate thereof, the polyvalent metal compound is present in a chemical solution containing the component (a) at a molar ratio of 0.01 to 0.7 (polyvalent metal/component (a)) relative to the component (a).
17. The method of alleviating disorders according to claim 16, wherein the polyvalent metal compound is caused to exist by adding a solution for dissolution and/or a solution for dilution to a liquid medicine and/or a preparation containing the component (A), and either one or both of the solution for dissolution and the solution for dilution contain the polyvalent metal compound.
18. A method of alleviating disorders according to claim 16 or 17, wherein the polyvalent metal compound is dissolved in a liquid medicine containing component (a).
19. A method of relieving disorders as claimed in any of claims 16 to 18, wherein the polyvalent metal compound is a magnesium compound or a calcium compound.
20. The method of mitigating of claim 19, wherein the polyvalent metal compound is a magnesium compound.
21. The method of mitigating of claim 20, wherein the magnesium compound is magnesium chloride.
22. The method of alleviating disorders according to any one of claims 16 to 21, wherein a pH of the liquid medicine containing the component (A) in which the polyvalent metal compound is present is 2.5 to 6.9.
23. A method of ameliorating the disadvantages of any of claims 16 to 22 wherein the site of administration is a blood vessel.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004-197223 | 2004-07-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1100529A true HK1100529A (en) | 2007-09-21 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2260429C9 (en) | Sodium chloride-containing moxifloxacin compositions | |
| JP7042531B2 (en) | Pharmaceutical composition containing deoxycholic acid | |
| HK52397A (en) | Injection and injection kit containing omeprazole and its analogs | |
| HUE033161T2 (en) | Tetracycline compositions | |
| CA2989372C (en) | Injectable pharmaceutical formulations of lefamulin | |
| CN1980670A (en) | Quinolone-containing medicinal composition | |
| CA2416600A1 (en) | Freeze-dried preparation of n-¬o-(p-pivaloyloxybenzenesulfonylamino)benzoyl|glycine monosodium salt tetrahydrate and a process for the maufacture thereof | |
| US20060252804A1 (en) | Flupirtin injectable galenic form | |
| HK1100529A (en) | Quinolone-containing medicinal composition | |
| CN105769756A (en) | Sitafloxacin fumarate injection and preparation method thereof | |
| WO2009103209A1 (en) | Stable s-(-)- nadifloxacin-l-arginine composition, its preparation method and use | |
| JP3775813B2 (en) | Composition for treating abnormal tissue, method for producing the same, and use thereof | |
| KR100738021B1 (en) | Ginkgo biloba extract containing high concentration | |
| JP2005200409A (en) | Injection | |
| KR20250009479A (en) | Nimodipine parenteral administration | |
| CN120713836A (en) | Nimodipine injection and preparation method thereof | |
| HK40054634B (en) | Aqueous paediatric retinol formulations | |
| HK40054634A (en) | Aqueous paediatric retinol formulations |