JP6426410B2 - Lyophilized formulation for storage at room temperature - Google Patents

Description

  The present invention relates to a lyophilized formulation that is stable at room temperature storage.

  The conventional injectable hump preparation is a lyophilized preparation containing mannitol as an additive. This preparation needs to be stored in a cold place from the viewpoint of stability, and from the medical site, a preparation that can be stored at room temperature and that is easier to handle has been required. With regard to preparations that are stored at room temperature, it is possible even under dynamic quasi-hard conditions (storage at 40 to 50 ° C for 1 to 3 months) in order to guarantee the quality even when stored under constant temperature fluctuations. It is necessary that the quality be maintained as much as possible.

  In freeze-dried preparations, disaccharides such as sucrose (purified sucrose) are known as additives for improving the chemical storage stability of the main drug (peptide, protein) (Patent Document 1). So, only small amounts at the laboratory level were used to evaluate the chemical stability of the main drug, and it was unclear whether it was stable from the viewpoint of the quality of the lyophilized preparation. In particular, refined sucrose is one of the typical stabilizers, and it can be said that the amount of use as a pharmaceutical additive is large and the degree of freedom of the amount used in formulation design is high. However, if the amount and concentration of the substance to be dried is increased in the preparation of the lyophilized formulation, there is a risk that important qualities may be lost, including stability and other formulation characteristics.

Japanese Patent No. 3555961

  The present invention is a freeze-dried preparation containing a physiologically active peptide as an active ingredient, which comprises purified white sugar as a main ingredient and which contains a certain amount or more and which is stable at room temperature while the main drug is chemically stable and the quality of other preparations is also stable. The task is to provide.

  A reconstitution solution of a lyophilized formulation of carperitide needs to be prepared to be isotonic with water for injection, as it may be administered directly to the patient. If the amount of redissolved solution is small, the influence of the decrease in the dosage guarantee amount due to the remaining drug solution in the vial becomes large, so it is desirable to use a fixed amount or more of the redissolved solution. In order to obtain isotonicity, it is necessary to use a certain amount or more.

  In the freeze-dried preparation, the appearance shape of the freeze-dried body and the water content are formulation characteristics that serve as an index for securing the important quality of the product. The lyophilizate having a poor appearance shape may cause dissolution failure at the time of re-dissolution, prolongation of the dissolution time, and the like, which may cause problems in the medical field. In addition, when the freeze-dried product contains a large amount of water, it lowers the glass transition temperature of the freeze-dried product to impair the chemical stability of the main drug or to promote the change in appearance of the freeze-dried product during storage. It could be

  In order to properly secure the appearance of the lyophilizate, it is necessary that the lyophilizate does not have an appearance abnormality in production (during the vacuum lyophilization step) and product storage after lyophilization.

  During the manufacturing process (vacuum lyophilization), as a typical cause of appearance abnormalities in the freeze-dried product, collapse of dried parts by steam (melting like collapse of microstructure) can be mentioned. In addition, as a typical phenomenon example of the appearance change of the freeze-dried product during product storage, there may be mentioned shrinkage (shrinkage of shape) due to the limit of the heat resistance of the freeze-dried product to the exposure temperature.

  Collapse during production is accelerated by the obstruction of water vapor passage (sublimation) due to the constriction or blockage of the water vapor passage path in the dried part, ie, an abnormality in the water removal process, in the sublimation process of the vacuum lyophilization process. In the vacuum lyophilization process, since sublimation proceeds from the upper surface to the lower surface direction (depth direction) of the lyophilization solution filled in the preparation container, in the vacuum lyophilization process, collapse causes a reduction in water removal efficiency. As a result, the water content of the freeze-dried product is kept high. That is, a lyophilizate having an abnormal appearance shape and a high water content may be obtained in the production stage, and at this time, a high water content is a result of changes in the appearance shape at the production stage and It can lower the glass transition temperature of the body and cause chemical stability and storage during storage.

  Shrinkage due to thermal exposure, such as during product storage, is likely to occur when the glass transition temperature of the lyophilisate is not properly designed for the storage temperature. If the temperature to which the lyophilizate is exposed exceeds the glass transition temperature of the components contained in the lyophilizate, there is a probability that the chemical reaction rate in the lyophilizate increases, or the shape of the lyophilizate changes, etc. Get higher. For example, in the case of a lyophilizate in which the main component is sucrose, sucrose is present as an amorphous solid when the temperature to which the lyophilizate is exposed is below the glass transition temperature of sucrose, but near the glass transition temperature When exposed to temperatures above that, the phase state is likely to be a rubbery region. When such a phase change occurs, in a lyophilizate containing a pharmaceutically active ingredient such as a peptide, the chemical reaction rate is significantly increased, and the chemical stabilization effect of the active ingredient by sucrose is lost. That is, the phase change of sucrose not only contributes to the physical property change of the shape change of the lyophilizate described above, but also the decrease of the chemical stabilization effect of the main drug.

  Thus, in a freeze-dried preparation using a certain amount or more of purified white sugar, it is necessary to design a preparation that can appropriately maintain the quality of the preparation. The water content can be used as an indicator.

  As a result of intensive studies on a lyophilized preparation of a physiologically active peptide stable at room temperature storage, the present inventors varied the content of refined sucrose at 100 to 1000 mg using a cylindrical glass vial with an inner diameter of 22.1 mm. As a result of preparing a freeze-dried preparation and conducting the characteristic evaluation at the time of manufacture and the stability test after heat severe storage, good appearance shape and moisture are obtained for the preparation of refined sucrose 300 to 500 mg and formulation having sucrose concentration of 125 mg / mL or less. The content was maintained, and it was found that the preparation with 100 mg or 1000 mg of purified sucrose could not maintain a good appearance shape and water content in manufacturing or heat stress tests, and further studies were conducted to complete the present invention. It reached.

The present invention provides the following.
(1) containing an effective amount of a peptidic drug, and about 0.50 to 1.85 mg / mm ² of purified sucrose with respect to the internal cross-sectional area of the container, and being stable at room temperature storage, A freeze-dried preparation characterized by
(2) The freeze-dried preparation according to (1), wherein the freeze-dried product has a good appearance after storage at 40 ° C. for one month, and the water content is 1% or less.
(3) The freeze-dried preparation according to (1), wherein the freeze-dried product has a good appearance after storage at 50 ° C. for one month, and the water content is 1% or less.
(4) The lyophilized formulation of (1), wherein the content of purified sucrose is about 0.75-1.35 mg / mm ^{2 with} respect to the internal cross-sectional area of the container.
(5) The lyophilized formulation of (1), wherein the container is a cylindrical vial having an inner diameter of about 20 to 29 mm and contains about 300 to 500 mg of purified sucrose.
(6) A lyophilized formulation according to (5), wherein the inner diameter of the cylindrical vial is about 22.1 mm.
(7) The freeze-dried preparation according to any one of (1) to (6), which is produced by freeze-drying a solution having a purified sucrose concentration of 140 mg / mL or less.
(8) The lyophilized formulation according to any one of (1) to (7), which contains 1 mg of carperitide as a peptidic drug.
(9) The lyophilized formulation according to any one of (1) to (8), which substantially comprises purified sucrose and a peptidic drug as solid components.
(10) An aqueous solution containing 140 mg / mL or less of purified sucrose and an effective amount of a peptidic drug, in an amount of about 0.50 to 1.85 mg / mm ^{2 with} respect to the internal cross-sectional area of the container. A method for producing a lyophilised preparation, characterized in that it is stable at room temperature storage, comprising the steps of: filling as such, and lyophilizing the filled container.
(11) The method according to (10), wherein the proportion of the preparation having good preparation quality characteristics is about 80% or more in the freeze-dried preparation to be manufactured.

  Since the freeze-dried preparation according to the present invention not only ensures the chemical stability of the active ingredient but also the physical stability of the freeze-dried product when stored at room temperature, it can be used as a storage location in distribution and medical fields Not only does it require the following equipment, but there is no need to bring it back to room temperature even when preparing a drug for use, and a uniform solution can be obtained in a short time when re-dissolving with an injection solution.

FIG. 1 is a photograph of an example of the appearance corresponding to the O judgment standard (good shape) in the judgment criteria of the appearance evaluation adopted in this example. FIG. 2 is a photograph of an example of appearance corresponding to the judgment criteria of Δ (generally good shape) in the judgment criteria of the appearance evaluation adopted in the present embodiment. FIG. 3 is a photograph of an example of the appearance corresponding to the x judgment standard (defective shape) in the judgment criteria of the appearance evaluation adopted in this example.

  Hereinafter, the present invention will be described in detail.

The present invention contains an effective amount of a peptidic drug, and about 0.50 to 1.85 mg / mm ² of purified sucrose with respect to the internal cross-sectional area of the container, and is stable at room temperature storage And a freeze-dried preparation characterized by

  In the present invention, a "lyophilized preparation" refers to a solid (a "lyophilized" obtained by injecting a predetermined amount of a solution of components having a predetermined composition (referred to as a "lysate") into a container and drying by a vacuum freeze drying method. Or "a freeze-dried cake") and a closed container closure system containing it. At the time of use at a medical site, a predetermined aqueous component is added to a predetermined amount container, and the lyophilizate is dissolved (referred to as "re-dissolution") and administered to a subject as a solution.

  In the present invention, "the internal cross-sectional area of the container" refers to the internal cross-sectional area in the horizontal cross-section of the barrel straight portion of the container used for lyophilization. Here, the torso straight portion of the container is a portion having a uniform horizontal cross section in a predetermined range in the vertical direction of the lower portion of the container. The internal cross-sectional area means the area inside the container wall in the horizontal cross section of the container.

  In the present invention, "storage at room temperature" means that the preparation is stored without using a temperature control facility such as a refrigerator, a freezer, or a heat storage container, for a period from manufacture of the preparation to use. Such pharmaceutical preparations that can be stored at room temperature must be confirmed to maintain stable quality for a predetermined period of time under the storage conditions. For formulations that store at room temperature conditions, fluctuations in the exposure temperature within a certain range are assumed, so especially at high temperatures such as 40 ° C., 50 ° C., 60 ° C., for a fixed period (for example, 1 month to 6 months) It is recommended that the stability of the stored quality in so-called heat and severe storage be confirmed.

  In the present invention, "stable formulation", "stable quality" or "stable formulation quality" means that important formulation characteristics and / or product quality are well maintained, for example, contained in the formulation It means that the preparation is physically stable, such as that the active ingredient is chemically stable and that the solubility upon re-dissolving the lyophilizate with water for injection and the like is well maintained. Do. The stability of the active ingredient means that the content of the active ingredient in the freeze-dried preparation containing the active ingredient is reduced in content, activity, purity, generation of decomposition products (formation of related substances), etc. Do.

  Furthermore, as properties that may affect the chemical stability, physical properties, and stability of such a lyophilized preparation, physical properties such as appearance (color, shape, etc.) of the freeze-dried body, and water content are also included. These physical properties can also be regarded as important formulation properties. That is, it is desirable that at least one, preferably all of such physical properties be well maintained even after stability testing of the lyophilized formulation. For example, the appearance shape affects the resolubility of the lyophilisate. In addition, the shape change caused in the lyophilization process affects the water removal efficiency, and when the change occurs, the water is not appropriately removed, and the possibility of increasing the water content at the time of production is increased. In addition, when the water content increases, the glass transition temperature of the main base material of the lyophilizate decreases, the chemical stability of the main agent may decrease, and the shape change may occur during storage of the preparation. Thus, the appearance shape and the water content of the lyophilizate are the formulation characteristics that may closely relate to the important quality of the formulation, ensuring the important product quality such as stability and solubility. It will be an indicator on

  In order to ensure storage stability at normal temperature (25 ° C.), it is desirable that the glass transition temperature of the product is 45 ° C. or higher, which is about 20 ° C. higher than normal temperature (F. Franks et al. “Protein / Nucleic Acid Enzymes, pp. 810-816, 41 (6), 1996). As described above, the glass transition temperature of purified sucrose is considered to be around 70 ° C. at 0% moisture, 40 to 50 ° C. at 1% retained water, and 30 to 40 ° C. at 2%. Therefore, in order to ensure storage stability at room temperature (25 ° C.), it is preferable that the freeze-dried preparation having purified sucrose as a main component has a water content of 1% or less as the freeze-dried product.

  In the present specification, when “about” is added to the description of numerical values, it means that a range of 30% above and below the explicitly indicated numerical values is permitted. Here, when “about” is added to the description of the numerical range, the above-mentioned acceptable range means that 30% below the lower limit value to 30% above the upper limit value is acceptable. The acceptable range is preferably 20%, more preferably 15%, still more preferably 10%, even more preferably 5%.

  Next, each component of the freeze-dried preparation of the present invention will be described in detail.

  The freeze-dried preparation of the present invention can use various peptidic drugs as an active ingredient, but is preferably carperitide. In the present specification, “carperitide” is a peptide hormone consisting of 28 amino acids: SLRRSSCFGG RMDRIGAQSG LGCNSFRY (SEQ ID NO: 1), and α-human atrial natriuretic peptide (“α-hANP” or simply Also referred to as "hANP". Carperitide can be produced by various known methods such as extraction / purification from a tissue derived from a living organism, biotechnological synthesis by genetic recombination, etc., chemical synthesis such as solid phase synthesis of peptide, etc. (For example, the re-listed 01/85945 gazette etc. reference). In addition, a freeze-dried lyophilized preparation containing 1 mg of carperitide in one vial is marketed as "Hump injection 1000". Also in the freeze-dried preparation of the present invention, when using carperitide as a physiologically active peptide, the content per vial is preferably 1 mg.

The lyophilizer of the present invention contains a predetermined amount of purified sucrose as a stabilizer. As the refined white sugar of the present invention, refined white sugar listed in the 16th revised Japanese Pharmacopoeia can be suitably used. Purified sucrose can provide the active ingredient peptide in the freeze-dried preparation of the present invention with chemical stability during storage at room temperature, and achieve an appearance and final water content that does not adversely affect other preparation quality and properties. It needs to be added. In the lyophilization process, the water content of the solution evaporates only from the liquid surface (upper part of the lyophilizate), so the efficiency of water removal is greatly affected by the depth of the solid component in the container. When the solid component in the container is shallow, water can be efficiently removed. On the other hand, when the solid component in the container is deep, water may be difficult to remove, and the water content of the final freeze-dried product may be high. That is, the physical stability of the lyophilisate depends on the content of refined sucrose with respect to the internal cross-sectional area of the barrel of the container used for lyophilization. In the present invention, the content of refined sucrose with respect to the internal cross-sectional area of the container is about 0.50 to 1.85 mg / mm ² , preferably about 0.65 to 1.60 mg / mm ² , more preferably It is about 0.75 to 1.35 mg / mm ² , even more preferably about 1.30 mg / mm ² .

  The content of purified white sugar per freeze-dried product is appropriately selected according to the size of the container. For example, when a cylindrical vial with an inner diameter of 22.1 mm is employed as a container, the amount of refined sucrose per lyophilizate is usually about 200 to 700 mg, preferably about 250 to 600 mg, and more preferably about 300. 500 mg, and even more preferably about 500 mg.

  The container used for the freeze-dried preparation of the present invention includes a barrel straight portion in the lower part of the container, and if it does not cause deterioration or deformation due to temperature change of the lyophilization operation, vial, ampoule, injection A variety of syringes and the like can be used. The cross section of the barrel straight portion may have various shapes, for example, may be polygonal (polygonal pillar vial) such as square or hexagonal, or may be circular (cylindrical vial). The size of the container is not particularly limited as long as it is a size that allows lyophilization, but the inner diameter of a generally used cylindrical vial is about 12 mm to 50 mm, and is appropriate depending on the amount of refined sucrose employed. An inner diameter vial can be selected. For example, when 300 mg of purified white sugar is used, a cylindrical vial having an inner diameter of about 14.6 to 29 mm (preferably, about 16 to 24 mm) is employed. Moreover, when using 500 mg as refined sucrose, a cylindrical vial with an inner diameter of about 19 to 34 mm (preferably, about 21 to 31.4 mm) can be used.

<Additives other than refined white sugar>
The freeze-dried preparation of the present invention may be a preparation consisting essentially of carperitide and purified white sugar, and if necessary, other components (a stabilizer other than purified white sugar, a buffer, a pH adjuster, etc. The composition may further contain a surfactant, a solubilizing agent, an antioxidant, a soothing agent, a tonicity agent, and the like. The content of components other than the main drug and purified white sugar does not substantially affect the glass transition temperature of the freeze-dried product, or an amount having a small influence on the glass transition temperature, and / or the stabilizing effect of the main drug by the purified white sugar The total amount of the content when using the component is preferably 20% by weight or less, more preferably 10% by weight or less, and further preferably, the total amount thereof is not reduced. It is at most 5 wt%, even more preferably at most 1 wt%.

  As a stabilizer other than purified white sugar, a sugar belonging to a disaccharide as well as purified white sugar such as trehalose, lactose and maltose, amino acids such as glycine, alanine, arginine, lysine, histidine and methionine which have been conventionally used as a stabilizer Preferably, polysaccharides such as heparin and dextran sulfate, sugar alcohols such as sorbitol and mannitol, proteins such as egg albumin and serum albumin can be suitably used. Among these, disaccharides are preferred, and trehalose is particularly preferred. Although the addition amount of stabilizers other than these refined sucrose is not restrict | limited in particular, 20 weight% or less of refined sucrose is preferable, and 10 weight% or less is more preferable.

  As a buffer used by this invention, a phosphate buffer, a citrate buffer, an acetate buffer, a glycine * hydrochloric acid buffer etc. are mentioned, for example. The buffer can be used to adjust the pH of the re-dissolved aqueous solution, as needed, to maintain the solubility and stability of carperitide. As the buffer, one having a pH of 4.0 to 6.5 after re-dissolution is preferable, and one that does not contain an electrolyte such as sodium salt or potassium salt to prevent salting out of carperitide Preferred and particularly preferred buffers include, for example, glycine / hydrochloric acid buffer. The amount of buffer added is preferably such that the concentration in the solution immediately before lyophilization in the preparation of the lyophilised formulation is in the range of 1 to 100 mM.

  As surfactant used by this invention, polysorbate 20, polysorbate 80, Pluronic F-68, polyethyleneglycol etc. are mentioned, for example, You may use 2 or more types together. As the surfactant, polysorbate surfactants are preferred, and polysorbate 80 is particularly preferred. Surfactants can be added as needed, for example, to prevent adsorption of carperitide in an aqueous solution to the container. The amount of surfactant added is preferably in the range of 0.001 to 2.0% by weight in the solution immediately before lyophilization when producing the lyophilized formulation.

  The lyophilization composition of the present invention may further contain an acid or a base as a pH adjuster in order to adjust the pH of the redissolved solution. Examples of the acid that may be further added to the freeze-dried preparation of the present invention include, for example, inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), organic acids (eg, formic acid, acetic acid, propionic acid, fumaric acid) Examples include one or more acids selected from acids, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like.

Among them, hydrochloric acid and acetic acid are preferable. The amount of these acids is not particularly limited, and may be added to the lyophilization composition in such an amount that the pH of the re-dissolution solution of the lyophilization composition can be adjusted within a predetermined range.
As the antioxidant used in the present invention, substances having self-oxidation (reducibility) such as sodium sulfite, sodium bisulfite, sodium pyrosulfite, L-cysteine hydrochloride, thioglycolic acid and the like, amino acids such as methionine, etc. It can be mentioned. However, when carperitide and a reducing substance coexist, the peptide may be degraded by reductive cleavage of a disulfide bond. Therefore, as a substance which prevents oxidation of a peptide, Preferably amino acids, such as a methionine, are mentioned, It is preferable to use in 0.001-0.1 weight part with respect to 1 weight part of refinement | purification sucroses.

Examples of the tonicity agent used in the present invention include monosaccharides such as glucose, sugar alcohols such as mannitol, and inorganic salts such as sodium chloride, preferably monosaccharides such as glucose or sugar alcohols such as mannitol. It is preferable to use it in the range of 0.001 to 0.2 parts by weight with respect to 1 part by weight of purified sucrose.
The soothing agent used in the present invention includes, for example, alcohols such as benzyl alcohol and chlorobutanol, lidocaine hydrochloride and the like, and the concentration in the solution at the time of producing the freeze-dried preparation is 0.001 to 2 It is preferable to use in the range of 0.1% by weight.

<Lyophilized formulation>
The lyophilized preparation of the present invention can be produced by known methods.
For example, a solution is prepared by dissolving a predetermined amount of carperitide or a salt thereof and a predetermined amount of purified sucrose in a predetermined amount of water or a suitable aqueous solvent (eg, a mixture of water and alcohol), and optionally an acid Add the solution to adjust the pH of the aqueous solution, and inject a sterile solution obtained by filtration and sterilization filtration using a filter (for example, a 0.22 μm pore diameter sterilization filter) into a vial or ampoule. The lyophilizing agent can be obtained by lyophilizing this container to make it solid.

  In preparation of the above-mentioned lyophilizer, the solution is prepared by dissolving the active ingredient peptide and purified sucrose in water or an aqueous solvent (for example, a mixture of water and alcohol) and adding an acid as necessary according to a known method. PH should be adjusted. In addition, the order of dissolving the active ingredient peptide and purified sucrose is not particularly limited.

  In the preparation of the above-mentioned lyophilizer, the concentration of the active ingredient peptide in the aqueous liquid is appropriately set to a pharmaceutically acceptable dose in the final product, but is usually 0.01 mg / mL to 5 mg / mL. . In a lyophilised formulation containing 1 mg of carperitide, the carperitide concentration of the lysate is adjusted to 0.2 mg / mL if the loading of lysate per vial is 5 mL.

  The lower limit of the concentration of purified sucrose in the aqueous solution to be subjected to the above-mentioned lyophilization depends on the composition of the other additives, but is usually about 10 mg / mL or more. The concentration of solid components contained in the solution to be subjected to lyophilization affects the water removal efficiency of the lyophilization process. Therefore, in order to achieve a low water content at the end of lyophilization, the purified sucrose concentration should be low. desirable. The upper limit of the concentration of purified sucrose in the solution is usually 140 mg / mL or less, preferably 125 mg / mL or less.

  The filter used for sterilization is preferably a sterilizing filter with a pore size of 0.22 μm or less. Examples of the sterilization filter include Durapore (registered trademark, manufactured by Nippon Millipore Co., Ltd.) or Zaltopore 2 (registered trademark, manufactured by Sartorius, Inc.).

  The solution prepared by the above steps is filled in a fixed amount in a container, and the filled container is subjected to lyophilization. The filling amount of the solution per container at this time varies depending on the size of the container, but the depth (liquid depth) of the filling solution is usually about 3 mm to 20 mm (preferably about 5 mm to 17 mm) . If the liquid depth is too small, a lyophilizate is not formed, and if it is too large, water removal at the lower part of the container may not proceed efficiently.

  As a lyophilization method, for example, a freezing process of freezing and freezing under normal pressure, a primary drying process of sublimating and drying free water not restricted by a solute under a reduced pressure, and a secondary drying process of removing adsorbed water and water of crystallization inherent to a solute There are three unit operation methods. The cooling temperature in the freezing process is preferably -60C to -40C, the temperature in the primary drying process is preferably -50C to 0C, and the temperature in the secondary drying process is preferably 4C to 40C. The vacuum pressure in the primary drying process is preferably controlled to 0.1 to 50 Pa, particularly preferably 0.5 to 30 Pa. The pressure in the drying cabinet after lyophilization is reduced. As a method of repressurization, aseptic air or inert gas (for example, sterile nitrogen gas, sterile helium gas, etc.) is sent into the chamber to temporarily repressurize to about 60 to 90 kPa, and then, if necessary, further The method of repressurization (secondary repressurization) is preferred. It is preferable to stop the vial after primary pressure reduction.

<Use of preparation>
The freeze-dried preparation of the present invention can be redissolved in water for injection or infusion (eg, physiological saline, glucose solution etc.) before use and used for injection, infusion and the like. However, when dissolved in physiological saline, carperitide may be gelled if the dissolution conditions are not appropriate, so it is necessary to adjust the drug concentration after reconstitution and to pay attention to the state at the time of use. In addition, glucose solution may be limited in use if the patient has diabetes or its risk. Therefore, it is desirable to use water for injection to redissolve the lyophilized preparation of the present invention.

  The lyophilizing agent of the present invention is, for example, various compositions for injection such as composition for subcutaneous injection, composition for intravenous injection, composition for intramuscular injection, composition for drip injection, composition for needle-free injection It can be used as a thing. In this case, the concentration of the active ingredient peptide in the composition for injection at the time of injection (in the case of a lyophilizing agent, the resolubilizing concentration) is usually about 0.01 mg / mL to 60 mg / mL, preferably about 0.05 mg / mL. mL-20 mg / mL.

  When the lyophilizer of the present invention is redissolved at the time of use and used for injection, it is preferable to prepare the above-mentioned aqueous liquid by a known aseptic preparation method such as filter sterilization. In addition, before preparing the lyophilizer of the present invention, saccharides and surfactants, or a mixture of saccharides, surfactants, and other additives if necessary, are subjected to sterilization treatment such as depyrogenation in advance. Can also be used.

Furthermore, the freeze-dried preparation of the present invention can be advantageously used not only as a preventive or therapeutic agent for acute heart failure, but also as a prophylactic or therapeutic agent for diseases associated with elevation of blood pressure and load on the heart.
The freeze-dried preparation of the present invention has an excellent blood pressure lowering action and a cardioprotective action as a single agent, and exhibits an action effective as a preventive or therapeutic agent for heart disease, but it is used in combination with other pharmaceutical ingredients (multidrug It can also be used in combination.

  Hereinafter, the present invention will be specifically described using examples. What is shown in the examples is one example of the embodiment of the present invention, and the present invention is not limited thereto. In this example, a cylindrical glass vial (body outer diameter: 24.5 mm, inner diameter: 22.1 mm) for "Hump injection 1000" was adopted as a container for the freeze-dried preparation.

<Example 1: Examination of compounding conditions of purified sucrose (sucrose placebo preparation)>
In order to find a formulation design of a freeze-dried formulation having refined sucrose incorporated as the main formulation component and having good product characteristics, the formulation conditions of refined sucrose in formulation formulation and manufacturing process (liquid for lyophilization) (hereinafter referred to as “blending sucrose” I examined the condition ").
The examination range of the amount of refined white sugar in this test was determined for the following reasons. In the case of the dosage regimen of Carperitide current product (product name: "Hump 1000 for injection"), one preparation (one vial) is redissolved with 10 mL of water for injection. From the viewpoint of maintaining or improving the efficiency of preparation, it is desirable that the type of re-dissolution be unchanged and that the amount be less than or equal to the current product (10 mL or less). On the other hand, in the preparation at a medical site, the remaining rate (residual solution rate) of the solution due to adhesion to the preparation container after withdrawal of the solution after re-dissolution with a syringe etc. increases as the solution amount decreases. In design, it is necessary to set the amount of re-dissolution so that this residual liquid rate becomes as small as possible. Therefore, in this product design, the amount of re-dissolution was set in the range of 1 to 10 mL.
In addition, carpertide preparations need to be isotonic after dissolution, as they may be directly administered without dilution by infusion after being redissolved in water for injection in a medical setting. In the case of a preparation containing purified white sugar as the main component, the amount of solution required to ensure isotonicity is about 10 times the amount of purified white sugar (about 1 mL of water for injection relative to 100 mg of purified white sugar). In this product design, the amount of water for injection was set to 1 to 10 mL, so the examination range of the amount of purified white sugar was set to 100 to 1000 mg.
In the present study, the amount of purified sucrose (hereinafter, “the amount of sucrose”) per preparation (one vial) and the concentration of the purified sucrose in the solution for lyophilization (hereinafter, “concentration of sucrose”) are variable factors. In addition, the appearance shape and the water content of the freeze-dried product were evaluated as formulation quality characteristics.
In addition, since this test focuses on the physical properties such as the appearance and moisture of the lyophilizate, the ratio of the content of carperitide to the study and the amount of refined sucrose to be studied makes the influence of carperitide on these physical properties almost negligible. Judging that this was negligible, this test was conducted using a preparation containing no carperitide (sucrose placebo preparation).

(1) Preparation of Sucrose Placebo Preparation (Formulation Examples 1 to 17)
Purified white sugar (Japanese Pharmacopoeia, Saline Port Segarase Co., Ltd.) was dissolved in purified water so as to have a predetermined white sugar concentration in each formulation example of Table 1. After filtering the white sugar solution through a filter (Stericup-GV 0.22 μm, PVDF, Millipore Corporation), use a Teha dispenser (FH-10s, Hirasawa Co., Ltd.) or a microscale pipette (PIPETMAN, GILSON, Inc., etc.) In the same manner, glass vials (body outer diameter: 24.5 mm, Yamato Special Glass Co., Ltd.) were filled in such a manner as to obtain a predetermined filling amount. After half-stopping a rubber stopper (V10-F8 D713 RB2-40, Daikyo Seiko Co., Ltd.) into the filled vial, it is carried into a lyophilizer (RL-30 KPs, Kyowa Vacuum Co., Ltd.) and pre-frozen (- Next, freeze drying (primary drying: -20 to -5 ° C setting, secondary drying: 40 ° C setting) is performed under vacuum conditions (20 Pa setting), and after the drying is completed, the vial is introduced with nitrogen Pressure was released. After all the rubber stoppers have been plugged into the vial, use a clamping machine (GAC-01, Inaba Machine Mfg. Co., Ltd.) to clamp the vial with a flip-off cap (AP cap, 20AP7.0H, Ishida Press Co., Ltd.) The white sugar placebo formulations of Formulation Examples 1 to 17 were obtained.

(2) Analysis of preparation quality characteristics of freeze-dried preparation after storage under heat and stress A thermostatic chamber in which the freeze-dried preparation prepared in (1) above is set at 40 ° C. 75% RH (LH 31-15M type, NAGANO SCIENCE CO., LTD. It stored for 1 month in a thermostat (LH20-01 type | mold, Nagano Scientific Machinery Mfg. Co., Ltd.) set to 50 degreeC. At the time of manufacture of the preparation and before and after storage under each condition, the appearance shape and the water content of the lyophilizate were evaluated by the following method.

[Method: Evaluation of appearance of freeze-dried product]
The appearance shape of the freeze-dried preparation was visually observed, and the code was judged in three steps as follows. At the time of manufacture, 23 to 25 randomly selected were observed. In heat and severe storage, before storage at each temperature, three were randomly selected from those with a good appearance shape, and the same formulation was observed before and after storage. The results are shown in Tables 2 and 3.
○: good shape (normal shape)
:: Almost good shape (only slight change is observed compared to the normal shape)
X: Defective shape (defective shape: significant changes such as significant shrinkage are observed as compared to a normal shape).

[Method: moisture measurement of freeze-dried product]
Measure 10 mg or more of the freeze-dried product in a glass stoppered collection tube under a humidity environment to reduce moisture absorption, and use a coulometric titration type trace water content measuring device (CA-100 type, Mitsubishi Chemical Corporation) to measure the water content ( The moisture content (%) of the freeze-dried body weight was measured. It measured about 2 or 3 randomly selected at each measurement, and the average value of the moisture content was shown in Table 2 and Table 3.

[Results] Table 2 shows the appearance shape and moisture content after storage for one month at 40 ° C. and 75% RH after storage for one month at 40 ° C. and 75% RH at the time of manufacturing the formulations of Formulation Examples 1 to 7 (sucrose amount 1000 mg or 500 mg / vial). The Similarly, the appearance shape and moisture content of the preparations of Formulation Examples 8 to 17 (the amount of sucrose 300 mg or 100 mg / vial) are shown in Table 3. For each formulation example, it is evaluated that the appearance shape is evaluated as ○ or 、 and the moisture content is 1% or less at the time of manufacturing and all heat storage conditions in order to determine that the formulation quality is good. It was taken as the judgment standard.
Formulations of Formulation Examples 5 to 12 (white sugar amount 500 mg / vial (sucrose concentration 125 mg / mL or less) or 300 mg / vial) conform to the appearance and moisture judgment criteria both during heat stress storage at the time of production. When carperitide formulations are produced under these conditions, it is shown that good product properties such as thermal stability can be ensured.
On the other hand, each of the preparations of Formulation Examples 1 to 4 (sucrose amount 1000 mg / vial or 500 mg / vial (sucrose concentration 160 mg / mL or more) causes obvious appearance defects (10% or more x judgment) at the time of production. Also, the moisture at the time of production was 1% or more, and both the appearance and the moisture were not suitable for the judgment criteria. When evaluation after heat and severe storage was carried out, a sample with appearance defect (inappropriate to the judgment standard) was recognized by storage at 50 ° C. This is anxious about the heat stability of the formulation whose water does not satisfy the judgment standard. It shows that there is.
Formulations of Formulation Examples 13 to 17 (Sucrose content 100 mg / vial) satisfy the judgment criteria for both appearance and moisture at the time of manufacture, but increase in moisture to 1% or more after storage for 1 month of heat stress Nonconformity). It was suggested that the preparation with a small amount of white sugar may be affected by the water content of the rubber stopper used for closing the preparation container, the water content may increase during storage, and the product characteristics may change.

※: The appearance evaluation at the time of manufacture evaluated the preparation of O judgment (there is no change in appearance) at random, and store it under each temperature. Appearance shows actual measurement value (determination code of 3 preparations). −: Not measured

※: Formulations with appearance evaluation ○ or 判定 (no appearance change or slight) are randomly selected and stored under each temperature. Appearance shows actual measurement value (determination code of 3 preparations). −: Not measured

From these results, using a glass vial with an outer diameter of 24.5 mm (inner diameter: 22.1 mm) as a container for lyophilization, in the manufacture of a lyophilization formulation having purified sucrose as the main solid component, an appearance shape, Sucrose mixing conditions that satisfy the criteria for water content are: 300 mg (0.78 mg / mm ² per container cross sectional area) to 500 mg / vial (1.30 mg / mm ² per container internal cross sectional area) for sucrose content The sucrose concentration was shown to be 48-125 mg / mL (filling volume 2.5-6.25 mL / vial).

Under these conditions, when focusing on the quality characteristics at the time of production, if the amount of refined white sugar per vial is large or the white sugar concentration of the filling solution is high, the proportion of appearance defects at the time of production is high Also tended to be higher. It is considered that water removal in the lyophilization process did not proceed normally in these lyophilizates. The water removal in the lyophilization process proceeds as the frozen moisture sublimes and is released from the upper surface of the lyophilizate, so the amount of sucrose per area of the upper surface of the lyophilizate (internal cross-sectional area of the container) decreases Water removal efficiency is considered to be high. Also in this examination, in the same size vial, the smaller the amount of sucrose and the lower the concentration of sucrose, the lower the moisture content at the time of production tends to be. Therefore, in order to ensure good formulation quality characteristics at the time of manufacture, it is necessary to reduce the amount of refined white sugar per internal cross-sectional area of the container (usually about 1.85 mg / mm ² or less). Also, for the same purpose, the concentration of the filling solution used for lyophilization is about 140 mg / mL or less, considering that the quality characteristics in the case of Formulation Example 4 (160 mg / mL) slightly did not reach the standard. It is considered desirable to be there.

Also, in order to ensure good quality characteristics after heat and severe storage, it is important that the water content at the time of manufacture be small, but even if the water content at the time of manufacture is sufficiently low, per vial If the amount of white sugar is too small, the influence of the absorption of the freeze-dried product during storage can not be ignored during storage, and the water content after storage will be above the specified value Was suggested. Since the size of the rubber stopper increases in proportion to the diameter of the vial, it is necessary to consider it as the amount of sucrose per internal cross sectional area of the container even when considering the effect of the water content of the rubber stopper. It is considered that it is necessary to be 50 mg / mm ² or more.

Example 2 Production and Evaluation of Active Preparations
A carperitide-containing preparation (containing 1 mg of carperitide) was prepared under the sucrose mixing conditions (300 to 500 mg per vial with an inner diameter of 22.1 mm) judged to be preferable in Example 1 and the sucrose concentration (125 mg / mL or less) The characteristics at the time of production and the thermal stability were evaluated.
(1) Preparation of a lyophilized preparation of Formulation Example A (carperitide 1 mg / vial, sucrose amount 500 mg / vial (1.30 mg / mm ² ), sucrose concentration 100 mg / mL (10%)) Carperitide 81.6 mg ( After 1% of design content of carperitide was designed, 2 g of additional preparation and 40 g of purified white sugar (Japanese Pharmacopoeia, Saltwater Port Sugar Co., Ltd.) were dissolved in purified water, and then the total volume was adjusted to 400 mL with purified water. This solution is filtered through a filter (Stericup-GV 0.22 μm, PVDF, Millipore Corporation), and then a Tehha dispenser (FH-10s, Hirasawa Co., Ltd.) or a microscale pipette (PIPETMAN, GILSON, Inc., etc.) is used. 5 mL was filled in a glass vial (body outer diameter 24.5 mm, inner diameter 22.1 mm) (Daiwa Special Glass Co., Ltd.). After half-stopping a rubber stopper (V10-F8 D713 RB2-40, Daikyo Seiko Co., Ltd.) into the filled vial, it is carried into a lyophilizer (RL-30 KPs, Kyowa Vacuum Co., Ltd.) and pre-frozen (- (50 ° C setting), followed by lyophilization (primary drying: -20 to -5 ° C setting, secondary drying: 40 ° C setting) under vacuum conditions (20 Pa setting), and after the end of drying, the vial is filled with nitrogen It pressured again. After all the rubber stoppers have been plugged into the vial, use a clamping machine (GAC-01, Inaba Machine Mfg. Co., Ltd.) to clamp the vial with a flip-off cap (AP cap, 20AP7.0H, Ishida Press Co., Ltd.) To obtain a carperitide-containing preparation of Formulation Example A.

(2) Preparation of a lyophilized preparation of combination example B (carperitide 1 mg / vial, sucrose amount 300 mg / vial (0.78 mg / mm ² ), sucrose concentration 75 mg / mL (7.5%)) Carperitide 102 mg (supplemented addition of 2% to the design content of 1 mg of carperitide) and 30 g of purified white sugar (Japanese Pharmacopoeia, Saltwater Port Semi-sugar Co., Ltd.) were dissolved in purified water, and then the total volume was made 400 mL with purified water. This solution is filtered through a filter (Stericup-GV 0.22 μm, PVDF, Millipore Corporation), and then a Tehha dispenser (FH-10s, Hirasawa Co., Ltd.) or a microscale pipette (PIPETMAN, GILSON, Inc., etc.) is used. Then, 4 mL was filled in a glass vial (body outer diameter 24.5 mm, inner diameter 22.1 mm) (Daiwa Special Glass Co., Ltd.). Thereafter, the carperitide-containing preparation of Formulation Example B was obtained by the same method as in Formulation Example A.

(3) Evaluation of heat and severe storage stability of carperitide-containing preparation One month in a constant temperature and humidity chamber (LH 31-15 M type, Nanono Scientific Machine Co., Ltd.) with the preparation of Formulation Examples A and B set at 40 ° C and 75% RH. It was stored for 1 month in a constant temperature bath (CH-P 30-01 type, Nanono Scientific Machinery Co., Ltd.) set at 50 ° C. for 3 months. With respect to these preparations, visual appearance determination (at the time of production: nine, after storage: three) was performed according to the same standard as in Example 1 at the time of manufacture, before and after each storage. In addition, for the preparation after storage, the content of carperitide and related substances was measured by the following method.

[Method: Measurement of Carperitide Content and Related Substances in Preparation]
Diluted acetic acid was added to one preparation to dissolve the contents, and then the total volume was adjusted to 10 mL to obtain a sample solution. In addition, this sample solution was diluted 20 times with dilute acetic acid to prepare a standard solution for related substances. As a standard solution for determination of carperitide, one prepared separately was used.
Measure sample solution, standard solution for determination of carperitide, standard solution for related substance test with reversed phase separation system using ODS column as stationary phase and water / acetonitrile as mobile phase by high performance liquid chromatograph (Shimadzu Corporation) (Number of measurements: 3).
The content was calculated as follows. The amount of carperitide per vial is calculated from the measurement results of the sample solution and standard solution for determination of carperitide by high performance liquid chromatography (detection: ultraviolet absorbance method), and the ratio to the design content of carperitide (1 mg) is determined Carperitide content (%).
The related substances were calculated as follows. From the measurement results of the sample solution and the standard solution for relative substances by high performance liquid chromatography (ultraviolet absorbance detection), the ratio of the peak area of the analog substance of the sample solution to the 20 times value of the peak area of This was regarded as the related substance mass (%).

[Result: Formulation characteristics and thermal stability of carperitide-containing preparation]
Table 4 shows the appearances of the preparations of Formulation Examples A and B at the time of production, and the evaluation results of the appearances and the ingredients after storage at 40 ° C., 75% RH for 1 month and 3 months, and at 50 ° C. for 1 month.
Formulation Example A (amount of sucrose: 500 mg / vial, 1.30 mg / mm ² , concentration of sucrose: 100 mg / mL), and Example B (amount of sucrose: 300 mg / vial: 0.78 mg / mm ² , sucrose) Each of the carperitide-containing preparations with a concentration of 75 mg / mL) maintained their external shape well from the normal shape during the heat stress period of 3 months at 40 ° C 75% RH and 1 month at 50 ° C. Is clear. In addition, it can be seen that the decrease in carperitide content and the increase in related substances are hardly observed during these heat and severe storage periods, and the chemical stability of the main drug is also extremely good. Further, the same tests were conducted separately under the same conditions for blending refined sucrose as in Formulation Examples A and B, and the moisture content at the time of heat stress storage was 0.5% or less at the time of production. From the above, it was shown that the lyophilized formulations prepared under these combination conditions have quality characteristics suitable for formulations stored at room temperature.

※: Actual measurement value (determination code of 3 preparations) is indicated.

Claims (8)

Glass cylindrical vial with an inner diameter of 20 to 29 mm, containing an effective amount of 1 mg of carperitide, which is a peptidic drug, and about 0.75 to 1.35 mg / mm ² of purified sucrose relative to the internal cross-sectional area of the container Lyophilized preparation characterized in that it is filled in and stable at room temperature storage.   The freeze-dried preparation according to claim 1, wherein the freeze-dried product has a good appearance after storage at 40 ° C for one month, and the water content is 1% or less.   The freeze-dried preparation according to claim 1, wherein the freeze-dried product has a good appearance after storage at 50 ° C for 1 month, and the water content is 1% or less.   The lyophilised preparation of claim 1, containing about 300 to 500 mg of purified white sugar.   5. The lyophilized formulation of claim 4, wherein the internal diameter of the cylindrical vial is about 22.1 mm.   The lyophilized preparation according to any one of claims 1 to 5, which substantially comprises purified sucrose and a peptidic drug as solid components. In an aqueous solution containing 140 mg / mL or less of purified sucrose and 1 mg of carperitide per vial, in a cylindrical glass vial having an inner diameter of 20 to 29 mm, the amount of purified sucrose relative to the internal cross-sectional area of the container is about 0.75 A method for producing a lyophilised preparation, characterized in that it is stable at room temperature storage, comprising the steps of: filling to ~ 1.35 mg / mm ² and lyophilizing the filled container.   The process according to claim 7, characterized in that in the freeze-dried preparation produced, the proportion of the preparation with good formulation quality properties is about 80% or more.