WO2016056527A1 - Method for producing freeze-dried preparation - Google Patents
Method for producing freeze-dried preparation Download PDFInfo
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- WO2016056527A1 WO2016056527A1 PCT/JP2015/078269 JP2015078269W WO2016056527A1 WO 2016056527 A1 WO2016056527 A1 WO 2016056527A1 JP 2015078269 W JP2015078269 W JP 2015078269W WO 2016056527 A1 WO2016056527 A1 WO 2016056527A1
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- piperacillin
- tazobactam
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- solution
- freeze
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a novel method for producing a lyophilized preparation for injection containing sodium tazobactam (Tazobactam sodium) and piperacillin sodium (Piperacillin sodium).
- Tazobactam sodium sodium tazobactam
- Piperacillin sodium Piperacillin sodium
- tazobactam and piperacillin are widely used worldwide under the trade name “Zosyn” (registered trademark) in the form of a freeze-dried formulation for intravenous injection.
- tazobactam free acid and piperacillin hydrate are dissolved in an aqueous sodium bicarbonate solution, and a solution containing a buffer (such as citrate) and an aminocarboxylic acid chelating agent (such as EDTA) is lyophilized.
- a buffer such as citrate
- an aminocarboxylic acid chelating agent such as EDTA
- the manufacturing method is known (see Patent Document 1).
- a method is known in which tazobactam free acid and piperacillin hydrate are dissolved in an aqueous sodium bicarbonate solution, and a solution obtained by degassing the dissolved carbon dioxide content to a certain amount is freeze-dried (patent) Reference 2).
- the pH is adjusted using piperacillin, so that the final content of the active ingredient cannot be accurately adjusted.
- the object of the present invention is to provide a novel method for producing a freeze-dried preparation (formulation) for injection mainly containing tazobactam sodium and piperacillin sodium.
- the amount of liquid to be dried is as small as possible. Therefore, when it is desired to use a sodium hydroxide solution that can be adjusted in pH and sodiumized in a small amount, sodium hydroxide is a strong alkali. Therefore, if a sodium hydroxide solution is used, the active ingredient may be decomposed.
- a sodium hydroxide solution prior to intravenous administration of the lyophilized preparation, it is necessary to redissolve the lyophilized preparation with water or the like.
- an operation such as stirring is necessary because of low solubility.
- bubbles are generated in the solution after stirring, it is preferable that the bubbles disappear quickly in the medical field.
- the present inventors have found that the above problem can be solved by a simple method of blowing carbon dioxide gas into a strongly alkaline sodium hydroxide aqueous solution, and have completed the present invention.
- Examples of the present invention include the following.
- a method for producing a freeze-dried preparation for injection (hereinafter referred to as “the method of the present invention”), which comprises the following steps (a) and (b): (A) Step of blowing carbon dioxide into sodium hydroxide aqueous solution (b) Step of dissolving tazobactam and piperacillin in the solution obtained in the step (a)
- the present invention is characterized in that tazobactam and piperacillin are dissolved in an aqueous sodium hydroxide solution into which carbon dioxide gas is blown in the production of a freeze-dried preparation for injection containing tazobactam sodium and piperacillin sodium.
- tazobactam and piperacillin are dissolved in an aqueous sodium hydroxide solution into which carbon dioxide gas is blown in the production of a freeze-dried preparation for injection containing tazobactam sodium and piperacillin sodium.
- the production method of the present invention even when a strongly alkaline aqueous sodium hydroxide solution is used, it is possible to prevent the pH of the solution from becoming too high by blowing carbon dioxide into the solution, thereby suppressing the decomposition of tazobactam and piperacillin.
- the compounding agent freeze-dried preparation for injection
- water for injection is added to the freeze-dried preparation obtained by the production method of the present invention and re-dissolved, so-called defoaming is good.
- the left container of each photograph represents a commercially available sample
- the right container represents a freeze-dried preparation sample obtained by the production method of the present invention.
- the upper left photo shows the state before redissolution
- the upper right photo shows the state immediately after redissolution with water for injection
- the left middle photo shows the state after 30 seconds of standing
- the right middle photo shows the state after 1 minute of standing
- the lower left photo shows the state after 2 minutes of standing
- the lower right photo shows the state after 6 minutes of standing.
- Step of blowing carbon dioxide gas into aqueous sodium hydroxide solution This step is a step of blowing carbon dioxide gas into the aqueous sodium hydroxide solution.
- the aqueous sodium hydroxide solution can be prepared by adding sodium hydroxide to water and dissolving it.
- the concentration of sodium hydroxide in the aqueous solution is, for example, suitably from 1 to 20% by mass, preferably from 2 to 10% by mass, more preferably from 3 to 5% by mass.
- water for preparing the aqueous solution include water for injection, purified water, distilled water, and physiological saline, and water for injection is preferable.
- a commercially available sodium hydroxide aqueous solution can be used as it is or after appropriately diluted with water.
- carbon dioxide gas is blown into the aqueous sodium hydroxide solution to prepare an aqueous sodium hydroxide solution in which carbonic acid is dissolved.
- the method for blowing carbon dioxide include a general gas blowing method. Specifically, for example, a carbon dioxide gas injection tube is inserted while stirring an aqueous sodium hydroxide solution with a stirrer or the like, and carbon dioxide gas is blown at a pressure that does not cause bumping.
- the pressure of the carbon dioxide gas to be blown is suitably 0.5 to 2.0 bar, preferably 0.5 to 1.0 bar.
- carbon dioxide gas is blown into an aqueous sodium hydroxide solution to adjust the aqueous solution within the range of pH 7.0 to 9.2 (preferably pH 7.5 to 8.0). If necessary, after the carbon dioxide gas is blown into the aqueous solution, or while blowing, the aqueous solution can be finely adjusted within the pH range with an appropriate acid.
- the acid for fine pH adjustment include hydrochloric acid, citric acid, and phosphoric acid. Of these, hydrochloric acid is particularly suitable.
- Step of dissolving tazobactam and piperacillin in the solution obtained in the step (a) This step is a step of dissolving tazobactam and piperacillin in an aqueous sodium hydroxide solution into which carbon dioxide gas has been blown. This is a step of obtaining an aqueous solution in which tazobactam and piperacillin are dissolved.
- the concentration of tazobactam in the aqueous solution is not particularly limited, but can be 1 to 20% by mass, for example, and preferably 3 to 7% by mass. If it is less than 1% by mass, it is inconvenient to obtain a freeze-dried preparation having a predetermined titer. When it is more than 20% by mass, stirring during dissolution is difficult.
- the concentration of piperacillin in the aqueous solution is not particularly limited, but can be 10 to 50% by mass, for example, and preferably 20 to 30% by mass. If it is less than 10% by mass, it is inconvenient to obtain a freeze-dried preparation having a predetermined titer. When it is more than 50% by mass, dissolution is difficult.
- the titer ratio of tazobactam and piperacillin in the aqueous solution is preferably 1: 8 (tazobactam: piperacillin).
- the dissolved tazobactam and piperacillin may be hydrates.
- piperacillin it is common to use hydrates.
- tazobactam and piperacillin there is no particular limitation on the order of dissolving tazobactam and piperacillin in the aqueous solution. Either may be dissolved first or both may be dissolved simultaneously.
- This dissolution can be performed by a conventional method. Specifically, for example, tazobactam and piperacillin hydrate can be added to a sodium hydroxide aqueous solution into which carbon dioxide gas has been blown, and dissolved while stirring with a stirrer or the like.
- the melting temperature include 3 to 15 ° C. More preferably, it is 4 to 10 ° C. If it is lower than 3 ° C, it takes time for dissolution, and if it is higher than 15 ° C, decomposition of tazobactam and piperacillin may be accelerated.
- a step of adjusting an aqueous solution of sodium hydroxide, in which tazobactam and piperacillin are dissolved, into which carbon dioxide gas is blown, to pH 5.5 to 6.8 (preferably pH 5.7 to 6.6) is adjusted with an acid.
- an acid for adjusting the pH include the same acids as described above. Of these, hydrochloric acid is particularly suitable.
- the liquid volume can be adjusted with water as necessary.
- water for adjusting the liquid amount include water for injection, purified water, distilled water, and physiological saline, and water for injection is preferable.
- Step of Blowing Inert Gas This step is a step of blowing an inert gas into a sodium hydroxide aqueous solution in which tazobactam and piperacillin are dissolved and carbon dioxide is blown.
- the inert gas examples include nitrogen gas and argon gas. Although it will not restrict
- the inert gas can be blown after dissolving tazobactam and piperacillin in the solution obtained in the step (a), while dissolving tazobactam and piperacillin in the solution obtained in the step (a). It can also be carried out at the stage of pH adjustment after the tazobactam and piperacillin are dissolved in the solution obtained in the step (a) and at the stage of liquid volume adjustment.
- the time for injecting the inert gas and the amount of the inert gas to be injected are not particularly limited in any inert gas.
- the amount of carbon dioxide in the solution obtained in the step (a) is 200 mg / L or less ( It is appropriate to blow inert gas until the amount of oxygen is preferably 10 ppm or less (preferably 1 ppm or less), preferably 75 mg / L or less.
- the solution obtained in the step (b) after the inert gas is blown is sterilized by filtration by a conventional method.
- the filtration sterilization method include filtration sterilization using a 0.22 ⁇ m membrane filter.
- step (D) Step of freeze-drying
- the solution obtained in step (c) is dispensed into a sterile container and freeze-dried by a conventional method.
- the inside of the vial after freeze-drying can be replaced with nitrogen gas and stoppered to obtain a freeze-dried preparation for injection according to the present invention (hereinafter referred to as “the preparation of the present invention”).
- tazobactam and piperacillin are considered to exist as sodium salts.
- tazobactam sodium is preferably contained in 0.25 g (titer) or 0.5 g (titer)
- piperacillin sodium is contained in 2.0 g (titer) or 4.0 g (titer) ( The titer ratio is 1: 8).
- the preparation of the present invention can generally be redissolved and used by adding any appropriate solution (re-dissolution solution).
- re-dissolution solution examples include water for injection, physiological saline, 5% (w / v) glucose injection solution, and other general infusion solutions.
- the amount of the redissolved solution varies depending on the use and the like, and is not particularly limited, but it is suitably 0.5 to 5 times the amount of the solution filled in the vial before lyophilization or 500 mL or less.
- the re-dissolved preparation of the present invention can be administered intravenously as, for example, an injection or an infusion.
- the dosage of the preparation of the present invention varies depending on the patient's condition such as age and weight, the nature and degree of the disease, etc., but 4.5 g (titer) as tazobactam sodium / piperacillin sodium is appropriate per adult. .
- This amount can be administered once to 5 times a day, preferably once to 4 times a day at an appropriate interval depending on the patient's condition such as age and weight, diseases, and the like.
- Example 1 2.4 kg of sodium hydroxide was dissolved in 56.25 L of water for injection, and carbon dioxide was blown to adjust the pH to about 7.7.
- a sodium hydroxide aqueous solution into which carbon dioxide gas was blown was finely adjusted to a pH of 7.7 with a 0.5 M aqueous hydrochloric acid solution, then 2.976 kg of tazobactam and 23.81 kg of piperacillin hydrate were bubbled with nitrogen gas.
- a 0.1 M aqueous hydrochloric acid solution and water for injection were added to obtain 125 L of an aqueous solution of pH 6.5.
- the prepared solution is sterilized by filtration and dispensed into sterile containers, followed by lyophilization according to a conventional method.
- a preparation of the present invention containing 0.5 g (titer) of tazobactam sodium and 4.0 g (titer) of piperacillin sodium was obtained.
- preparation of the present invention containing 0.25 g (titer) of tazobactam sodium and 2.0 g (titer) of piperacillin is referred to as preparation 2.25 of the present invention and 0.5 g (titer) of piperacillin sodium 4.0 g of piperacillin sodium.
- preparation 4.5 of the present invention is referred to as the preparation 4.5 of the present invention.
- Example 1 Change in pH over time The change in pH of the preparation of the present invention obtained in Example 1 was observed in comparison with a commercially available product (ZOSIN (registered trademark) for intravenous injection 2.25, 4.5). did. The results are shown in Table 1.
- Table 1 the numerical values in parentheses are the results of the pH measurement method described in the interview form of ZOSIN (registered trademark), and the numerical values without parentheses are for injections listed in the 16th revised Japanese Pharmacopoeia Second Supplement. The results obtained by the pH measurement method described in the section of tazobactam / piperacillin are respectively shown.
- Example 2 Purity test of tazobactam and piperacillin Purity test of tazobactam and piperacillin in the preparation of the present invention obtained in Example 1 was carried out under the conditions of 40 ° C / 75% RH or 60 ° C / 75% RH. Zocine (registered trademark) for intravenous injection 2.25, 4.5) and the same method. The results are shown in Tables 2 and 3. The contents of tazobactam and piperacillin were determined by the purity test method described in the section of tazobactam for injection and piperacillin listed in the 16th revised Japanese Pharmacopoeia Second Supplement.
- Example 3 Foam-out test 20 mL of water for injection was added to each of the preparation 4.5 of the present invention obtained in Example 1 and a commercially available product (4.5 for zocine (registered trademark) intravenous injection), and the freeze-dried product was It was dissolved by inversion and left to stand until it disappeared.
- FIG. 1 shows the state of bubble breakage at that time.
- the preparation of the present invention is excellent in foaming after redissolving with water for injection.
- the production method of the present invention is equivalent in quality to a commercially available product ZOSIN (registered trademark), and is useful in producing a freeze-dried preparation with good foam breakage.
Abstract
Description
また、凍結乾燥製剤を静脈内投与するに先立ち、水等で凍結乾燥製剤を再溶解する必要がある。タゾバクタムとピペラシリンとを配合した注射用凍結乾燥製剤を水等に溶解する際、溶解度が低いために攪拌等の操作が必要となる。通常、攪拌後の溶液に泡が発生するところ、医療現場においては、その泡は速やかに消失する方が好ましい。 Needless to say, in the production of a freeze-dried preparation, it is advantageous that the amount of liquid to be dried is as small as possible. Therefore, when it is desired to use a sodium hydroxide solution that can be adjusted in pH and sodiumized in a small amount, sodium hydroxide is a strong alkali. Therefore, if a sodium hydroxide solution is used, the active ingredient may be decomposed.
In addition, prior to intravenous administration of the lyophilized preparation, it is necessary to redissolve the lyophilized preparation with water or the like. When a freeze-dried preparation for injection containing tazobactam and piperacillin is dissolved in water or the like, an operation such as stirring is necessary because of low solubility. Usually, when bubbles are generated in the solution after stirring, it is preferable that the bubbles disappear quickly in the medical field.
本発明として、例えば、下記のものを挙げることができる。 As a result of intensive studies, the present inventors have found that the above problem can be solved by a simple method of blowing carbon dioxide gas into a strongly alkaline sodium hydroxide aqueous solution, and have completed the present invention.
Examples of the present invention include the following.
(a)水酸化ナトリウム水溶液に炭酸ガスを吹き込む工程
(b)タゾバクタム及びピペラシリンを上記(a)工程で得られた溶液に溶解する工程 [1] A method for producing a freeze-dried preparation for injection (hereinafter referred to as “the method of the present invention”), which comprises the following steps (a) and (b):
(A) Step of blowing carbon dioxide into sodium hydroxide aqueous solution (b) Step of dissolving tazobactam and piperacillin in the solution obtained in the step (a)
[5]更に次の(c)に記載の工程を含む、上記[1]~[4]いずれか一つに記載の凍結乾燥製剤の製造方法。
(c)不活性ガスを吹き込む工程
[6]前記不活性ガスが窒素ガスである、上記[5]記載の凍結乾燥製剤の製造方法。 [4] The method for producing a lyophilized preparation according to the above [3], wherein the acid is hydrochloric acid, citric acid, or phosphoric acid.
[5] The method for producing a lyophilized preparation according to any one of the above [1] to [4], further comprising the following step (c):
(C) Step of blowing inert gas [6] The method for producing a lyophilized preparation according to [5] above, wherein the inert gas is nitrogen gas.
The present invention is characterized in that tazobactam and piperacillin are dissolved in an aqueous sodium hydroxide solution into which carbon dioxide gas is blown in the production of a freeze-dried preparation for injection containing tazobactam sodium and piperacillin sodium. As a result, even when a strong alkaline sodium hydroxide aqueous solution is used, the active ingredient can be sodiumized without any particular problem while minimizing the degradation of tazobactam and piperacillin.
According to the production method of the present invention, even when a strongly alkaline aqueous sodium hydroxide solution is used, it is possible to prevent the pH of the solution from becoming too high by blowing carbon dioxide into the solution, thereby suppressing the decomposition of tazobactam and piperacillin. The compounding agent (freeze-dried preparation for injection) can be produced. Moreover, when water for injection is added to the freeze-dried preparation obtained by the production method of the present invention and re-dissolved, so-called defoaming is good.
I.本発明製法について
(a)水酸化ナトリウム水溶液に炭酸ガスを吹き込む工程
本工程は、水酸化ナトリウム水溶液に炭酸ガスを吹き込む工程である。
水酸化ナトリウム水溶液は、水に水酸化ナトリウムを加え、溶解することにより調製することができる。該水溶液中の水酸化ナトリウムの濃度としては、例えば1~20質量%が適当であり、好ましくは2~10質量%、より好ましくは3~5質量%である。この水溶液調製のための水としては、例えば、注射用水、精製水、蒸留水、生理食塩水を挙げることができるが、注射用水が好ましい。 The present invention is described in detail below.
I. About the manufacturing method of the present invention (a) Step of blowing carbon dioxide gas into aqueous sodium hydroxide solution This step is a step of blowing carbon dioxide gas into the aqueous sodium hydroxide solution.
The aqueous sodium hydroxide solution can be prepared by adding sodium hydroxide to water and dissolving it. The concentration of sodium hydroxide in the aqueous solution is, for example, suitably from 1 to 20% by mass, preferably from 2 to 10% by mass, more preferably from 3 to 5% by mass. Examples of water for preparing the aqueous solution include water for injection, purified water, distilled water, and physiological saline, and water for injection is preferable.
本工程は、炭酸ガスを吹き込んだ水酸化ナトリウム水溶液に、タゾバクタム及びピペラシリンを溶解する工程である。タゾバクタム及びピペラシリンが溶解した水溶液を得る工程である。 (B) Step of dissolving tazobactam and piperacillin in the solution obtained in the step (a) This step is a step of dissolving tazobactam and piperacillin in an aqueous sodium hydroxide solution into which carbon dioxide gas has been blown. This is a step of obtaining an aqueous solution in which tazobactam and piperacillin are dissolved.
本工程は、タゾバクタム及びピペラシリンが溶解した、炭酸ガスを吹き込んだ水酸化ナトリウム水溶液に、不活性ガスを吹き込む工程である。 (C) Step of Blowing Inert Gas This step is a step of blowing an inert gas into a sodium hydroxide aqueous solution in which tazobactam and piperacillin are dissolved and carbon dioxide is blown.
前記(c)工程で得られた溶液を無菌容器に分注し、常法により凍結乾燥を行う。そして、一般的には凍結乾燥後のバイアル内部を窒素ガスで置換し、打栓して、本発明に係る注射用凍結乾燥製剤(以下、「本発明製剤」という)を得ることができる。 (D) Step of freeze-drying The solution obtained in step (c) is dispensed into a sterile container and freeze-dried by a conventional method. In general, the inside of the vial after freeze-drying can be replaced with nitrogen gas and stoppered to obtain a freeze-dried preparation for injection according to the present invention (hereinafter referred to as “the preparation of the present invention”).
本発明製剤中、タゾバクタムナトリウムは0.25g(力価)又は0.5g(力価)、ピペラシリンナトリウムは2.0g(力価)又は4.0g(力価)含有されていることが好ましい(力価比として1:8)。 In the preparation of the present invention, tazobactam and piperacillin are considered to exist as sodium salts.
In the preparation of the present invention, tazobactam sodium is preferably contained in 0.25 g (titer) or 0.5 g (titer), and piperacillin sodium is contained in 2.0 g (titer) or 4.0 g (titer) ( The titer ratio is 1: 8).
本発明製剤は、一般には任意の適当な溶液(再溶解液)の添加によって再溶解し使用することができる。このような再溶解液としては、注射用水、生理食塩水、5%(w/v)ブドウ糖注射液、その他一般輸液を挙げることができる。この再溶解液の液量は、用途等によって異なり特に制限されないが、凍結乾燥前にバイアル瓶中に充填した液量の0.5~5倍量、又は500mL以下が適当である。 II. Regarding the preparation of the present invention The preparation of the present invention can generally be redissolved and used by adding any appropriate solution (re-dissolution solution). Examples of such redissolved solution include water for injection, physiological saline, 5% (w / v) glucose injection solution, and other general infusion solutions. The amount of the redissolved solution varies depending on the use and the like, and is not particularly limited, but it is suitably 0.5 to 5 times the amount of the solution filled in the vial before lyophilization or 500 mL or less.
The dosage of the preparation of the present invention varies depending on the patient's condition such as age and weight, the nature and degree of the disease, etc., but 4.5 g (titer) as tazobactam sodium / piperacillin sodium is appropriate per adult. . This amount can be administered once to 5 times a day, preferably once to 4 times a day at an appropriate interval depending on the patient's condition such as age and weight, diseases, and the like.
注射用水56.25Lに水酸化ナトリウムを2.4kg溶解し、炭酸ガスを吹き込み、pHを約7.7に調整した。炭酸ガスを吹き込んだ水酸化ナトリウム水溶液を、0.5Mの塩酸水溶液でpHを7.7に微調整した後、タゾバクタムを2.976kg、ピペラシリン水和物を23.81kg、窒素ガスでバブリングしながら加え、さらに0.1Mの塩酸水溶液と注射用水を加えて、pH6.5の水溶液125Lを得た。調製後の溶液を濾過滅菌し、無菌容器に分注したのちに、常法に従って凍結乾燥を実施し、各容器中にタゾバクタムナトリウム0.25g(力価)・ピペラシリンナトリウム2.0g(力価)、又はタゾバクタムナトリウム0.5g(力価)・ピペラシリンナトリウム4.0g(力価)を含む本発明製剤を得た。 [Example 1]
2.4 kg of sodium hydroxide was dissolved in 56.25 L of water for injection, and carbon dioxide was blown to adjust the pH to about 7.7. A sodium hydroxide aqueous solution into which carbon dioxide gas was blown was finely adjusted to a pH of 7.7 with a 0.5 M aqueous hydrochloric acid solution, then 2.976 kg of tazobactam and 23.81 kg of piperacillin hydrate were bubbled with nitrogen gas. In addition, a 0.1 M aqueous hydrochloric acid solution and water for injection were added to obtain 125 L of an aqueous solution of pH 6.5. The prepared solution is sterilized by filtration and dispensed into sterile containers, followed by lyophilization according to a conventional method. In each container, 0.25 g of tazobactam sodium (titer), 2.0 g of piperacillin sodium (titer) Alternatively, a preparation of the present invention containing 0.5 g (titer) of tazobactam sodium and 4.0 g (titer) of piperacillin sodium was obtained.
実施例1で得られた本発明製剤のpHの経時変化を、市販品(ゾシン(登録商標)静注用2.25、同4.5)と比較し観察した。その結果を表1に示す。なお、表中、括弧書きの数値は、ゾシン(登録商標)のインタビューフォームに記載のpH測定方法による結果を、括弧なしの数値は、第16改正日本薬局方第二追補に収載された注射用タゾバクタム・ピペラシリンの項に記載されたpH測定方法による結果を、それぞれ表す。 [Test Example 1] Change in pH over time The change in pH of the preparation of the present invention obtained in Example 1 was observed in comparison with a commercially available product (ZOSIN (registered trademark) for intravenous injection 2.25, 4.5). did. The results are shown in Table 1. In the table, the numerical values in parentheses are the results of the pH measurement method described in the interview form of ZOSIN (registered trademark), and the numerical values without parentheses are for injections listed in the 16th revised Japanese Pharmacopoeia Second Supplement. The results obtained by the pH measurement method described in the section of tazobactam / piperacillin are respectively shown.
実施例1で得られた本発明製剤中のタゾバクタムおよびピペラシリンの純度試験を40℃/75%RHまたは60℃/75%RHの条件で、市販品(ゾシン(登録商標)静注用2.25、同4.5)と共に常法により行った。その結果を表2及び表3に示す。なお、タゾバクタムとピペラシリンの含有量は、第16改正日本薬局方第二追補に収載のされた注射用タゾバクタム・ピペラシリンの項に記載された純度試験の方法により行った。 [Test Example 2] Purity test of tazobactam and piperacillin Purity test of tazobactam and piperacillin in the preparation of the present invention obtained in Example 1 was carried out under the conditions of 40 ° C / 75% RH or 60 ° C / 75% RH. Zocine (registered trademark) for intravenous injection 2.25, 4.5) and the same method. The results are shown in Tables 2 and 3. The contents of tazobactam and piperacillin were determined by the purity test method described in the section of tazobactam for injection and piperacillin listed in the 16th revised Japanese Pharmacopoeia Second Supplement.
実施例1で得られた本発明製剤4.5及び市販品(ゾシン(登録商標)静注用4.5)のそれぞれに注射用水20mLを加え、凍結乾燥物がなくなるまで転倒混和により溶解し静置した。その際の泡切れの状態を図1に示す。 [Test Example 3] Foam-out test 20 mL of water for injection was added to each of the preparation 4.5 of the present invention obtained in Example 1 and a commercially available product (4.5 for zocine (registered trademark) intravenous injection), and the freeze-dried product was It was dissolved by inversion and left to stand until it disappeared. FIG. 1 shows the state of bubble breakage at that time.
従って、本発明製剤は、注射用水で再溶解した後の泡切れが優れていることが明らかである。 After standing for 1 minute, the commercial product showed clear bubbles in the upper part, but in the preparation of the present invention, it was difficult to see the upper bubbles, and fine bubbles were observed from the middle to the upper part. After 2 minutes of standing, all the bubbles disappeared in the preparation of the present invention, but bubbles were observed on the liquid surface of the commercial product. Finally, after 7 minutes and 30 seconds of standing, bubbles disappeared from the commercial product.
Therefore, it is clear that the preparation of the present invention is excellent in foaming after redissolving with water for injection.
Claims (2)
- 次の(a)及び(b)に記載の工程を含むことを特徴とする、注射用凍結乾燥製剤の製造方法。
(a)水酸化ナトリウム水溶液に炭酸ガスを吹き込む工程
(b)タゾバクタム及びピペラシリンを上記(a)工程で得られた溶液に溶解する工程
The manufacturing method of the freeze-dried formulation for injection characterized by including the process as described in following (a) and (b).
(A) Step of blowing carbon dioxide into sodium hydroxide aqueous solution (b) Step of dissolving tazobactam and piperacillin in the solution obtained in the step (a) - 前記(a)工程において炭酸ガスを吹き込むことにより、水酸化ナトリウム水溶液をpH7.0~9.2の範囲内に調整することを含む、請求項1記載の凍結乾燥製剤の製造方法。
The method for producing a lyophilized preparation according to claim 1, comprising adjusting the aqueous sodium hydroxide solution to a pH in the range of 7.0 to 9.2 by blowing carbon dioxide in the step (a).
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