Medical device containing a cake composition comprising aripiprazole as active ingredient and cake c

专利摘要:

公开号:ES2884825T9
申请号:ES12703898T
申请日:2012-01-17
公开日:2022-01-25
发明作者:Shogo Hiraoka；Kiyoshi Taniguchi
申请人:Otsuka Pharmaceutical Co Ltd；
IPC主号:

专利说明:

[0001] Medical device containing a cake composition comprising aripiprazole as active ingredient and cake composition comprising aripiprazole as active ingredient
[0002] technical field
[0003] The present invention relates to a medical device equipped with a storage container containing an independently prepared lyophilized cake composition comprising aripiprazole as an active ingredient, in which there is a space between an internal wall of the storage container and the cake composition. , and to a cake composition comprising aripiprazole as an active ingredient and having a specific strength and shape.
[0004] prior art
[0005] Aripiprazole, which is used as an active ingredient in pharmaceutical compositions, is known as an atypical antipsychotic useful for the treatment of schizophrenia, and is represented by the following structural formula:
[0007]
[0010] A pharmaceutical composition comprising aripiprazole as an active ingredient is used, for example, by the following method: the pharmaceutical composition is suspended in a dispersion medium and the suspension thus obtained is lyophilized, thereby preparing a cake composition. The cake composition is mixed with a desired dispersion medium (injection liquid) and thus resuspended at the time of use. The resuspension is then injected intramuscularly or subcutaneously (for example, see patent documents 1 and 2).
[0011] Such a cake composition is produced by freeze-drying a medical fluid in a medical device such as a syringe, which also serves as a storage container (for example, see Patent Document 3). Furthermore, Patent Document 3 employs a form, the so-called double-chamber syringe, in which after freeze-drying a solution to prepare a freeze-dried substance in a syringe, the syringe is sealed by a stopper, and furthermore, a liquid is enclosed. injection into a separate chamber in the syringe.
[0012] The medical device having a shape similar to a syringe has a syringe barrel whose inner wall is treated with silicone to allow a sealing piston, such as a stopper, to slide smoothly into the syringe barrel. However, when a lyophilized substance is prepared in a storage container by enclosing a medical fluid of a pharmaceutical composition and lyophilizing the medical fluid in the storage container, the lyophilized substance comes into contact with the silicone-treated inner wall of the storage container. and the silicone used to treat the inner wall of the storage container may be mixed into the lyophilized substance due to a long period (several months) of storage.
[0013] reference list
[0014] Patent bibliography
[0015] PTL 1: US Patent No. 5006528
[0016] PTL 2: Japanese Unexamined Patent Publication No. 2007-509148
[0017] PTL 3: Japanese Unexamined Patent Publication No. H8-112333 (corresponding to WO 2005/041937) PTL 3: Japanese Unexamined Patent Publication No. H8-112333
[0018] US 2005/152981 relates to a process for making sterile aripiprazole having an average particle size of less than 100 microns but preferably greater than 25 microns using a converging jet crystallization process. The resulting bulk aripiprazole of desired particle size can be used to form a sterile lyophilized aripiprazole formulation which, upon constitution with water and intramuscular injection, releases aripiprazole over a period of at least about one week and up to about eight weeks. weeks.
[0019] WO 2009/017250 relates to a method of producing a suspension of aripiprazole, wherein the aripiprazole has an average particle size of 1 to 10 µm, the method comprising the steps of: (a) bulk aripiprazole blending and a vehicle for forming a primary suspension; (b) subjecting the primary suspension to a first comminution using, for example, a high shear pulverizing machine, a dispersing machine that applies a shear force to a material to be processed, a colloid mill, a dispersing machine ultrasonic or high pressure jet type emulsification dispersing machine to form a secondary suspension; and (c) subjecting the secondary slurry to a second spray using, for example, a high pressure jet type emulsification dispersing machine to form a final sterile slurry; and to a method of producing a lyophilized formulation from the aripiprazole suspension.
[0021] EP 0962229 discloses a medical syringe assembly including a first opening and a second opening at opposite ends of a tubular barrel having an inner wall. The inner wall includes an inner surface. A plug is slidably received in the tubular cylinder having an adjusting surface and including a portion for adjusting the inner wall surface of said tubular cylinder. A lubricant is disposed over a limited area of at least one element of the inner wall of the tubular cylinder and the fitting surface of said plug, whereby a sufficient quantity of lubricant is available to provide adequate friction reduction between the fitting surface. the inner wall of the tubular cylinder and the fitting surface of the plug.
[0023] Summary of the invention
[0025] technical problem
[0027] When a lyophilized substance was prepared in a storage container whose inner wall had been treated with silicone by enclosing a suspension (dispersion) of a pharmaceutical composition comprising aripiprazole as an active ingredient and lyophilizing the suspension (dispersion) in the storage container, and when the silicone was mixed into the lyophilized substance due to a long period (several months) of storage and the mixture was resuspended in a dispersion medium, the phenomenon of agglomeration of aripiprazole in the suspension was observed. Specifically, it became apparent that there is a problem that the presence of silicone causes an increase in the average particle size of aripiprazole in resuspension.
[0029] Such agglomeration of aripiprazole results in a reduced dissolution rate because the area in contact with the particles does not contribute to dissolving the particles. When the dissolution rate changes as described above, a dissolution profile results in which blood levels differ between the dispersion of aripiprazole in the suspension before undergoing lyophilization and the dispersion of aripiprazole in the suspension obtained by resuspending the suspension. lyophilized substance. This greatly affects the pharmacological efficacy and raises the following serious problem: the medicinal properties of aripiprazole are unable to sufficiently show its efficacy; clogging occurs when using the drug in an injection form; and physical stimulation occurs at the injection site due to the increased particle size.
[0031] An object of the present invention is to provide, with respect to the above problems, a medical device containing a cake composition containing aripiprazole as an active ingredient and which can suppress agglomeration of aripiprazole in a suspension obtained by resuspending a lyophilized substance; and a cake composition comprising aripiprazole as an active ingredient.
[0033] Solution to the problem
[0035] The present inventors conducted extensive studies in order to solve the above problem, and as a result, found that providing a space between the silicone-treated inner wall of the storage container and the cake composition enables the frequency of contact between the cake composition to be reduced. silicone and the cake composition and suppress mixing of the silicone in the suspension when the cake composition is resuspended. The present inventors also found a cake composition which can inhibit the breakage of the cake composition in the storage container, which is caused by external physical impacts; reduce the frequency of contact with the silicone used to treat the inner wall; and rapidly resuspended in a dispersion medium.
[0036] The present invention has been achieved by further studies based on the above findings.
[0038] [Item 1] A medical device containing an independently prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone, in which there is a space between the inner wall of the storage container and cake composition.
[0040] [Item 2] The medical device containing the cake composition according to item 1, wherein the cake composition is a cake composition that was freeze-dried in a container separate from the storage container.
[0042] [Item 3] The medical device containing the cake composition according to item 1 or 2, wherein the apparent volume of the cake composition represents 30 to 99% of the volume of the storage container.
[0043] [Item 4] The medical device containing the cake composition according to any one of items 1 to 3, wherein the container is cylindrical and the cake composition has a cylindrical shape.
[0044] [Item 5] The medical device containing the cake composition according to item 4, wherein an upper surface of the cylindrical cake composition is raised.
[0045] [Item 6] The medical device containing the cake composition according to item 4 or 5, wherein a lateral surface of the cylindrical cake composition is inclined, the angle of the inclination being 0.1 to 10°.
[0046] [Item 7] The medical device containing the cake composition according to any one of items 1 to 6, wherein the silicone-treated storage container is a vial or a syringe.
[0047] [Item 8] The medical device containing the cake composition according to item 7, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber.
[0048] [Item 9] The medical device containing the cake composition according to item 7, wherein the syringe has a chamber (A) for containing the cake composition and a chamber (B) for containing an injection liquid;
[0049] the chamber (A) is disposed on the side where a needle is located and the chamber (B) is disposed on the side where a plunger is located; Y
[0050] the cake composition is contained in chamber (A) and
[0051] the injection liquid is contained in chamber (B).
[0052] [Item 10] The medical device containing the cake composition according to any one of items 1 to 9, wherein the cake composition has a strength of 5 to 100 N.
[0053] [Item 11] A cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N, wherein the cake composition has a cylindrical shape and a side surface of the cylindrical cake composition is inclined, being the angle of inclination from 0.1 to 10°.
[0054] [Item 12] The cake composition according to item 11, wherein the percentage of aripiprazole in the cake composition is 60 to 95% by mass.
[0055] [Item 13] The cake composition according to item 11 or 12, wherein the amount of aripiprazole in the cake composition is 0.1 to 0.6 g.
[0056] [Item 14] The cake composition according to any one of items 11 to 13, obtained by freeze-drying 0.25 to 12 g of a suspension having a solid content of aripiprazole of 5 to 45% by mass.
[0057] [Item 15] The cake composition according to item 11, wherein an upper surface of the cylindrical cake composition is raised.
[0058] [Item 16] The cake composition according to any one of items 11 to 15, wherein the cake composition is used to be placed in a medical device comprising a cylindrical storage container.
[0059] [Item 17] The cake composition according to item 16, wherein the cake composition is a dough that was freeze-dried in a container separate from a storage container in the medical device.
[0060] [Item 18] A method for producing a medical device containing a cake composition comprising aripiprazole as an active ingredient, the method comprising
[0061] a step of enclosing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall of the storage container and the cake composition.
[0062] [Item 19] The method for producing the medical device according to item 18, wherein the silicone-treated storage container is a vial or a syringe.
[0063] [Item 20] The method for producing the medical device containing the cake composition according to item 19, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber.
[0064] [Item 21] The method for producing the medical device containing the cake composition according to item 20, wherein the syringe has a chamber (A) for containing the cake composition and a chamber (B) for containing a liquid injection;
[0065] the chamber (A) is disposed on the side where a needle is located and the chamber (B) is disposed on the side where a plunger is located; Y
[0066] the cake composition is contained in chamber (A) and
[0067] the injection liquid is contained in chamber (B).
[0068] [Item 22] A method for producing a cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N, the method comprising
[0069] a step of freeze-drying a suspension comprising aripiprazole as an active ingredient, wherein the cake composition has a cylindrical shape and a lateral surface of the cylindrical cake composition is inclined, the angle of the inclination being 0.1 to 10° .
[0070] The medical device containing a cake composition and the cake composition of the present invention are described in detail below.
[0071] The present invention relates to a medical device containing an independently prepared lyophilized cake composition comprising aripiprazole as active ingredient in a storage container whose inner wall is treated with silicone.
[0072] As used herein, "cake" in the cake composition means a dried solid that maintains the shape of the liquid prior to drying. For example, when using a vial having an internal columnar shape, the cake is a dried solid that maintains the columnar shape.
[0073] The cake composition of the present invention comprising aripiprazole as an active ingredient can be produced by freeze-drying a suspension comprising aripiprazole as an active ingredient.
[0074] The cake composition is enclosed in a storage container whose inner wall is treated with silicone, thereby allowing a space to be provided between the storage container and the cake composition. By providing a space between the silicone-treated inner wall of the storage container and the cake composition as described above, it is possible to suppress an increase in the average particle size of aripiprazole, which is caused by mixing of the silicone in the cake. cake composition when the cake composition that has been stored for a long period of time is resuspended in a dispersion medium. In other words, providing a gap can suppress agglomeration of aripiprazole particles.
[0075] When a cake composition is produced by placing the suspension in a conventional storage container and freeze-drying the suspension therein, the cake composition adheres to the inner wall of the silicone-treated storage container. Therefore, when the cake composition is resuspended, a large amount of the silicone is mixed into the suspension. This undesirably causes an increase in the average particle size of aripiprazole, which is an active ingredient.
[0076] The silicone treatment is carried out on the inner wall of the storage container. When the storage container is a vial, for example, the inner wall of the storage container means the inner side surface of the vial. When the storage container is a syringe, the inner wall means the inner surface of the syringe barrel. In the vial, the silicone inner wall treatment provides functions to reduce the amount of medical fluid remaining on the inner surface of the vial and to minimize the amount of medical fluid inserted therein. Also, in the syringe, the inner wall treatment with silicone provides a function as a lubricant for sliding a plunger and plugs (sealing pistons) provided in the syringe barrel.
[0077] Silicone treatment means applying and adhering silicone to the inner wall of the storage container and, if necessary, drying the surface to which the silicone is applied.
[0078] A vial, syringe or the like is used as a storage container which is treated with silicone. In the case of a syringe, a prefilled syringe is used in which the cake composition is enclosed. Thus, the syringe itself also serves as a storage container. Also, as the syringe, a single-chamber syringe or a syringe having multiple chambers in which a cake composition is contained in one of the chambers (hereinafter also referred to as a double-chamber syringe) is used.
[0079] A double-chamber syringe comprises a chamber (A) for containing a cake composition and a chamber (B) for containing an injection liquid (injection liquid), and has a structure that the chamber (A) is arranged in the side where a needle is located and the chamber (B) is arranged on the side where a plunger is located. The dual-chamber syringe is described below, with reference to the figures.
[0080] Figure 1 is a cross-sectional view showing an embodiment of a dual-chamber syringe. A dual-chamber syringe 1 comprises the following plugs (sealing pistons) on a syringe barrel 2, in the order described from the side on which a needle is located (i.e., one side of the end 6 on which a needle is located). a needle): a front cap 3, a central cap 4 and a terminal cap 5. Chamber A is defined by front cap 3 and center cap 4 and chamber B is defined by center cap 4 and end cap 5. The front plug 3 can be dispensed with. A front assembly 12 is provided which houses the front cap 3 when the syringe is used on the side of the end 6. When the front cap 3 is not provided, the syringe 1 may have a usual shape in which the end of the syringe 1 , but not the front assembly, is molded into a shape to which a needle is attached. When the front cap 3 is provided, the front cap 3 is housed in the front assembly 12 and a space is created between the front cap 3 and the front assembly 12, thereby forming a passage for discharging a suspension obtained by resuspending a composition 8 of cake in an injection liquid 9 to the end 6.
[0082] The cake composition 8 is enclosed in chamber (A) and the injection liquid 9 for resuspending the cake composition 8 is enclosed in chamber (B). In addition, the inner wall of the syringe tube 2 is treated with silicone 10. In addition, a branch 11 having an externally protruding shape from the inside of the side surface of the syringe tube is provided to transfer the injection liquid 9 to the chamber (A) in which the cake composition 8 is enclosed. The branch 11 is provided towards the end side 6 from the central plug 4. During storage, the injection liquid 9 is prevented from flowing to the chamber (A) side.
[0083] The dual-chamber syringe 1 may comprise one branch 11 or multiple branches 11.
[0085] The manner of use of the dual-chamber syringe 1, when used as the medical device of the present invention, is explained with reference to attached figures 2 to 4 .
[0087] A needle 13 is inserted into the end 6 of the double chamber syringe 1 and a plunger 14 is inserted into an opening 7 (see Figure 2).
[0089] The plunger 14 is pressed on the end 6 side from the opening 7 and thus the end cap 5 slides to the end 6 side. By further pressing on the plunger 14, the center cap 4 and the front cap 3 they also slide as the end cap 5 slides. When the central plug 4 reaches the bypass 11, the injection liquid 9 flows through the bypass 11 into the chamber (A) in which the cake composition 8 is enclosed (see Figure 3).
[0091] The cake composition in chamber (A) is resuspended by the injection liquid 9 that flowed therein, thereby providing a suspension 15. Furthermore, the front plug 3 lodges in the front assembly 12 as it is pressed. the plunger 14 and the resuspension 15 is discharged from the end 6 in which the needle 13 is inserted, through the space created between the front plug 3 and the front assembly 12 (see figure 4).
[0093] The length of the syringe barrel in the syringe (the length in which the stopper may be located) is preferably about 50 to 200 nm, and more preferably about 70 to 110 mm.
[0095] Also, the distance from the center of the front cap to the center of the center cap is preferably about 5 to 40 mm, and more preferably about 15 to 35 mm. The distance between the center part of the center cap to the center part of the end cap is preferably about 2 to 50 mm, and more preferably about 10 to 30 mm.
[0097] Also, the inner diameter of the syringe barrel is preferably about 5 to 30 mm, and more preferably about 10 to 20 mm.
[0099] The double-chamber syringe thus configured is preferable from the viewpoint that a cake composition and a dispersion medium (injection liquid) for resuspending the cake composition can be simultaneously enclosed in such a double-chamber syringe and therefore, the step of injecting a dispersion medium (injection liquid) at the time of use can be omitted.
[0101] When a single-chamber syringe is used as a storage container, an injection liquid is introduced into the syringe from the outside at the time of use, and thus the cake composition is resuspended for use.
[0103] The shape of the cake composition enclosed in the storage container is not particularly limited, as long as a space is created between the inner wall of the storage container and the cake composition. When the storage container is cylindrical such as a syringe tube, for example, the cake composition is preferably formed in a cylindrical shape.
[0105] In one embodiment, the cake composition is cylindrical and the container (which is separate from the storage container) used to freeze-dry the cake composition is molded using plastic so that the cake composition can be easily removed from the container and that the side of the container can be tilted further, as shown in Figure 5, to facilitate the molding of the part that will be in contact with a liquid. When the cake composition is shaped to have the slope described above, the angle ("a" in Figure 5) of the slope is from 0.1 to 10 degrees and preferably from 0.5 to 3 degrees. The slant can be partially or fully formed around the circumference.
[0107] Furthermore, as shown in Fig. 6, the upper surface of the cylindrical cake composition is raised. This provides a reducing effect of the contact area with the storage container (for example, in the case of the double chamber syringe, the contact with the front cap or the center cap is reduced). The distance ("L" in Figure 6) between the peak of the raised portion and the top surface is preferably about 0.5 to 5 mm, and more preferably about 1 to 3 mm.
[0109] The cylindrical cake composition may have a raised circumference to allow reduction of the contact area with the storage container (for example, in the case of the dual-chamber syringe, to reduce contact with the front cap or center cap). .
[0111] The apparent volume of the cake composition preferably represents about 30% or more, more preferably about 40% or more, and still more preferably 50% or more of the volume of the storage container from the viewpoint of inhibit breakage of the cake composition due to impact with the inner wall of the storage container during the production and transportation of the medical device of the present invention and shortens the overall length of the syringe. Further, the apparent volume of the cake composition is preferably about 99% or less, more preferably about 90% or less, and still more preferably 80% or less from the viewpoint of reducing the adhesion frequency of the silicone cake composition used to treat the inner wall of the storage container.
[0113] The term "bulk volume" means the volume of the cake composition when the cake composition is considered as a mass without microscopic pores, spaces, cracks and the like.
[0115] Also, the volume of the storage container refers to the volume occupied by the portion in which the cake composition is enclosed. For example, in the case of the double chamber syringe described below having multiple chambers, the volume of the storage container means the volume of the chamber portion (chamber (A)) in which the cake composition is enclosed.
[0117] The specific bulk volume of the cake composition is preferably from about 250 to 12,000 mm3, more preferably from about 500 to 5,000 mm3, and still more preferably from 800 to 1,600 mm3.
[0118] Furthermore, the volume of the storage container is preferably from about 250 to 40,000 mm3, more preferably from about 500 to 17,000 mm3, and even more preferably from 800 to 5,300 mm3.
[0119] The cake composition is obtained as follows: a cake composition is independently obtained by preparing a suspension composition comprising aripiprazole as an active ingredient and subsequently lyophilizing the suspension composition, and the independently obtained cake composition is transferred to the storage container . Therefore, it is preferable to freeze-dry the suspension in a container separate from the storage container to produce a cake composition mass and transfer the mass to the storage container.
[0121] As the material for the separate container, plastic is preferable, olefin-based resin and the like being more preferable, for example, from the following points of view: Although the resulting cake composition slightly expands when freeze-dried in the production of the cake composition, the expansion does not result in a strong adhesion between the cake composition and the container, or even if the adhesion occurs between the cake composition and the container, the cake composition can be easily removed from the container by deforming the container ; when the suspension is to be prepared aseptically, the container can be easily molded in an aseptic atmosphere and easily sterilized by radiation; and such materials are cost-effective and disposable. Non-limiting examples of the olefin resin include polyethylene-based resin, polypropylene-based resin, and the like.
[0123] The shape of the container (which is independent of the storage container) which is used to produce the cake composition is suitably determined depending on the shape of the cake composition. Hereinafter, a method for producing a cylindrical cake composition is described with reference to the figures, based on the shape of the container.
[0125] Figure 7 is a schematic view showing the shape of the container (which is separate from the storage container) used to produce the cylindrical cake composition. The container 16 has an opening 17 at the top. The suspension is poured through opening 17 and freeze-dried, thereby molding a cake composition in container 16. The molded cake composition can be easily removed from container 16 by pressing the lower surface 18. The inner surface of the container is preferably sloped to facilitate removal of the cake composition. The angle (a' in Figure 7) is the same as the angle of the resulting cake composition. The angle is 0.1 to 10 degrees and preferably 0.5 to 3 degrees. The slant can be partially or fully formed around the circumference.
[0126] In addition, the lower surface of the container (which is independent of the storage container) is preferably raised, so that the contact area with the storage container can be reduced (for example, in the case of the double chamber syringe, it is reduced). contact with the front cap or center cap) and the lyophilized cake can be easily removed from the container (which is separate from the storage container). Furthermore, in order to allow the resulting cake composition to be easily removed by pressing the bottom surface 18, the container may be provided with an outer frame 19 as shown in the schematic view of Fig. 8 and the cross-sectional view. from figure 9.
[0127] Examples of the silicone applied to the inner surface of the storage container include silicone oil or a silicone derivative that is used in known medical applications. Specifically, silicone is a linear polymer having a siloxane bond as backbone with a C i-6 alkyl group in the side chain. More specifically, the silicone may be one with the repeating unit represented by the following formula (1):
[0129]
[0132] In the formula (1), R1 and R2 are the same or different, and each represents a hydrogen atom or a C1-6 hydrocarbon group, where n is an integer from 1 to 1,000. Specific examples of hydrocarbon groups represented by R1 and R2 include methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group. When n is 2 or more, the repeat units may be the same or different. Specific examples of the silicone oil include dimethylpolysiloxane. The silicone oil derivative may be one in which the side chain substituent of the silicone and/or some of the terminal S1 substituents are replaced by, for example, a polyoxyalkylene group or a vinyl group.
[0133] The silicone oil and silicone oil derivative can be obtained from commercially available products, for example, Shin-Etsu Silicone KM72® and Shin-Etsu Silicone KF96ADF®, both produced by Shin-Etsu Chemical Co., Ltd., and Dow Corning® (produced by Dow Corning Corporation). An emulsion (Dow Corning* 365, 35% dimethicone NF emulsion (produced by Dow Corning Corporation)) containing a surfactant and water can also be used as the silicone oil.
[0134] The average molecular weight of the silicone is not particularly limited, and is preferably from 10 to 100,000. 000, more preferably from 100 to 10,000,000 and even more preferably from 200 to 10,000.
[0135] The average particle size of the aripiprazole contained in the cake composition which is stored in the storage container is preferably 0.1 µm or more, more preferably 0.5 µm or more, and still more preferably 1.5 µm or more. am or greater when used as a sustained release injectable preparation because, with these intervals, a sustained release lasting as long as 1 month can desirably be obtained. From the point of view of slowing sedimentation, improving ease of manufacture and preventing needle clogging during injection when, for example, a pre-filled syringe is used as a storage container, the average particle size of aripiprazole in the composition of cake is preferably less than 200 µm, more preferably less than 10 µm, and even more preferably about 4 µm or less.
[0136] Herein, "average particle size" refers to a volume-average diameter as measured by a laser diffraction scattering method. The particle distribution is measured using a laser diffraction scattering method and the average particle size is calculated based on the particle distribution. From the viewpoint of achieving sufficient strength to allow the cake composition to be removed from the container used for lyophilization, which is independent of the storage container, the content of the aripiprazole in the cake composition is preferably 60% by mass. or more, more preferably 65% by mass or more, and still more preferably 70% by mass or more. Furthermore, the content of the aripiprazole in the cake composition is preferably 95 mass% or less, more preferably 90 mass% or less, and still more preferably 80 mass% or less in order to stabilize the dispersion of the aripiprazole. in a liquid containing a suspending agent and the like.
[0137] The amount of the aripiprazole contained in the cake composition is preferably 0.1 g or more, more preferably 0.15 g or more, and still more preferably 0.2 g or more from the viewpoint of the dose that is necessary to maintain the effective blood concentration required in treatment after administration to the body. Furthermore, the amount of the aripiprazole contained in the cake composition is preferably 0.6 g or less, more preferably 0.55 g or less, and still more preferably 0.5 g or less from the viewpoint of safety with respect to physical stimulus to the body when given all at once.
[0138] Aripiprazole contained in the cake composition is known to exist in a variety of crystalline forms, including monohydrate forms (hydrated aripiprazole A) and many anhydrous forms, specifically, such as anhydrous crystal B, anhydrous crystal C, anhydrous crystal D, crystal E anhydrous, anhydrous crystal F and anhydrous crystal G. All of these forms can be used in the cake composition of the present invention.
[0140] The cake composition of the present invention may also appropriately contain other components, such as a suspending agent, a bulking agent, a buffer, a pH regulator, an excipient, a lubricant, a fluidizer, a disintegrant, a filler, a surfactant, a preservative, a flavoring agent, an odor-improving agent and a tonicity agent, in addition to aripiprazole which is used as an active ingredient.
[0142] The additives may be those disclosed in Japanese Unexamined Patent Publication No. 2007-509148 (WO2005/041937 translation).
[0144] The content of the suspending agent in the cake composition is preferably about 0.1 to 10% by mass, and more preferably about 1 to 5% by mass. Preferable examples of suspending agents include sodium carboxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, or a mixture of two or more thereof. However, the suspending agent is not limited thereto, and sodium carboxymethylcellulose and polyvinylpyrrolidone can be preferably used.
[0146] Examples of other suspending agents suitable for use as a carrier for aripiprazole include various polymers, low molecular weight oligomers, natural products, and surfactants (both nonionic and ionic). Specific examples include Cetylpyridinium Chloride, Gelatin, Casein, Lecithin (Phosphatide), Dextran, Glycerol, Gum Arabic, Cholesterol, Tragacanth, Stearic Acid, Benzalkonium Chloride, Calcium Stearate, Glyceryl Monostearate, Cetostearyl Alcohol, Cetomacrogol Wax Emulsifier, sorbitan ester, polyoxyethylene alkyl ether (for example, a Macrogol ether such as Cetomacrogol 1000), a polyoxyethylene castor oil derivative, and a polyoxyethylene sorbitan fatty acid ester (for example, commercially available Tween®, including Tween20® and Tween80® (produced by ICI Specialty Chemicals)). Other examples include polyethylene glycols (eg, Carbowax 3350® and 1450® and Carbopol 934® (produced by Union Carbide)), dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, calcium carboxymethylcellulose, hydroxypropylcellulose (for example, HPC, HPC-SL, and HPC-L), methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, magnesium aluminosilicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide- formaldehyde and 4-(1,1,3,3-tetramethylbutyl)-phenol (also known as Tyloxapol, Superione, and Triton), poloxamers (for example, Pluronic F68® and F108®, which are block copolymers of ethylene oxide and propylene's OXID); poloxamine (also known as, for example, Tetronic 908® and Poloxamine 908®, which are tetrafunctional block copolymers derived from the continuous addition of propylene oxide and ethylene oxide to ethylenediamine (produced by BASF Wyandotte Corporation, Parsippany, NJ); charged phospholipids, such as dimyristoylphosphatidylglycerol and dioctyl sulfosuccinate (DOSS); Tetronic 1508® (T-1508; produced by BASF Wyandotte Corporation), dialkyl esters of sodium sulfosuccinate (for example, Aerosol OT®, which is a dioctyl ester of sodium sulfosuccinate (produced by American Cyanamid)); Duponol P® (a sodium lauryl sulfate; produced by DuPont); Triton X-200® (an alkyl aryl polyether sulfonate; produced by Rohm and Haas); Crodestas F-110® ( a mixture of sucrose stearate and sucrose distearate; produced by Croda Inc.) p-isononylphenoxypoly-(glycidol) (also known as Olin-10G® or Surfactant 10-G® (Olin Chemicals. Stamford, Conn.)); Crodestas SL-40 ® (produced by Croda, Inc.); SA9OHCO (C1bH ³⁷ CH ² (CON(CH ³ ))-CH ² (CHOH) ⁴ (CH ² or H ⁾² (produced by Eastman Kodak Co.); decanoyl-N-methylglucamide; ndecyl-pD-glucopyranoside; n- Decyl-pD-maltopyranoside; n-dodecyl-pD-glucopyranoside; n-dodecyl-pD-maltoside; heptanoyl-N-methylglucamide; n-heptyl-pD-glucopyranoside; n-heptyl-pD-thioglucoside; n-hexyl-pD- glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl-pD-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-pD-glucopyranoside; and octyl-pD-thioglucopyranoside.
[0148] Most of these suspending agents are known pharmaceutical excipients, and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986), which specifically incorporates herein for reference. Suspending agents are commercially available, and can be produced by techniques known in the art.
[0150] The content of the bulking agent (also called cryoprotective/lyoprotective agent) in the cake composition is preferably about 5 to 40% by mass, more preferably about 10 to 30% by mass. by mass and still more preferably about 15 to 25% by mass. The bulking agent can be selected from, for example, mannitol, sucrose, maltose, xylitol, glucose, starch, and sorbitol, or a mixture of two or more thereof. However, the bulking agent is not limited thereto, and mannitol can be preferably used.
[0152] Preferable examples of buffers include sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate and TRIS buffer, or a mixture of two or more thereof. However, the buffer is not limited thereto, and sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate are preferably used.
[0154] When the cake composition is formed into a suspension by being dispersed in a dispersion medium at the time of use, the pH adjuster is used to adjust the pH of the aripiprazole suspension to about 6 to 7.5, preferably about 7. When the pH of the suspension obtained by dispersing the cake composition in a dispersion medium is higher than the desired value, ie about 7, an acid pH regulator is used. When the pH of the suspension is lower than the desired value, ie about 7, a basic pH regulator is used. As acidic pH regulator, hydrochloric acid or acetic acid, preferably hydrochloric acid, is used. Examples of basic regulators include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. Among these, sodium hydroxide is preferably used.
[0156] The suspension comprising aripiprazole before lyophilization as the active ingredient, which is the suspension used to prepare the cake composition, can be obtained by mixing a dispersion medium with a composition suitably comprising aripiprazole (i.e. the active ingredient). active), suspending agent, bulking agent, buffer, pH regulator, excipient. aforementioned lubricant, fluidizer, disintegrant, filler, surfactant, preservative, flavoring agent, odor-improving agent, tonicity agent and the like, such that the content thereof will be in the desirable ranges described above.
[0158] As the dispersion medium, water or a hydrated solvent containing water and an organic solvent is used. The organic solvent is one that is miscible with water. Examples thereof include alcohols, such as methanol, ethanol, propanol, and isopropanol; ketones, such as acetone; ethers, such as tetrahydrofuran; dimethylformamide; and mixtures thereof. Of these, ethanol is particularly preferred. The amount of water used for the hydrated solvent is not particularly limited, and is, for example, preferably at least 10% by mass of the solvent.
[0160] Preferably, a wet spray technique is used, and the dispersed aripiprazole particles are sprayed in the presence of a spray medium to have a desired average particle size.
[0162] Preferably, an antiseptic wet spray technique is used, such as wet ball milling, high pressure homogenization or high shear homogenization. In addition to these pulverizing techniques, a low energy or high energy mill (eg roller mill) can also be used.
[0164] The use of, for example, controlled crystallization is also possible.
[0166] A homogeneous suspension of aripiprazole having a desired average particle size can be obtained using the aforementioned methods.
[0168] The average primary particle size of aripiprazole in the suspension is preferably 0.1 µm or larger, more preferably 0.5 µm or larger, and still more preferably 1.5 µm or larger in a release injectable preparation. sustained because, with these intervals, a sustained release lasting as long as a month can desirably be obtained. From the viewpoint of slowing sedimentation, improving ease of manufacture and preventing needle clogging during injections, the average particle size of aripiprazole in the cake composition is preferably less than 200 µm, more preferably less than 10 |im and even more preferably about 4 |im or less.
[0170] "Average particle size" can be measured using the same method that was used to measure cake composition. The term "primary particle size" refers to the particle size of each individual particle, not the particle size of agglomerated particles.
[0172] "Average particle size" refers to a volume average diameter as measured by a laser light scattering (LLS) method. The particle distribution is measured by LLS, and the average particle size is calculated based on the particle distribution.
[0174] Aripiprazole with the desired average primary particle size can be produced preferably using, for example, a converging jet crystallization method (see Japanese Unexamined Patent Publication No. 2007-509153 (translation of WO2005/041970) filed by Bristol-Myers Squibb), or a wet spray method using a high-pressure homogenizer (see Japanese Patent Application No. 2007-200088 filed by Otsuka Pharmaceutical Co., Ltd.).
[0175] The crystal forms of the aripiprazole contained in the suspension may be the same as those of the aripiprazole contained in the cake composition.
[0177] The solid content of aripiprazole in the suspension is preferably 5% by mass or more, more preferably 10% by mass or more, and still more preferably 20% by mass or more, since having such a solid content reduces syringe size by reducing cake volume after lyophilization, imparts cake strength to resist generation of fine particles, and allows for smaller dose delivery. Furthermore, the solid content of aripiprazole in the suspension is preferably 45 mass% or less, more preferably 40 mass% or less, and still more preferably 35 mass% or less, since having a solid content of This type achieves excellent production efficiency due to good fluidity of liquid during production and reduces the load on manufacturing equipment due to low viscosity.
[0179] The amount of aripiprazole contained in the suspension is preferably 0.1 g or more, more preferably 0.15 g or more, and still more preferably 0.2 g or more from the point of view of the dose that is necessary to maintain the concentration. effective blood supply required in treatment after administration to the body. Furthermore, the amount of aripiprazole contained in the suspension is preferably 0.6 g or less, more preferably 0.55 g or less, and still more preferably 0.5 g or less from the viewpoint of safety with respect to physical stimulation. for the body when given at one time.
[0181] The cake composition can be prepared by freeze-drying the suspension. The conditions for lyophilization can be suitably selected. For example, lyophilization can be performed by freezing the suspension at -50 to -30°C, followed by drying for 12 hours at a reduced pressure of preferably about 5 to 40 Pa and more preferably about 5 to 20 Pa, at a temperature preferably from about -15 to 10°C and more preferably from about -10 to 5°C.
[0183] The cake composition obtained by freeze-drying the suspension does not break even when external physical impacts are applied thereto, and can keep its shape as a dough.
[0185] The strength of the cake composition is 5N or more, more preferably about 10N or more, and still more preferably about 20N or more from the following viewpoint. That is, the cake composition is not broken during production, transportation or the like due to vibration from outside, etc.; the cake composition can be easily removed from the container used for freeze-drying, which is separate from the storage container; etc. Further, the strength of the cake composition is 100 N or less, more preferably about 80 N less, and still more preferably about 50 N less from the viewpoint that, for example, the cake composition can be quickly suspended. in a dispersion medium when used.
[0187] The strength of the cake composition can be measured using a stress measuring apparatus, such as an Autograph AG-I Universal Tester (Shimazu Corporation). The strength of the cake composition is measured, for example, by crushing and pressing the cake composition in the vertical direction (ie from the top and the bottom) and measuring the stress applied until it breaks.
[0189] When the cake composition is stored in a container whose inner wall is treated with silicone, in order to reduce contact with silicone, it is necessary to prevent the generation of fine particles due to impacts applied during transportation, etc. With this in mind, the amount of fine particles formed by breaking the cake composition is preferably about 100 mg or less, more preferably about 30 mg or less, and still more preferably about 10 mg or less. Also, from the standpoint of appearance, it is preferable that the generation of fine particles is reduced. The weight of fine particles generated is preferably about 25% or less, more preferably about 10% or less, and even more preferably about 3% or less relative to the total weight of the cake composition.
[0191] The breakage of the cake composition is evaluated in the following manner. The cake composition is placed on a screen with a diameter of 80 mm and openings of 2 mm and covered with a lid at a location 22 mm above the screen, and the screen containing the cake composition is fixed in a device Bioshaker V-BR-36 produced by TAITEC Co., Ltd. After shaking at 300 rpm for 10 minutes, the weight of the powder passed through the sieve is measured.
[0193] The cake composition of the present invention can be resuspended by adding the dispersion medium used to prepare the suspension that was used before lyophilization. Examples of the dispersion medium used for this purpose include water (preferably distilled water), an aqueous polymer solution and an aqueous surfactant solution. The resulting resuspended solution is used as injection liquid.
[0195] The amount of the dispersion medium used to resuspend the cake composition is not particularly limited, provided that it can be administered subcutaneously or intramuscularly. The amount thereof is preferably 0.5 to 3 ml, and more preferably 1 to 2 ml.
[0196] The series of procedures for obtaining a medical device containing the cake composition of the present invention is preferably carried out in a sterilized room.
[0197] The medical device containing the cake composition of the present invention has a space between the cake composition and the storage container whose inner wall is treated with silicone. This prevents direct contact of the cake composition with the silicone. Therefore, it is possible to suppress the agglomeration of aripiprazole caused by the silicone applied to the inner wall of the storage container when the freeze-dried cake composition is resuspended after long-term storage.
[0198] The cake composition of the present invention comprising aripiprazole as an active ingredient has a specific strength that prevents the cake composition from breaking when external physical impacts are applied and allows the cake composition to be quickly resuspended when mixed with a mixing medium. dispersion at the time of use. Therefore, the cake composition of the present invention is suitably used as a cake composition enclosed in a medical device.
[0199] Advantageous effects of the invention
[0200] The medical device containing the cake composition of the present invention has a space between the cake composition and the silicone-treated inner wall of the storage container. This reduces the frequency with which the cake composition will be in contact with the silicone and reduces the risk of the silicone contaminating the suspension when the cake composition is resuspended. This allows the aripiprazole, which is an active ingredient contained in the suspension, after resuspension to be satisfactorily redispersed without agglomeration.
[0201] In addition, since the cake composition of the present invention containing aripiprazole as an active ingredient has specific strength, it will not break even when external physical impact is applied during production and transportation. Furthermore, the cake composition can be rapidly dispersed without agglomeration when resuspended in a dispersion medium at the time of use.
[0202] Brief description of the drawings
[0203] Figure 1 is a sectional view illustrating one embodiment of a dual chamber syringe.
[0204] Figure 2 is a sectional view showing the dual-chamber syringe at the time of use.
[0205] Figure 3 is a sectional view showing the dual-chamber syringe at the time of use.
[0206] Figure 4 is a sectional view showing the dual-chamber syringe at the time of use.
[0207] Figure 5 is a schematic diagram illustrating a cylindrical cake composition having a sloped side surface.
[0208] Figure 6 is a schematic diagram illustrating a cylindrical cake composition having a sloped side surface and a raised top surface.
[0209] Figure 7 is a schematic diagram illustrating one embodiment of the shape of a container, which is separate from the storage container, used to prepare the cylindrical cake composition.
[0210] Figure 8 is a schematic diagram illustrating one embodiment of the shape of a container, which is separate from the storage container, used to prepare the cylindrical cake composition.
[0211] Figure 9 is a sectional view of the schematic diagram illustrating an embodiment of the shape of a container, which is separate from the storage container, used to prepare the cylindrical cake composition. Figure 10 is a photograph of the lateral surface of the cake composition prepared in Example 1.
[0212] Figure 11 is a photograph of the lateral surface of the cake composition prepared in Example 6.
[0213] Description of achievements
[0214] examples
[0215] The present invention is described below in more detail with reference to examples and examples comparatives. However, it should be understood that the present invention is not limited to the following embodiments.
[0217] • Example 1
[0219] The components shown below were individually dissolved or suspended in water to prepare a dispersion containing the components in the following amounts per 1 mL of the final dispersion: 12.48 mg carboxymethylcellulose, 62.4 mg mannitol, 1.11 mg of sodium dihydrogen phosphate monohydrate and 312.0 mg of aripiprazole hydrate. The pH was adjusted to about 7 with sodium hydroxide.
[0221] This suspension was preliminarily pulverized with a high shear rotary homogenizer (Clearmix, produced by M Technique Co., Ltd.) and then repeatedly wet pulverized with a high pressure homogenizer (produced by Niro) at 550 bar to a medium size. of 3 µm or less particle to thereby produce a suspension containing about 30% aripiprazole.
[0223] About 1.7 ml of the suspension prepared above (containing about 510 mg of aripiprazole) was inserted into a polyethylene molded plastic container having an inner side surface inclined at an angle of 2° and having a bottom surface with a thickness of 1 mm or less, the container being deformable to allow a lyophilized product to be expelled therefrom when the bottom surface is pressed from the outside. The container containing the suspension was transferred to a freeze-dryer and freeze-dried according to the cycle described below to obtain a cake composition. The theoretical content of aripiprazole in the cake composition was about 77% by mass. The obtained cake composition had an apparent volume that was substantially equal to the originally inserted volume, with only a slight increase being observed. Therefore, the apparent volume was approximately 1,700 mm3. Figure 10 shows a photograph of the cake composition.
[0225] (a) Thermal treatment: the product was frozen by keeping it at about -40°C for at least 3 hours.
[0226] (b) Primary drying: Primary drying was continued for at least 24 hours at an increased storage temperature of about -5°C under a pressure of about 20 Pa or less.
[0228] The obtained cake composition was removed from the plastic container. The cake composition was shaped such that the top surface was raised 2 mm from the inserted liquid level and the side surface was inclined at an angle of 1° or more. Other cake compositions prepared simultaneously were also measured. The results showed that all cake compositions were raised 0.5 mm or more.
[0230] The strength of the obtained cake composition was measured using an Autograph AG-I universal testing instrument (Shimadzu Corporation) by crushing and pressing the cake composition of Fig. 6 from the top and the bottom. The cake composition had a strength of 49 N.
[0232] Results and Discussion
[0234] The cake composition obtained in Example 1 had a relatively high strength of 49 N. Therefore, the freeze-dried cake composition was easily removed from the container without breaking when it was ejected from the container.
[0235] The cake composition obtained in Example 1 was characterized by slight swelling when freeze-dried. In Example 1, the inner side surface of the plastic container was slanted. Thus, by using a container that could be deformed by pressing the bottom surface, the freeze-dried cake composition was easily removed from the container without the need to use other moving parts to expel the cake composition from the container or to apply a release agent to the inner surface. container, while maintaining its lyophilized form inside the container.
[0237] • Examples 2-1 to 2-9
[0239] 1. Production of siliconized syringe
[0241] Dow Corning® 365, a 35% dimethicone NF emulsion (produced by Dow Corning Corporation) was diluted to various concentrations with purified water. The thus prepared silicone oil emulsion was applied to a glass syringe (internal diameter 0 14.0 x length 106 mm; internal area 4,660 mm2, capacity 16,309 mm3) and the water was evaporated to dryness at about 300°C. .
[0243] Silicone oil applied to the inner surface of the glass was quantified by washing the inner surface of the glass tube with methyl isobutyl ketone and then measuring the dissolution using an atomic absorption spectrometer with a Si measuring lamp under the following conditions.
[0245] Measurement wavelength: 251.6nm
[0246] Drying: from 50 to 80°C, 40 s
[0247] Calcination: 1,000°C, 20s
[0248] Atomization: 2,700°C, 5s
[0249] Cleaning: 2,800°C, 15s
[0250] Cooldown: 17s
[0251] 2. Re-suspension of the cake composition
[0252] A suspension containing about 30% aripiprazole with an average particle size of 2.1 µm was prepared and lyophilized in the same manner as in Example 1 to obtain a cake composition.
[0253] The cake composition was transferred from the plastic container to a siliconized syringe produced as described in item 1. A stopper was fitted inside the syringe. To maintain tightness during storage, the stopper was characterized as slightly larger than the internal diameter of the syringe and slippery due to silicone oil applied to the internal lateral surface of the syringe. The cake composition was transferred to the syringe and then stored at room temperature for about 1 month. The amount of silicone oil in the cake composition was determined by extracting a resuspension of the cake composition in water with methyl isobutyl ketone and then measuring the dissolution of methyl isobutyl ketone using an atomic absorption spectrometer.
[0254] After storage for about 1 month, the cake composition was resuspended in about 2 ml of water and the particle size in the suspension was measured using a laser diffraction particle size analyzer produced by Shimadzu Corporation (SALD-3000J or SALD -3100). Measurement was performed at a refractive index of 2.00 to 0.201, using water as the measurement medium in a circulation cell. Independently, the suspension was sonicated for 1 min with an ultrasonic wave generator coupled to the particle size analyzer and the mean particle size of the sonicated suspension was measured in the same manner as described. previously.
[0255] Table 1 shows the average particle size of aripiprazole before lyophilization, the concentration of silicone oil applied to the syringe, the amount of silicone oil in the syringe, the amount of silicone oil after storage for 1 month of the syringe containing the cake composition at room temperature and from the resuspension of the cake composition, and the average particle size of aripiprazole after resuspension. Table 1
[0258] Results and Discussion
[0260] As shown in Table 1, the amount of silicone oil in the resuspended cake compositions varied according to the concentration of silicone oil in the applied emulsion.
[0262] Furthermore, even when the concentration of silicone oil in the applied emulsion was 0%, silicone oil was detected in the cake composition (reference example). This was probably because the silicone oil originally contained in the plug had transferred into the cake composition. However, since the cake composition had a convex, i.e., raised, top surface, as described in Example 1, which minimized contact of the cake composition with the plug, the amount of silicone oil mixed in the cake composition it was extremely small.
[0264] No change in the average particle size of aripiprazole was observed in any of the syringes prepared using various concentrations of the silicone oil emulsions in Examples 2-1 through 2-9. Particle agglomeration due to silicone oil can be confirmed by a reduction in particle size in the measurement under ultrasonic irradiation. The particle size was measured before and after ultrasonic irradiation, and no change in particle size was observed in between. Therefore, it was determined that no agglomeration had occurred.
[0266] Example 3
[0268] A suspension containing about 30% by mass of aripiprazole was prepared and lyophilized in the same manner as in Example 1 to obtain a cake composition.
[0270] As the syringe, a double-chamber syringe with an inner diameter of 14 mm was used as shown in Fig. 1 (capacity of the chamber in which the cake composition was enclosed: about 3,000 mm3), and a central plug 4 as shown in figure 1 using the hermetic cap method. After approximately 1.7 ml of water was inserted into the syringe, an end cap was fitted using the airtight cap method.
[0272] The aripiprazole-containing cake composition obtained by lyophilization in a plastic container was removed from the plastic container by pressing the bottom surface of the plastic container and directly transferred to a space above a central plug 4 as shown in Fig. 1 into the syringe into which water was inserted. A front plug 3 was fitted as shown in Figure 1 using the tight cap method. A front assembly 12 as shown in Fig. 1 was fitted onto the syringe to obtain a pre-filled syringe containing the cake composition with aripiprazole as the active ingredient.
[0274] The apparent volume of the cake composition was approximately 60% of the capacity of the pre-filled syringe storage container (the capacity of the chamber in which the cake composition was enclosed). The end cap was depressed by a plunger to allow water, as a redispersion medium, to flow into chamber A in which the cake composition was enclosed. After mixing, the syringe was shaken vigorously to achieve complete resuspension. The end cap was pressed against the end to expel the medicinal fluid from the syringe. The amount of medicinal fluid remaining in the syringe was measured and found to be about 36 to 40 mg (about 38 mg on average).
[0276] This is the amount of medicinal fluid remaining in the gaps of the cap and front assembly, ie the so-called dead space of the outlet. The pre-filled syringe obtained by this method was considered to fully perform the functions required for administration.
[0278] Similarly, using a pre-filled syringe in which the cake composition containing aripiprazole as the active ingredient was enclosed, the end cap was slowly pressed to allow water, as a redispersion medium, to flow into a front chamber for approximately 5 seconds. . Without shaking the syringe at all, the end cap was pressed against the end to expel the suspension from the syringe.
[0280] The amount of medicinal fluid remaining in the syringe was measured and found to be about 74 to 95 mg (about 85 mg on average). The amount of medicinal fluid remaining in the gaps of the plug and the front assembly, ie, the so-called dead space of the outlet, was about 38 mg on average. Since the syringe was not shaken, approximately 47 mg remained in the syringe, which was obtained by subtracting 38 mg from 85 mg. However, the pre-filled syringe obtained by this method was considered to be satisfactory in performing the functions required for administration.
[0282] • Example 4
[0284] The components shown below were individually dissolved or suspended in water to prepare a dispersion containing the components in the following amounts per 1 mL of the final dispersion: 8.32 mg of carboxymethylcellulose, 4.16 mg mannitol, 0.74 mg sodium dihydrogen phosphate monohydrate, and 208.0 mg aripiprazole hydrate. The pH was adjusted to about 7 with sodium hydroxide.
[0286] This suspension was preliminarily pulverized with a high shear rotary homogenizer (Clearmix, produced by M Technique Co., Ltd.) and then repeatedly wet pulverized with a high pressure homogenizer (produced by Niro) at 550 bar to a medium size. of particle of 3 µm or less to thereby produce a suspension containing about 20% by mass of aripiprazole.
[0288] About 2 ml of the suspension prepared above (containing about 400 mg of aripiprazole) was inserted into a molded polyethylene plastic container having an inner side surface inclined at an angle of 2° and having a bottom surface with a thickness of 2°. 1 mm or less, the container being deformable to allow a lyophilized product to be expelled therefrom when the lower surface was pressed from the outside. The container containing the suspension was transferred to a freeze-dryer and freeze-dried according to the cycle described below to obtain a cake composition. The theoretical content of aripiprazole in the cake composition was about 77% by mass. The obtained cake composition had an apparent volume that was substantially equal to the originally inserted volume, with only a slight increase being observed. Therefore, the apparent volume was approximately 2,000 mm3.
[0290] (a) Thermal treatment: the product was frozen by keeping it at about -40°C for at least 3 hours.
[0291] (b) Primary drying: Primary drying was continued for at least 24 hours at an increased storage temperature of about -5°C under a pressure of about 20 Pa or less.
[0293] The obtained cake composition was removed from the plastic container by pressing the lower surface of the plastic container. The cake composition was easily removed from the container while retaining its lyophilized form within the container, without the need to use other moving parts to expel the cake composition from the container or to apply a release agent to the internal surface of the container.
[0295] • Examples 5-1 to 5-3
[0297] A suspension containing approximately 30% by mass of aripiprazole was prepared in the same manner as in Example 1. This suspension was diluted with purified water to obtain suspensions containing approximately 10% by mass, 20% by mass and the 30% by mass of aripiprazole. These suspensions were freeze-dried in the same manner as in Example 1 to obtain cake compositions. Table 2 shows the ease of removal of the obtained cake compositions from the containers.
[0299] Table 2
[0304] Results and Discussion
[0306] Each of the aripiprazole-containing cake compositions obtained by lyophilization in a plastic container was removed from the plastic container by pressing the lower surface of the plastic container. All the cake compositions obtained in Examples 5-1 to 5-3 were easily removed from the containers. The strength of the cake compositions obtained by lyophilization was measured using an Autograph AG-I universal tester (Shimadzu Corporation) in the same manner as in Example 1. The cake composition produced using the suspension containing about 10% The aripiprazole dough prepared in Example 5-1 had a strength of about 7N. Even when the container is configured to allow easy removal, the cake composition must have some strength.
[0308] • Example 6
[0310] A container was produced as described in example 1 using polypropylene, and a cake composition was produced in the same manner as in example 1.
[0312] The cake composition obtained by lyophilization in the plastic container was removed from the plastic container pressing the bottom surface of the plastic container and transferred directly into a syringe. The cake composition was easily removed from the container while retaining its lyophilized form within the container, without the need to use other moving parts to expel the cake composition from the container or to apply a release agent to the internal surface of the container. Figure 11 shows a photograph of the cake composition obtained.
[0313] It was confirmed that the obtained cake composition had a raised portion on the circumference of the upper surface. The cake composition obtained was raised 0.5 mm or more on the circumference of the upper surface, although the shape was different from that of the cake composition obtained using the polyethylene container described above in Example 1.
[0315] The cake composition was enclosed in a syringe to produce a prefilled syringe (capacity of the chamber in which the cake composition was enclosed: about 3,500 mm3). The apparent volume of the cake composition was approximately 50% of the capacity of the pre-filled syringe storage container (the capacity of the chamber in which the cake composition was enclosed). The syringe used was of the so-called single-chamber type, which only has one space to contain a medicinal agent. The lyophilized cake composition was easily resuspended by drawing water as redispersion medium into the syringe during resuspension.
[0317] • Example 7
[0319] A suspension containing about 30% by mass of aripiprazole was obtained in the same manner as in Example 1. About 1.5 ml to about 1.7 ml of this suspension were inserted into a plastic container molded with polyethylene and it was lyophilized to obtain a cake composition. The obtained cake composition weighed about 600 mg. This cake composition was placed on a screen with openings of 2 mm and a diameter of 80 mm and covered with a lid 22 mm above the screen. The sieve was fixed in a Bioshaker V-BR-36 device produced by TAITEC Co., Ltd., and shaken at 300 rpm for 10 minutes. The amount of powder that passed through the sieve openings was about 1 to 9 mg.
[0321] Results and Discussion
[0323] The results of example 7 showed that, despite being produced by freeze-drying, this cake composition was not brittle and was less likely to break and generate fine dust due to impacts during transportation, etc. In general, freeze-dried cake compositions are brittle and often break due to strong impacts as in the above test. If fine powder is generated from this pharmaceutical preparation, it may come into contact with the silicone on the inner surface A in Fig. 1 and thereby increase the particle size, etc. Furthermore, the generation of fine dust would give rise to an undesirable appearance. The above results showed that this production method can produce a cake composition whose surface is not brittle and from which fine dust is unlikely to be generated.
[0325] • Examples 8-1 to 8-3
[0327] A suspension containing approximately 30% aripiprazole was obtained in the same manner as in Example 1, except that sucrose was used instead of mannitol. The suspension was diluted with purified water in the same manner as in Example 5 to obtain suspensions containing about 10% by mass, 20% by mass and 30% by mass of aripiprazole. Suspensions were lyophilized using plastic containers. As in Example 1, without the need to use other moving parts to expel the cake composition from the container or to apply a release agent to the internal surface of the container, each cake composition was easily removed from the container while retaining its original content. lyophilized form inside the container. Table 3 shows the ease of removal of the obtained cake compositions from the containers.
[0329] Table 3
[0334] Results and Discussion
[0336] Even when mannitol was used instead of sucrose, the cake composition produced using a suspension that contained about 10% by mass of aripiprazole had a strength of about 11 N.
[0337] • Comparative Examples 1-1 to 1-9
[0338] A suspension containing about 30% by mass of aripiprazole with an average particle size of 2.2 µm was prepared in the same manner as in Example 1. In the syringes produced by applying silicone oil emulsions of various concentrations prepared in Example 2 and drying, a center plug with an outside diameter slightly larger than the inside diameter of the syringe was fitted using the tight cap method. Approximately 1.5 mL of the suspension was inserted into the space above the center plug and lyophilized as such within the syringe. After lyophilization, a front cap was fitted using the tight cap method. After lyophilization, the syringes were stored at room temperature for about 1 month, and the amount of silicone oil in the cake composition was measured in the same manner as in Example 2. In each of the syringes containing the composition of cake, the cake composition adhered to the syringe barrel and there was no space between the inner wall of the syringe and the cake composition.
[0339] Table 4 shows the average particle size of aripiprazole before lyophilization, the concentration of silicone oil applied to the syringe, the amount of silicone oil in the syringe, the amount of silicone oil after storage for 1 month of the syringe containing the cake composition at room temperature and from the resuspension of the cake composition, and the average particle size of aripiprazole after resuspension. Table 4
[0343] Results and Discussion
[0344] The results shown in Table 4 indicate that the higher the concentration of the silicone oil emulsion applied to the syringe, the higher the silicone oil content of the cake composition; and the higher the concentration of silicone oil applied to the syringe, the greater the change in average particle size. Compared to a pre-filled syringe preparation using the cake composition obtained by lyophilization in a different storage container than that described in Example 2, different results were obtained even at the same applied silicone oil emulsion concentration.
[0345] Even when the silicone oil concentration in the applied emulsion was 0%, silicone oil was detected in the cake composition. This was probably because the silicone oil originally contained in the plug had transferred into the cake composition.
[0346] When agglomerated particles were measured under ultrasonic irradiation, the size of the loose particles changes. When the particle size was measured under ultrasonic irradiation in this comparative example, a reduction in particle size was observed. This result indicates that, according to the method comprising the lyophilization in a syringe, the silicone oil causes agglomeration.
[0348] • Comparative Examples 2-1 to 2-12
[0350] Suspensions containing about 20% by mass of aripiprazole with an average particle size of 2.0 µm and 2.4 µm were individually prepared in the same manner as in example 4. In syringes produced by applying the oil emulsions silicone of various concentrations prepared in Example 2, a center plug with an outer diameter slightly larger than the inner diameter of the syringe was fitted using the tight cap method. Approximately 2 mL of the suspension was inserted into the space above the center plug and lyophilized as such within the syringe. In each of the syringes containing the cake composition, the cake composition adhered to the syringe barrel and there was no gap between the inner wall of the syringe and the cake composition.
[0352] After lyophilization, the syringes were stored at room temperature for 1 month, 2 months, and 3 months. After storage, the cake composition inside the syringes was resuspended in approximately 2 ml of water and the average particle size was measured in the same manner as in Example 2. Table 5 shows the concentration of silicone oil applied to the syringe, the mean particle size of aripiprazole before lyophilization and the mean particle size of aripiprazole after storage at room temperature for 1 month, 2 months and 3 months and resuspension.
[0354] Table 5
[0359] Results and Discussion
[0361] As shown in Table 5, the results indicate that the higher the concentration of the silicone oil emulsion applied to the syringe, the greater the change in particle size. As in Comparative Example 1, even with the use of a suspension containing about 20% by mass of aripiprazole, if the cake composition obtained by lyophilization was resuspended into a syringe as such, changes in the average size were observed. of aripiprazole particle.
[0363] • Comparative example 3
[0365] A suspension containing about 30% by mass of aripiprazole was prepared in the same manner as in Example 1. In a syringe produced by applying a 5% by mass silicone oil emulsion in the same manner as in Example 2, a center plug with an outer diameter slightly larger than the inner diameter of the syringe was fitted using the tight cap method. Approximately 1.5 ml of the suspension was inserted into the space above the center plug and the syringe was transferred to a lyophilizer. The suspension was lyophilized according to the cycle described below to prepare a syringe in which the cake composition was enclosed. In the syringe containing the cake composition, the cake composition adhered to the syringe barrel and there was no space between the inner wall of the syringe and the cake composition.
[0366] (a) Heat treatment: The product was frozen by keeping it at about -40°C for about 3 hours.
[0367] (b) Primary drying: Primary drying was continued for at least 24 hours at an increased storage temperature of about -5°C under a pressure of about 20 Pa or less.
[0368] A front stopper was fitted above the cake composition inside the obtained syringe (on the needle side, at the position of front stopper 3 shown in Fig. 1) using the hermetic cap method. Approximately 1.7 mL of water as redispersion medium was inserted into chamber B, which is defined by the center cap and end cap of the prefilled syringe. The end cap was fitted using the tight cap method. A front assembly was incorporated into the ejection portion of the syringe tip. The end cap was slowly pressed to allow water as a redispersion medium to flow into a front chamber for about 5 seconds. Without shaking the syringe at all, the end cap was pressed against the end to expel the medicinal fluid from the syringe. The amount of medicinal fluid remaining in the syringe was measured and found to be about 159 mg.
[0369] Results and Discussion
[0370] In general, a dual chamber prefilled syringe preparation is prepared by lyophilizing it inside a syringe as described in Comparative Example 3. Similarly to the above, after allowing water to flow into a front chamber for a period of about 5 seconds, a medicinal fluid was ejected without shaking the syringe at all. The amount of remaining medicinal fluid was measured and found to be about 159 mg, that is, a very large amount. Therefore, the results show that, compared with the method of Example 3, in which about 85 mg of medicinal fluid remained, the general method described in Comparative Example 3 showed poor redispersibility.
[0371] List of reference signs
[0372] To: Camera
[0373] B: Camera
[0374] 1: Double chamber syringe
[0375] 2: syringe tube
[0376] 3: Front plug
[0377] 4: Center Plug
[0378] 5: End cap
[0379] 6: tip
[0380] 7: Opening
[0381] 8: Cake Composition
[0382] 9: injection liquid
[0383] 10: silicone
[0384] 11: Bypass
[0385] 12: Front Assembly
[0386] 13: Hypodermic needle
[0387] 14: Plunger
[0388] 15: Suspension
[0389] to: Angle
[0390] a': Angle
[0391] L: Length from top raised point to top surface 16: Bowl
[0392] 17: Opening
[0393] 18: Bottom surface
[0394] 19: Outer frame

权利要求:
Claims (18)
[1]
1. Medical device containing a separately prepared lyophilized cake composition comprising aripiprazole as active ingredient in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall of the storage container and the cake composition cake.
[2]
2. Medical device containing the cake composition according to claim 1, wherein the cake composition is a cake composition that was freeze-dried in a container separate from the storage container.
[3]
3. Medical device containing the cake composition according to claim 1 or 2, wherein the apparent volume of the cake composition represents 30 to 99% of the volume of the storage container.
[4]
4. Medical device containing the cake composition according to any one of claims 1 to 3, wherein the container is cylindrical and the cake composition has a cylindrical shape.
[5]
5. Medical device containing the cake composition according to claim 4, wherein an upper surface of the cylindrical cake composition is raised.
[6]
Medical device containing the cake composition according to claim 4 or 5, wherein a lateral surface of the cylindrical cake composition is inclined, the angle of the inclination being 0.1 to 10°.
[7]
7. Medical device containing the cake composition according to any one of claims 1 to 6, wherein the silicone-treated storage container is a vial or a syringe.
[8]
The cake composition-containing medical device of claim 7, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber.
[9]
9. Medical device containing the cake composition according to claim 7, wherein the syringe has a chamber (A) for containing the cake composition and a chamber (B) for containing an injection liquid; the chamber (A) is disposed on the side where a needle is located and the chamber (B) is disposed on the side where a plunger is located; Y
the cake composition is contained in chamber (A) and
the injection liquid is contained in chamber (B).
[10]
10. Medical device containing the cake composition according to any one of claims 1 to 9, wherein the cake composition has a resistance of 5 to 100 N.
[11]
11. Cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N, wherein the cake composition has a cylindrical shape and a lateral surface of the cylindrical cake composition is inclined, the angle of tilt from 0.1 to 10°.
[12]
12. Cake composition according to claim 11, wherein the percentage of aripiprazole in the cake composition is 60 to 95% by mass.
[13]
13. Cake composition according to claim 11 or 12, wherein the amount of aripiprazole in the cake composition is 0.1 to 0.6 g.
[14]
Cake composition according to any one of claims 11 to 13, obtained by freeze-drying 0.25 to 12 g of a suspension having a solid content of aripiprazole of 5 to 45% by mass.
[15]
The cake composition according to claim 11, wherein an upper surface of the cylindrical cake composition is raised.
[16]
16. Cake composition according to any one of claims 11 to 15, wherein the cake composition is used to be placed in a medical device.
[17]
The cake composition according to claim 16, wherein the cake composition is a dough that was freeze-dried in a container separate from a storage container in the medical device.
[18]
18. Method for producing a medical device containing a cake composition comprising aripiprazole as active ingredient, the method comprising
a step of enclosing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall of the storage container and the cake composition.
Method for producing the medical device according to claim 18, wherein the silicone-treated storage container is a vial or a syringe.
Method for producing the medical device containing the cake composition according to claim 19, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber. Method for producing the medical device containing the cake composition according to claim 20, wherein the syringe has a chamber (A) for containing the cake composition and a chamber (B) for containing an injection liquid;
the chamber (A) is disposed on the side where a needle is located and the chamber (B) is disposed on the side where a plunger is located; Y
the cake composition is contained in chamber (A) and
the injection liquid is contained in chamber (B).
Method for producing a cake composition comprising aripiprazole as an active ingredient and having a resistance of 5 to 100 N, the method comprising
a step of freeze-drying a suspension comprising aripiprazole as an active ingredient, wherein the cake composition has a cylindrical shape and a lateral surface of the cylindrical cake composition is inclined, the angle of the inclination being 0.1 to 10° .

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP2011011711|2011-01-24|

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PCT/JP2012/051285|WO2012102216A1|2011-01-24|2012-01-17|Medical device containing a cake composition comprising aripiprazole as an active ingredient, and a cake composition comprising aripiprazole as an active ingredient|

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