JP2007016022A - Stabilized milnacipran formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a milnacipran formulation stabler than conventionally known milnacipran formulations and to provide a method for stabilizing the milnacipran formulation. <P>SOLUTION: The problems can be solved as follows. A milnacipran-containing composition in which the milnacipran or a salt thereof is made to exist in a porous carrier is used as a formulation and an HPMC (hydroxypropyl methyl cellulose) capsule is filled with powder containing the milnacipran or the salt thereof. The milnacipran and an additive without causing an interaction with the milnacipran with time are combined. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a stabilized milnacipran formulation with improved formulation degradation.

  Milnacipran (chemical name: (±) -cis-2-aminomethyl-N, N-diethyl-1-phenylcyclopropanecarboxamide) is representative of imipramine because it inhibits reuptake of noradrenaline in addition to serotonin. Side effects (anticholinergic action, cardiac / circulatory) of tricyclic antidepressants due to their extremely low affinity for receptors of various neurotransmitters in the brain. Developed as a new antidepressant called SNRI (Serotonine Noradrenarine Selective Reuptake Inhibitor) with reduced impact on the device, and as a film-coated tablet (trade name: Toledomine Tablet) in Japan and as a capsule ( (Product name: IXEL) It is sold in.

Regarding milnacipran, the production method is reported in Patent Documents 1 to 3. Non-patent document 1 reports that tablet hardness of toledomine tablets decreases due to storage at high humidity, and formulations containing milnacipran are reported in patent documents 4 and 5.
Japanese Patent Publication No. 63-23186 Japanese Patent Publication No. 05-67136 Japanese Patent No. 2964041 Special Table 2000-516946 JP-T-2002-519370 “Pharmavision”, PharmaVision Inc., June 2003, Vol. 7, No. 6, p. 24

  An object of the present invention is to provide a milnacipran formulation that is more stable than a conventionally known milnacipran formulation and a method for stabilizing the milnacipran formulation.

  The present inventors manufacture and store various preparations containing milnacipran, and when the preparations are discolored over time during handling or stored under high humidity, the adherence between the preparations and packaging It has been found that there are new problems to be overcome that have not been conventionally known in milnacipran formulations, such as the occurrence of adhesion to containers.

  For example, in film-coated tablets, the film coating peels off due to adhesion, and the tablet is likely to be deformed or damaged, and the granules and powders are likely to be consolidated or agglomerated. When a capsule is subjected to a dissolution test, the dissolution of milnacipran from the capsule is significantly delayed, so there is a concern about the emergence of medicinal effects when taken, and when stored under high humidity, deformation, damage, Stickiness or adhesion tends to occur. In addition, when a sugar-coated tablet is subjected to a dissolution test, the dissolution of milnacipran from the sugar-coated tablet varies from sugar-coated tablet to individual sugar-coated tablets, and thus there may be a difference in the expression of medicinal effects when taken. Toledomine tablets (film-coated tablets) use anhydrous calcium hydrogen phosphate, an additive with low hygroscopicity among pharmaceutically acceptable additives, taking into account stability under high humidity. It is formulated by the method. However, preparation deterioration due to storage under high humidity has not been prevented, and a stable milnacipran preparation has not been obtained even under storage under high humidity.

  As a result of intensive studies to further solve the above problems, the present inventors surprisingly found that (1) (i) even if it is an inorganic compound such as anhydrous calcium hydrogen phosphate, granulation, spray drying, etc. By using a milnacipran-containing composition in which milnacipran dissolved in a solvent is adsorbed on a porous material (carrier) that has been made porous by operation and dried, the tablet composition is exactly the same as the pharmaceutical composition. Can prevent stickiness or adhesion due to storage under high humidity. (Ii) In capsules, elution is not delayed by filling capsules with milnacipran adsorbed on a porous carrier. It can prevent deformation, breakage, stickiness or adhesion when stored under humidity. (2) The powder containing milnacipran is made of hydroxypropylmethylcellulose (HPMC). Capillary filling can prevent deformation, breakage, stickiness or adhesion when stored under high humidity. (3) For sugar-coated tablets, a milnacipran-containing composition in which milnacipran is adsorbed porously is used. Can be used as a sugar-coated tablet to prevent dissolution variation from tablet to tablet, and (4) Combine milnacipran with additives such as D-mannitol that do not interact with milnacipran over time Thus, it was found that the appearance change or discoloration of the milnacipran-containing composition and / or milnacipran formulation was prevented, and the present invention was completed.

That is, the present invention relates to the following.
[1] A milnacipran-containing composition used for producing a milnacipran formulation, wherein milnacipran or a salt thereof is present in a porous carrier;
[2] The composition according to [1], wherein the milnacipran or a salt thereof is milnacipran hydrochloride;
[3] The composition according to [1] or [2] above, wherein the porous carrier is a porous carrier comprising a pharmaceutically acceptable inorganic substance;
[4] The porous carrier is anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, kaolin, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium magnesium aluminosilicate, diatomaceous earth, synthetic silicic acid [1] to [3], which are one or a combination of two or more of aluminum, dry aluminum hydroxide gel, magnesium carbonate, calcium carbonate, silicon dioxide, bentonite, calcium sulfate, activated carbon and mesoporous silica. A composition according to any of the above;
[5] The porous carrier is a combination of one or more of anhydrous calcium hydrogen phosphate, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicic acid, and magnesium magnesium aluminometasilicate The composition according to any one of [1] to [4],
[6] The composition according to [1] to [5], wherein the porous carrier is a porous carrier containing anhydrous calcium hydrogen phosphate;
[7] The composition according to [1] or [2] above, wherein the porous carrier is a porous carrier comprising a pharmaceutically acceptable organic substance;
[8] The above [1], [2], or [7], wherein the porous carrier is starches and granulated products thereof, crystalline cellulose and granulated products thereof, cellulose derivatives, dextrin, lactose, or lauryl methacrylate. A composition according to claim 1;
[9] Any one of [1] to [8] above, wherein milnacipran or a salt thereof is present in the porous carrier by adding milnacipran or a salt thereof to the porous carrier and then drying. A composition according to claim 1;
[10] Porous formed and / or formed in a porous carrier by wet granulation of milnacipran or a salt thereof, a pharmaceutically acceptable additive, and a pharmaceutically acceptable binder and then drying. A milnacipran-containing composition in which milnacipran or a salt thereof is present in a carbonaceous carrier;
[11] A stabilized milnacipran formulation comprising the milnacipran-containing composition according to any one of [1] to [10] above;
[12] A milnacipran formulation with improved tackiness, comprising the milnacipran-containing composition according to any one of [1] to [10] above;
[13] A milnacipran formulation comprising the milnacipran-containing composition according to any one of [1] to [10] above, wherein the milnacipran contained in the entire formulation or the milnacipran formulation A milnacipran formulation characterized in that more than 80% of the salt is present in the milnacipran-containing composition;
[14] The milnacipran formulation according to any one of the above [11] to [13], wherein the milnacipran formulation is a sugar-coated tablet;
[15] A milnacipran formulation in which the milnacipran-containing composition described in any one of [1] to [10] is filled in a capsule;
[16] A milnacipran formulation in which the milnacipran-containing composition described in any one of [1] to [10] is filled in a hydroxypropylmethylcellulose (HPMC) capsule;
[17] A porous carrier is formed by granulating a pharmaceutically acceptable additive and a pharmaceutically acceptable binder to form a porous carrier, followed by drying after adding a milnacipran solution. A method for producing a milnacipran-containing composition in which milnacipran or a salt thereof is present;
[18] A method for stabilizing a milnacipran formulation, characterized in that milnacipran or a salt thereof is present in a porous carrier;
[19] A method for stabilizing dissolution of milnacipran sugar-coated tablets, characterized in that milnacipran or a salt thereof is present in a porous carrier;
[20] A method for inhibiting film peeling of a milnacipran formulation tablet, characterized in that, in the milnacipran formulation tablet coated with a film, milnacipran or a salt thereof is present in a porous carrier;
[21] A method for inhibiting an increase in adhesion of a milnacipran tablet, wherein milnacipran or a salt thereof is present in a porous carrier;
[22] A method for inhibiting a decrease in fluidity of a powder of a milnacipran formulation in powder form, wherein milnacipran or a salt thereof is present in a porous carrier;
[23] A method for suppressing stickiness of the surface of a milnacipran capsule preparation, wherein the capsule is filled with a milnacipran-containing composition in which milnacipran or a salt thereof is present in a porous carrier;
[24] The method for stabilizing a milnacipran formulation according to the above [18] to [23], wherein the milnacipran or a salt thereof is milnacipran hydrochloride;
[25] Use of a porous carrier for improving the stability of a milnacipran formulation containing milnacipran or a salt thereof.
[26] Use of the porous carrier according to [25], wherein the milnacipran or a salt thereof is milnacipran hydrochloride;
[27] A milnacipran formulation, wherein a powder obtained by mixing milnacipran or a salt thereof and a pharmaceutically acceptable carrier is filled in an HPMC capsule;
[28] The dissolution test method for milnacipran sugar-coated tablets according to [14] above, wherein the milnacipran sugar-coated tablets are not retained in the center of the bottom of the vessel during stirring in the second method of the Japanese Pharmacopoeia dissolution test;
[29] In the dissolution test method for milnacipran sugar-coated tablets according to [28], a vessel having a convex portion at the center of the bottom of the vessel is used;
[30] In the dissolution test method for milnacipran sugar-coated tablets according to [28] above, a method is used in which a container in which a disk is placed at the center of the bottom of the vessel is used;
[31] In the dissolution test method for milnacipran sugar-coated tablets according to [28] to [30], a method using a rotation speed of 75 rpm or more;
[32] At least one substance selected from the group consisting of milnacipran or a salt thereof, D-mannitol, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carmellose, and calcium hydrogen phosphate A milnacipran-containing composition containing more than one type.

  According to the present invention, a milnacipran formulation that can prevent stickiness or adhesion, deformation, discoloration, breakage, caking, aggregation, and the like of a milnacipran formulation even when stored under high humidity, and provides a stable dissolution milnacipran formulation be able to.

1. Milnacipran formulation containing a composition in which milnacipran or a salt thereof is present in a porous carrier In the present invention, milnacipran is also known as F2207, TN-912, dulcipran, midariplan, or midariplan Its chemical name is (±) -cis-2-aminomethyl-N, N-diethyl-1-phenylcyclopropanecarboxamide. Milnacipran can be synthesized by a known method (Merck Index 12th edition, entry 6281).

  The salt of milnacipran is not particularly limited as long as it is a salt of milnacipran and an acidic substance that forms a salt, but a pharmaceutically acceptable salt is preferable. The pharmaceutically acceptable salt is not limited as long as it is a salt formed with a pharmaceutically acceptable acidic substance. For example, hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, phosphoric acid Salt, acetate, lactate, succinate, citrate, maleate, tartrate, fumarate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, mandelate, etc. Is exemplified. Of these, hydrochloride is preferable. The hydrochloride salt is sometimes referred to as milnacipran hydrochloride or milnacipran hydrochloride.

In the present invention, the porous carrier has fine voids on the surface and inside and has a large specific surface area, but is not particularly limited as long as it can carry a substance on the surface or inside.
The porous carrier in which milnacipran or a salt thereof can be present is not particularly limited, but the component (pharmaceutically acceptable additive) forming the porous carrier itself may be porous or porous. It may be made porous by aggregating the components forming the carrier.

The component (pharmaceutically acceptable additive) forming the porous carrier is preferably pharmaceutically acceptable. For example, as the inorganic compound, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, kaolin, hydrous dioxide Silicon, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium metasilicate aluminate, diatomaceous earth, synthetic aluminum silicate, dry aluminum hydroxide gel, magnesium carbonate, calcium carbonate, silicon dioxide, bentonite, calcium sulfate, activated carbon Or mesoporous silica etc. are illustrated. Anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicic acid, or magnesium metasilicate aluminate is more preferable, anhydrous calcium hydrogen phosphate or calcium hydrogen phosphate is further Preferably, anhydrous calcium hydrogen phosphate is mentioned as a particularly preferred example.
In addition, the component forming the porous carrier can be selected from the viewpoint of the small amount of the decomposition product generated when the milnacipran-containing composition comprising the component is stored under certain conditions. It is preferable to select a porous component that reduces the amount. For example, a certain condition is usually an environment and a storage period indicated as a storage method, and includes a storage of 36 months at 25 ° C. and a relative humidity of 60%. In addition, storage for 6 months at 40 ° C. and 75% relative humidity is mentioned in the short term, and storage at 60 ° C. for 2 weeks in the short term.
The method for measuring the amount of decomposed product is not particularly limited, but a liquid chromatographic method using a detector such as an ultraviolet absorptiometer is usually exemplified. According to “International Guidelines on Harmonization (ICH)“ Guidelines Concerning Drug Impurities Among Drugs Containing New Active Ingredients ”, the degradation products found in the stability test conducted under the storage conditions described as the storage method are 0 Since it is necessary to confirm safety even if the content is 5% or more, the amount of decomposition products generated when stored under a certain condition is preferably less than 0.5%. The milnacipran formulation of the present invention using anhydrous calcium hydrogen phosphate as the porous carrier showed a degradation product of less than 0.1% under storage conditions at 60 ° C. for 2 weeks.

  Examples of components (pharmaceutically acceptable additives) that form organic porous carriers include starches or granulated products thereof, crystalline cellulose or granulated products thereof, cellulose derivatives, dextrin, lactose, or lauryl methacrylate. Illustrated.

  As the most preferable example of the component (pharmaceutically acceptable additive) forming the porous carrier, anhydrous calcium hydrogen phosphate is exemplified. The anhydrous calcium hydrogen phosphate is more preferably a porous one produced by spray drying.

  In the present invention, the method for allowing milnacipran to exist in the porous carrier is not particularly limited as long as the obtained milnacipran-containing composition is stabilized. For example, as a method for directly adsorbing to a porous carrier, there are a spray adsorption method, a mixed adsorption method, and a spray-drying adsorption method, which will be described later, and as a method for adsorbing while forming a porous carrier, a wet granulation method or the like Is mentioned.

  In the present invention, “stabilized” includes a state in which the preparation is less sticky, adherent, discolored (change in appearance), agglomeration, and the like. In addition, a state in which variation in dissolution of milnacipran from the preparation during the dissolution test is small is also included in “stabilized”.

The milnacipran-containing composition of the present invention can be produced by, for example, a conventional method after milnacipran dissolved in a solvent is adsorbed on a porous carrier and dried.
In adsorption of milnacipran on a porous carrier, it is necessary to prepare a milnacipran solution. However, as a solvent for dissolving milnacipran, a solvent having low toxicity is preferable, and a pharmaceutically acceptable solvent is used. Further preferred. Examples of the solvent include water, ethanol, methanol, acetone and the like, and preferably water. It is also preferable to use a mixture of two or more of these solvents. The amount of the solvent for dissolving milnacipran is not particularly limited as long as milnacipran is dissolved. For example, the lower limit is 0.5 parts by weight or more, preferably 1 part by weight of milnacipran. Is 1.0 part by weight or more, more preferably 2.0 parts by weight or more. Further, the upper limit is usually 5 parts by weight or less, preferably 3 parts by weight or less, because if the amount of the solvent is too large, it causes problems such as production time.

  An appropriate amount of the porous carrier can be selected when adsorbing milnacipran on the porous carrier. In formulating, the amount of milnacipran, which is an active ingredient, in one preparation can be changed depending on the indication and patient's symptoms, but it is usually 10 to 100 mg. The amount of the porous carrier for adsorbing this amount of milnacipran is exemplified by 25 to 250 mg in one preparation. A more preferable amount of milnacipran contained in one preparation is 15 to 25 mg, and a preferable amount of the porous carrier to adsorb this amount of milnacipran is 40 to 80 mg in one preparation. One kind of porous carrier for adsorbing milnacipran contained in one preparation may be used, but several kinds may be contained.

  The method for adsorbing milnacipran directly on a porous carrier is not particularly limited, but i) a solution of milnacipran, or a solution or suspension of a milnacipran solution containing a pharmaceutically acceptable carrier. Either one is spray-adsorbed on the porous carrier and then dried (spray adsorption method), or ii) the solution of milnacipran is added to the porous carrier and adsorbed by mixing with a mixer, and then dried. Or (iii) a method in which a suspension obtained by adding a porous carrier to a milnacipran solution is spray-dried and adsorbed (spray-drying adsorption method).

  Specifically, as a spray adsorption method, a porous carrier is placed in a fluidized bed granulator (ST-1 type: manufactured by POWREC), and the porous carrier is floated by blowing from the bottom of the fluidized bed granulator. The milnacipran solution is sprayed by a spray nozzle and adsorbed thereto, followed by drying in a fluidized bed granulator. The air supply temperature when the porous carrier is flowed and the milnacipran solution is spray-adsorbed is not particularly limited, but is usually 20 to 60 ° C, particularly preferably 30 to 50 ° C. Moreover, the temperature at the time of drying will not be specifically limited if milnacipran does not raise | generate decomposition | disassembly, but it is 70-80 degreeC normally.

Specifically, as a mixed adsorption method, a solution containing milnacipran is added to a porous carrier, and mixed with a mixer used in the production of a normal preparation such as a V-type mixer or a rocking mixer, and thereafter And a method of drying with a fluidized bed granulator.
More specifically, in the mixed adsorption method, specifically, a porous carrier is put into a mixer used in the production of a normal preparation such as a V-type mixer or a rocking mixer, and milnacipran is contained therein. The solution is added and the mixer is rotated to mix and adsorb the milnacipran to the porous carrier. After mixed adsorption, it is necessary to dry the porous carrier on which milnacipran is adsorbed. Examples of the drying include a method of drying by blowing and flowing in a fluidized bed granulator, and a method of drying while blowing in a shelf dryer.
Although the temperature at the time of drying will not be specifically limited if milnacipran does not raise | generate decomposition | disassembly etc., Usually, it is 70-80 degreeC.

Examples of the spray-drying adsorption method include a method of spray-drying with a spray dryer (OCA-8 type: manufactured by Okawara Chemical Co., Ltd.).
More specifically, in the spray-drying adsorption method, specifically, milnacipran is dissolved in water, a porous carrier is added to this aqueous solution, and the mixture is stirred to form a slurry. This is a method for obtaining a porous carrier powder adsorbed with milnacipran by spraying it in a high temperature atmosphere using an OCA-8 type (Okawara Kako) and drying it.
Although the temperature at the time of spraying and drying is not particularly limited as long as milnacipran does not decompose or the like, it is usually 100 to 200 ° C, preferably 150 to 180 ° C.

Further, milnacipran can be present in the porous carrier while forming a porous material. As the method, there is a wet granulation method. Examples of the wet granulation method in the present invention include, but are not limited to, a stirring granulation method and a fluidized bed granulation method.
Agitation granulation involves the use of suitable pharmaceutically acceptable additives, i.e. the ingredients forming the porous carrier described above and suitable pharmaceutically acceptable binders such as pregelatinized starch, pullulan, hydroxypropyl methylcellulose, In this method, a solution such as gum arabic is added and stirred and granulated to first form a porous carrier, and then a milnacipran solution is added thereto and stirred and then dried. In this case, two production facilities such as a stirring granulator in the granulation step and a fluidized bed granulator in the drying step are required.
In the fluidized bed granulation method, a milnacipran is contained while forming a porous carrier from the components that form the porous carrier using a fluidized bed granulator and flowing the porous carrier in an air stream. The solution is sprayed and adsorbed on the porous carrier and dried as it is, and it is possible to carry out the process from adsorption to drying with a single production facility, so that the production process can be simplified and the production cost can be reduced. It becomes.

  Whether the porous carrier has been formed can be determined by taking out the granulated material and directly observing the state of the particles with an electron microscope or the like, or measuring the specific surface area of the granulated material by gas adsorption method or mercury intrusion method, etc. Can be confirmed.

  The milnacipran-containing composition of the present invention thus obtained can be used as it is, or further by adding a pharmaceutically acceptable carrier to obtain the milnacipran formulation of the present invention. The milnacipran formulation is a stable formulation in which deterioration such as stickiness or adhesion, deformation, breakage, consolidation, or aggregation is prevented. Examples of the formulation include, but are not limited to, granules, powders, powders, film-coated tablets, capsules, dragees, and the like. The preparation is not particularly limited as long as it is stabilized, but it is preferable that 80% or more of milnacipran or a salt thereof contained in the whole preparation is present in the milnacipran-containing composition, and 85% or more is present. More preferably, it is more preferably 90% or more, particularly preferably 95% or more, and most preferably 99% or more.

When the milnacipran-containing composition of the present invention is made into a tablet, the milnacipran-containing composition produced by the above method may be compressed by a conventional method. It can also be obtained by uniformly mixing a body and a pharmaceutically acceptable carrier, and then directly or after granulating as appropriate.
It is preferable that the tablet has a size that does not hinder the administration. In this case, the weight of one tablet is usually 50 to 300 mg, preferably 100 to 200 mg. Moreover, the magnitude | size of a tablet is 5-10 mm in diameter normally, Preferably it is 6-8 mm.

  The tablets thus obtained may be film-coated tablets by film coating with an appropriate coating base or the like, or sugar-coated tablets by sugar coating.

  As a film coating method, for example, a coating base as exemplified in the section of Development of Pharmaceuticals published by Yodogawa Shoten, Volume 12, Formulation Material IV, Chapter 2, 2.1.5 Coating Agent was dissolved. A preferred example is a method in which the liquid is sprayed on a tablet containing milnacipran by a spray or the like and dried. As an apparatus for performing this, it is preferable to use a film coating machine including a spray gun, a pan, a blower, and the like.

  In addition, other substances can be added to the coating base used in the film coating according to the physical properties and purposes. For example, a pharmaceutically acceptable substance such as a plasticizer, a dispersant, and a colorant can be appropriately selected and used for film coating in combination with the aforementioned coating base. As the amount of film coating, the total weight of the coating base is desirably in the range of 1 to 20%, preferably 2 to 10% with respect to the weight of the plain tablet containing milnacipran.

As a method for sugar coating on tablets, binders such as gelatin, gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, carmellose sodium, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, or tragacanth, precipitated calcium carbonate, talc, A syrup solution containing solids such as titanium oxide, crystalline cellulose, calcium lactate, calcium sulfate, or bentonite is dropped onto a tablet containing milnacipran and spread to fill the edges of the tablet, creating a rounded shape Then, a series of methods is exemplified in which a syrup solution such as sucrose, D-mannitol, erythritol, or maltitol is dropped and spread to smooth the tablet surface.
The amount to be sugar-coated is 10 to 150%, preferably 20 to 100%, of the total weight of the sugar-coated portion with respect to the weight of the plain tablet containing milnacipran. Further, the thickness of the sugar coating layer is preferably in the range of 0.1 to 1.5 mm, preferably 0.4 to 1.0 mm, but is not limited thereto.
As an apparatus for performing sugar coating, it is preferable to use a sugar coating machine including a bread and a blower. Moreover, it can be manufactured by a Doria coater (Pauleck Co., Ltd.) etc. as well as film coating.

  The sugar-coated tablets prepared in this way are compared with those prepared by simply mixing milnacipran and a pharmaceutically acceptable carrier with a sugar-coated tablet. Variation can be reduced. The variation in elution is a variation in elution rate.

  In the present invention, the “capsule” is not particularly limited, and examples thereof include gelatin capsules and HPMC capsules. The capsule can be obtained by filling a hard capsule such as a gelatin capsule with a uniform mixture of the milnacipran porous carrier adsorbed powder of the present invention and a pharmaceutically acceptable carrier. It is preferable that the capsule has a size that does not hinder the use of the capsule. In this case, the amount of the powder filled in one capsule is usually 50 to 300 mg, preferably 100 to 200 mg. Moreover, the magnitude | size of a hard capsule is 1-5 normally, Preferably it is 2-4.

  In the dissolution test, the capsule prepared in this manner is filled with a hard capsule such as a gelatin capsule or an HPMC capsule with a powder in which milnacipran and a pharmaceutically acceptable non-porous carrier are uniformly mixed. Therefore, it is preferable to use a milnacipran porous carrier-adsorbed powder because the elution is quicker than the capsule obtained. In addition, by filling capsules with mixed powder containing milnacipran porous carrier adsorbent powder, a stabilized milnacipran formulation with reduced adhesion even when stored under high humidity is obtained. Obtainable. Although it does not specifically limit as a capsule, A gelatin capsule or a HPMC capsule etc. are illustrated, Since a HPMC capsule has better stability than a gelatin capsule, a HPMC capsule is more preferable.

The present invention provides a method for stabilizing a milnacipran formulation by allowing milnacipran or a salt thereof to be present in a porous carrier by the above method. Specifically, the milnacipran formulation containing milnacipran present in a porous carrier can prevent and / or improve stickiness, adhesion between formulations, and adhesion to packaging containers. When the Nasiplan formulation is a film-coated tablet, it is possible to prevent and / or stabilize the degradation of the milnacipran formulation, for example, by preventing the tablet from being damaged by film peeling.
According to the present invention, a milnacipran formulation with improved stickiness or adhesion is provided, and particularly preferably, a milnacipran formulation with improved tackiness is provided. The milnacipran formulation of the present invention can be stably stored even under high humidity. For example, the milnacipran formulation of the present invention can be stored stably without causing deterioration of the formulation such as stickiness even if stored for 1 day at a relative humidity of 92%, and sticky, etc. even if stored for 1 week at a relative humidity of 86%. It can be stored stably without causing deterioration of the preparation. In addition, when the milnacipran formulation is a granule, powder, or powder, it can suppress caking, aggregation, or decrease in fluidity. In the case of a capsule, the stickiness of the capsule surface of the capsule Can be suppressed. Although it does not specifically limit as a capsule, A gelatin capsule or an HPMC capsule etc. are illustrated and an HPMC capsule is more preferable.
The use of a porous carrier for improving the stability of a milnacipran formulation containing milnacipran or a salt thereof is also within the scope of the present invention. As the porous carrier, those formed from the components forming the porous carrier are preferable.

  Fluidity can be mentioned as an index of formulation deterioration of granules and powders containing milnacipran. This fluidity can be evaluated by measuring the angle of repose of a granule or powder. For example, the angle of repose is measured before and after storing a granule or powder at high humidity, and if the angle of repose is larger than before storage, the fluidity is deteriorated. Granules and powders with a large angle of repose are difficult to take out from the container and are an obstacle to taking. The angle of repose is not particularly limited, but can be measured by using a three-wheeled cylindrical rotation angle repose angle measuring instrument or the like.

  As an indicator of formulation deterioration of tablets and / or capsules containing milnacipran, adhesion and / or stickiness can be mentioned. This adhesion and / or stickiness can be evaluated by placing a tablet on a smooth glass plate without irregularities, gradually tilting the tablet, and measuring the angle at which the tablet and / or capsule slides down. For example, the angle at which the tablet and / or capsule slides before and after storing the tablet and / or capsule at high humidity is measured, and the adhesion deteriorates if the angle at which the tablet and / or capsule slides is larger than before the storage. It turns out that. Tablets and / or capsules with increased adhesion / stickiness may adhere to containers and medicine bags, making it difficult to take out, and eventually leading to breakage of the tablets and / or capsules.

2. Milnacipran formulation filled in HPMC capsule Further, a milnacipran formulation filled in HPMC capsule with a composition obtained by mixing milnacipran or a salt thereof and a pharmaceutically acceptable carrier according to the present invention is also provided. Provided.
The “composition formed by uniformly mixing milnacipran or a salt thereof and a pharmaceutically acceptable carrier” is the above-mentioned 1. As shown in Fig. 4, it may be a composition in which milnacipran is present in a porous carrier, or milnacipran or a salt thereof is not present in a porous carrier without containing a porous carrier. The milnacipran-containing composition to be filled is not particularly limited as long as it is filled in the HPMC capsule, but milnacipran or a salt thereof is allowed to exist in the porous carrier. Preferably it is. There is also another embodiment in which milnacipran or a salt thereof is preferably not present in the porous carrier. Thus, the milnacipran formulation filled in the HPMC capsule has high stability under high humidity, and specifically, the stickiness or adhesion of the capsule surface is improved.

  The apparatus used for uniformly mixing milnacipran or a salt thereof and a pharmaceutically acceptable carrier is not particularly limited as long as it is usually used for production of a preparation. For example, a V-type mixer And a rocking mixer. Moreover, what was granulated suitably using the granulator etc. which are normally used for manufacture of a formulation as the mixture mixed uniformly as mentioned above can also be filled into a HPMC capsule. The powder containing milnacipran filled in the HPMC capsule is not limited to the powder existing in the porous carrier, and milnacipran or a salt thereof and a pharmaceutically acceptable carrier. It may be a powder obtained by uniformly mixing.

  As an indicator of formulation deterioration of capsules containing milnacipran, adhesion and / or stickiness can be mentioned. This adhesion and / or stickiness can be evaluated by placing the capsule on a smooth glass plate having no irregularities, gradually tilting the capsule, and measuring the angle at which the capsule slides. For example, the angle at which the capsule slides before and after storing the capsule at high humidity is measured, and if the angle at which the capsule slides is larger than before the storage, the adhesion and / or stickiness deteriorates. Capsules with increased adhesion and / or stickiness may adhere to containers and medicine bags, making it difficult to take out and eventually leading to breakage of the capsules.

3. Dissolution test method with stabilized dissolution of milnacipran sugar-coated tablets containing a composition in which milnacipran or a salt thereof is present in a porous carrier. The milnacipran sugar-coated tablets containing a composition in which milnacipran or a salt thereof represented by the formula (1) is present in a porous carrier have stable dissolution and no variation in dissolution rate. The present invention also provides a dissolution test method for milnacipran sugar-coated tablets.

  Among the milnacipran preparations, the dissolution of milnacipran from the tablet is remarkably slowed when the sugar-coated tablets are dropped immediately below the rotation axis of the paddle during the dissolution test. In addition, a slight shift in the drop position affects the elution of each tablet. Since the dissolution test is intended for evaluation to ensure the quality of the solid preparation for internal use at a certain level, such a slight shift in the dropping position should not affect the test result. Usually, the dissolution test of a formulation containing milnacipran follows the dissolution test method 2 (paddle method) described in the general test method of the Japanese Pharmacopoeia, and water kept at 37 ° C. is used as the test solution. The paddle rotation can be performed at 50 rpm. In the case of the normal paddle method, the flow rate of the test solution is faster near the tip of the stirring blade of the paddle, the flow rate is slower as it approaches the rotation axis, and the flow rate immediately below the rotation axis is considered to be the slowest. In the dissolution test, if the flow rate of the test solution, that is, the dropping position of the preparation such as a tablet in the vessel affects the disintegration of the preparation, it is considered that the dissolution of the drug from the preparation is delayed. According to the dissolution test method of the present invention, the above 1. The dissolution of the milnacipran sugar-coated tablet containing the composition in which the milnacipran or a salt thereof shown in (1) is present in the porous carrier can be stabilized.

Specifically describing the dissolution test of the present invention, in the case of milnacipran-containing sugar-coated tablets, the rotation speed of the paddle capable of evaluating the result without affecting the drop position during the dissolution test is preferably 75 rpm or more as a lower limit, 80 rpm The above is more preferable, and 85 rpm or more is more preferable. Although it does not specifically limit as an upper limit, 200 rpm or less is preferable, 150 rpm or less is more preferable, and 100 rpm or less is further more preferable. In addition, when a dissolution test of a milnacipran-containing sugar-coated tablet is to be performed, if the test must be performed at a paddle rotation speed of 50 rpm, the sugar-coated tablet has a convex portion so that the sugar-coated tablet does not fall directly under the rotation axis of the paddle. By using peak vessel (manufactured by Vankel), appropriate elution evaluation can be performed. When the peak vessel cannot be used, an elution evaluation similar to that when the peak vessel is used can be performed by placing a disk of an appropriate size at the lowest part of the vessel. The size of the disc is not particularly limited, but a circular shape having a diameter of 3 to 20 mm and a height of 3 to 15 mm is exemplified, a circular shape having a diameter of 5 to 15 mm and a height of 3 to 10 mm is more preferable, and a diameter of 8 to 12 mm. A circular shape having a height of 4 to 6 mm is more preferable. When testing at a paddle speed of 75 rpm or higher, the presence of a peak vessel or disk is not necessary, but the test can also be performed in the presence of a peak vessel or disk.
Thus, the present invention can provide a dissolution test method that stabilizes dissolution of the milnacipran formulation of the sugar-coated tablet of the present invention.

4). Milnacipran-containing composition and / or milnacipran formulation in which discoloration is prevented Further, according to the present invention, a milnacipran-containing composition and / or milnacipran formulation in which an appearance change during storage is prevented is provided. The The milnacipran-containing composition and / or milnacipran formulation, whose appearance change or discoloration is prevented, is added to milnacipran and is pharmaceutically acceptable and does not interact with milnacipran over time. It can be obtained by combining with an agent and mixing with a mixer or the like. For example, in the case of preparations such as granules, powders and tablets, other additives may be added. These are not particularly limited, but are pharmaceutically acceptable and interact with milnacipran over time. A combination with an additive that does not cause an action is preferred.

  Preferred additives that do not interact with milnacipran over time include D-mannitol, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, carmellose, or calcium hydrogen phosphate More preferably, D-mannitol, corn starch, partially pregelatinized starch, carboxymethyl starch sodium, or calcium hydrogen phosphate is exemplified, and D-mannitol or calcium hydrogen phosphate is particularly preferably exemplified. These preferable additives that do not interact with milnacipran over time may be used singly or in combination of two or more, but preferably one. There is also another embodiment in which two or more types are preferable.

  The “milnacipran-containing composition” in the “milnacipran-containing composition in which a change in appearance during storage is prevented” refers to 1. The composition may be one in which milnacipran is present in the porous carrier as shown in Fig. 1, or milnacipran or a salt thereof is not present in the porous carrier without containing the porous carrier. There is no particular limitation as to whether milnacipran or a salt thereof is present in the porous carrier.

  The change in appearance is exemplified by discoloration, and the degree of discoloration can be obtained by measuring the color difference (ΔE) using a color difference meter or the like. According to the NBS unit, it is considered that the change in color tone can be detected when ΔE exceeds 3.0. In the case of a milnacipran-containing composition, ΔE after storage at 60 ° C. for 2 weeks is preferably 3.0 or less.

  EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

The following [Example 1-1] to [Example 1-11] are all milnacipran produced using a milnacipran-containing composition in which a milnacipran salt is present in a porous carrier. Relates to the formulation.
[Example 1-1]
150 g of milnacipran hydrochloride (Pierre Fabre) dissolved in 84 g of purified water and added to 375 g of porous anhydrous calcium hydrogen phosphate (Fuji Kagaku Kogyo, trade name, Fujicalin) manufactured by spray drying method The mixture was adsorbed with a V-type mixer for 30 minutes, then taken out and dried at 50 ° C. for 15 hours, and passed through a 710 μm mesh to obtain an adsorbed powder. Carmellose calcium (product name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd., 50 g) and light anhydrous silicic acid (product name, Adzolida-101, manufactured by Freund Sangyo) 2.5 g are added to 437.5 g of this adsorbed powder. Was mixed for 10 minutes, and further 10 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a tableting powder. This was tableted using a 6 mm diameter, 8R mortar to obtain 100 mg tablets (uncoated tablets) per tablet containing 25 mg of milnacipran hydrochloride.

[Example 1-2]
150 g of milnacipran hydrochloride (Pierre Fabre) dissolved in 84 g of purified water and flowed into 375 g of porous anhydrous calcium hydrogen phosphate (trade name, Fujicalin, manufactured by Fuji Chemical Industry) manufactured by spray drying. Spraying was performed at a supply air temperature of 40 ° C. using a layer granulator, and after completion of spraying, the supply air temperature was raised to 70 ° C. and drying was performed until the exhaust temperature reached 40 ° C. Thereafter, the powder was taken out from the fluidized bed granulator and passed through a 710 μm mesh to obtain an adsorption powder. Carmellose calcium (product name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd., 50 g) and light anhydrous silicic acid (product name, Adzolida-101, manufactured by Freund Sangyo) 2.5 g are added to 437.5 g of this adsorbed powder. Was mixed for 10 minutes, and further 10 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a tableting powder. This was tableted using a mortar with a diameter of 6 mm 8 R to obtain 100 mg tablets (uncoated tablets) per tablet containing 25 mg of milnacipran hydrochloride.

[Example 1-3]
Dissolve 25 g of milnacipran hydrochloride (Pierre Fabre) in 14 g of purified water, add it to 62.5 g of porous magnesium silicate (trade name, magnesium silicate manufactured by Kyowa Chemical Industry Co., Ltd.) The mixture was mixed and adsorbed by a machine for 30 minutes, and then taken out and dried by standing at 50 ° C. for 12 hours. 10.5 g of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., trade name, LH-31) is added to this adsorption powder, mixed for 10 minutes with a V-type mixer, and further magnesium stearate (trade name, manufactured by Taihei Chemical Co., Ltd.). , Magnesium stearate) was added and mixed for 5 minutes, and this was tableted using a 6 mm diameter, 8R mortar to obtain 100 mg tablets (uncoated tablets) containing 25 mg of milnacipran hydrochloride. .

[Example 1-4]
Dissolve 25 g of milnacipran hydrochloride (Pierre Fabre) in 14 g of purified water, add it to 62.5 g of porous calcium silicate (Eisai, trade name, Florite RE), and use a V-type mixer. The mixture was adsorbed for 30 minutes and then taken out, dried by standing at 50 ° C. for 12 hours, and passed through a 710 μm mesh to obtain an adsorption powder. 10.5 g of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., trade name, LH-31) is added to this adsorption powder, mixed for 10 minutes with a V-type mixer, and further magnesium stearate (trade name, manufactured by Taihei Chemical Co., Ltd.). , Magnesium stearate) was added and mixed for 5 minutes, and this was tableted with a 12R mortar with a diameter of 8 mm to obtain 100 mg tablets (plain tablets) containing 25 mg of milnacipran hydrochloride. .

[Example 1-5]
In 875 ml of purified water, 67 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5RW) is dissolved, 30 g of talc (manufactured by Hayashi Kasei), 10 g of titanium oxide (manufactured by Wako Pure Chemical Industries, trade name, titanium dioxide), ethyl cellulose water Tablets obtained in Example 1-1 were obtained by dispersing 33.35 g of a dispersion (trade name, Aqua Coat, manufactured by Asahi Kasei) and 8 g of triethyl citrate (trade name, Citroflex 2 manufactured by Morimura Shoji Co., Ltd.). Uncoated tablets) were coated with 5 mg with a coating machine (Dower coater DRC-300, manufactured by Paulek) to obtain 105 mg film-coated tablets.

[Example 1-6]
In 875 ml of purified water, 67 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5RW) is dissolved, 30 g of talc (manufactured by Hayashi Kasei), 10 g of titanium oxide (manufactured by Wako Pure Chemical Industries, trade name, titanium dioxide), ethyl cellulose water Tablets obtained in Example 1-2 were obtained by dispersing 33.35 g of a dispersion (trade name, Aqua Coat, manufactured by Asahi Kasei) and 8 g of triethyl citrate (trade name, Citroflex 2 manufactured by Morimura Shoji Co., Ltd.). Uncoated tablets) were coated with 5 mg with a coating machine (Dower coater DRC-300, manufactured by Paulek) to obtain 105 mg film-coated tablets.

[Example 1-7]
Dissolve 125 g of milnacipran hydrochloride (Pierre Fabre) in 70 g of purified water and flow into 315 g of porous anhydrous calcium hydrogen phosphate (trade name, Fujicalin, manufactured by Fuji Chemical Industry) manufactured by spray drying. Spraying was performed at a supply air temperature of 40 ° C. using a layer granulator, and after completion of spraying, the supply air temperature was raised to 70 ° C. and drying was performed until the exhaust temperature reached 40 ° C. Thereafter, the powder was taken out from the fluidized bed granulator and passed through a 710 μm mesh to obtain a powder.

[Example 1-8]
The tableting powder obtained in Example 1-1 was filled with No. 4 gelatin capsules (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps) to obtain capsules containing 25 mg of milnacipran hydrochloride per capsule. .

[Example 1-9]
The tableting powder obtained in Example 1-1 was filled with 100 mg of No. 4 HPMC capsules (trade name, QUALI-V, manufactured by Shionogi Qualicaps) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. It was.

[Example 1-10]
The tableting powder obtained in Example 1-2 was filled with 100 mg of No. 3 gelatin capsule (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. .

[Example 1-11]
The tableting powder obtained in Example 1-2 was filled with 100 mg of No. 3 HPMC capsule (manufactured by Shionogi Qualicaps, trade name, QUALI-V) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. It was.

[Comparative Example 1-1]
125 g of milnacipran hydrochloride (Pierre Fabre), anhydrous calcium hydrogen phosphate (trade name, anhydrous calcium hydrogen phosphate GS) 312.5 g, carmellose calcium (product name of Gotoku Pharmaceutical, trade name) ECG-505) 25 g was put into a high speed mixer (Fukae Powtech) and mixed for 3 minutes at a blade rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm. To this, 30 g of 50% ethanol aqueous solution was added, and the blade rotation speed and cross The mixture was stirred and granulated for 3 minutes at the same rotational speed as that during mixing.
This is put into a fluidized bed granulator (made by Paulec, LAB-1), dried at an air supply temperature of 80 ° C., taken out when the exhaust temperature reaches 50 ° C., and sized through a mesh with an opening of 850 μm. I did it. To this granulated powder, 25 g of carmellose calcium (product name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 2.5 g of light anhydrous silicic acid (product name, Adzolida-101, manufactured by Freund Sangyo) were added. After mixing for 10 minutes, 10 g of magnesium stearate (trade name, manufactured by Taihei Chemical Co., Ltd., magnesium stearate) was added and mixed for 5 minutes to obtain a tableting powder. This was tableted using a 6 mm diameter, 8R mortar to obtain 100 mg tablets (uncoated tablets) per tablet containing 25 mg of milnacipran hydrochloride.

[Comparative Example 1-2]
In the tablet (plain tablet) obtained in Comparative Example 1-1, 134 g of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5RW) was dissolved in 1750 ml of purified water, 60 g of talc (manufactured by Hayashi Kasei), titanium oxide. (Toho Titanium, trade name, titanium dioxide) 20 g, ethyl cellulose aqueous dispersion (Asahi Kasei, trade name, Aqua Coat) 66.7 g, triethyl citrate (Pfizer Pharmaceutical, trade name, Citroflex) 16 g were dispersed. The solution was coated with 5 mg by a coating machine (manufactured by POWREC, Doria Coater DRC-300) to obtain 105 mg coated tablets.

[Comparative Example 1-3]
125 g of milnacipran hydrochloride (Pierre Fabre) and 315 g of anhydrous calcium hydrogen phosphate (trade name, anhydrous calcium hydrogen phosphate GS) 315 g are put into a high-speed mixer (Fukae Powtech) and blade The mixture was mixed for 3 minutes at a rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm, 30 g of purified water was added thereto, and both the blade rotation speed and the cross screw rotation speed were stirred and granulated for 3 minutes at the same rotation speed. This was left to stand and dried at 50 ° C. for 8 hours, and a powder was obtained through a 710 μm mesh.

[Comparative Example 1-4]
175 g of milnacipran hydrochloride (Pierre Fabre), finely divided anhydrous calcium hydrogen phosphate (trade name, anhydrous calcium hydrogen phosphate GS) 204.4 g, carmellose calcium (product name of Gotoku Pharmaceutical, trade name) ECG-505) 16.1 g was put into a high-speed mixer (Fukae Pautech), mixed for 3 minutes at a blade rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm, and 30 g of 50% ethanol aqueous solution was added to the blade rotation speed. The mixture was granulated with stirring for 3 minutes at the same rotational speed as when mixing with the cross screw. This is put into a fluidized bed granulator (made by Paulec, LAB-1), dried at an air supply temperature of 80 ° C., taken out when the exhaust temperature reaches 50 ° C., and sized through a mesh with an opening of 850 μm. I did it. Carmelose calcium (trade name, ECG-505, 16.1 g) and light anhydrous silicic acid (Freund Sangyo, trade name, Adzolida-101) 1.4 g are added to this granulated powder, and V-type mixing is performed. The mixture was further mixed for 15 minutes, and further 7 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a capsule-filled powder. This was filled with 100 mg of No. 4 gelatin capsule (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule.

[Comparative Example 1-5]
100 mg of the capsule-filled powder obtained in Comparative Example 1-4 was filled into a No. 3 gelatin capsule (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. .

In the following Examples, [Example 2-1] and [Example 2-2] are preparations in which HPMC capsules are filled with a mixed powder with a non-porous carrier, and [Example 2-3] is porous. Formulation in which milnacipran-containing composition in which milnacipran salt is present in a carrier is filled in a gelatin capsule, [Example 2-4] contains milnacipran salt in which milnacipran salt is present in a porous carrier The present invention relates to a preparation filled with HPMC capsules.
[Example 2-1]
175 g of milnacipran hydrochloride (Pierre Fabre), finely divided anhydrous calcium hydrogen phosphate (trade name, anhydrous calcium hydrogen phosphate GS) 204.4 g, carmellose calcium (product name of Gotoku Pharmaceutical, trade name) ECG-505) 16.1 g was put into a high-speed mixer (Fukae Pautech), mixed for 3 minutes at a blade rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm, and 30 g of 50% ethanol aqueous solution was added to the blade rotation speed. The mixture was granulated with stirring for 3 minutes at the same rotational speed as when mixing with the cross screw. This is put into a fluidized bed granulator (made by Paulec, LAB-1), dried at an air supply temperature of 80 ° C., taken out when the exhaust temperature reaches 50 ° C., and sized through a mesh with an opening of 850 μm. I did it. Carmelose calcium (trade name, ECG-505, 16.1 g) and light anhydrous silicic acid (Freund Sangyo, trade name, Adzolida-101) 1.4 g are added to this granulated powder, and V-type mixing is performed. The mixture was further mixed for 15 minutes, and further 7 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a capsule-filled powder. This was filled with 100 mg of No. 4 HPMC capsule (manufactured by Shionogi Qualicaps, trade name, QUALI-V) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule.

[Example 2-2]
Capsules filled in Example 2-1 were filled with 100 mg of No. 3 HPMC capsule (manufactured by Shionogi Qualicaps, trade name, QUALI-V) to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. It was.

[Example 2-3]
150 g of milnacipran hydrochloride (Pierre Fabre) dissolved in 84 g of purified water and flowed into 375 g of porous anhydrous calcium hydrogen phosphate (trade name, Fujicalin, manufactured by Fuji Chemical Industry) manufactured by spray drying. Spraying was performed at a supply air temperature of 40 ° C. using a layer granulator, and after completion of spraying, the supply air temperature was raised to 70 ° C. and drying was performed until the exhaust temperature reached 40 ° C. Thereafter, the powder was taken out from the fluidized bed granulator and passed through a 710 μm mesh to obtain an adsorption powder. Carmellose calcium (product name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd., 50 g) and light anhydrous silicic acid (product name, Adzolida-101, manufactured by Freund Sangyo) 2.5 g are added to 437.5 g of this adsorbed powder. Was mixed for 10 minutes, and further 10 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a tableting powder. This was filled with No. 3 gelatin capsules (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps) to obtain capsules containing 25 mg of milnacipran hydrochloride per capsule.

[Example 2-4]
The tableting powder obtained in Example 2-3 was filled with No. 3 HPMC capsules (trade name, QUALI-V, manufactured by Shionogi Qualicaps) to obtain capsules containing 25 mg of milnacipran hydrochloride per capsule. It was.

[Comparative Example 2-1]
The capsule filling powder obtained in Example 2-1 was filled with No. 4 gelatin capsule (trade name, Qualicaps gelatin, manufactured by Shionogi Qualicaps), and a capsule containing 25 mg of milnacipran hydrochloride per capsule was obtained. .

[Comparative Example 2-2]
The capsule filling powder obtained in Example 2-1 was filled with No. 3 gelatin capsule (manufactured by Shionogi Qualicaps, trade name, Qualicaps gelatin) at 100 mg to obtain a capsule containing 25 mg of milnacipran hydrochloride per capsule. .

The following [Example 3-1] and [Example 3-2] relate to sugar-coated tablets.
[Example 3-1]
240 g of milnacipran hydrochloride (manufactured by Pierre Fabre) was dissolved in 134.4 g of purified water, and 280.32 g of porous anhydrous calcium hydrogen phosphate produced by a spray drying method (trade name, manufactured by Fuji Chemical Industry Co., Ltd.) Fujicalin) was sprayed using a fluidized bed granulator at a supply air temperature of 40 ° C. After the spraying was completed, the supply air temperature was raised to 70 ° C. and dried until the exhaust temperature reached 40 ° C. Thereafter, the powder was taken out from the fluidized bed granulator and passed through a 710 μm mesh to obtain an adsorption powder. Carmellose calcium (trade name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd., 36.8 g) and light anhydrous silicic acid (product name, Adzolida-101, manufactured by Freund Sangyo) 1.6 g are added to 433.6 g of this powder. The mixture was mixed for 10 minutes with a mixer, and 8 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was further added and mixed for 5 minutes to obtain a tableting powder. This was tableted using a mortar with a diameter of 5 mm and 3.5 R to obtain 60 mg tablets (uncoated tablets) containing 25 mg of milnacipran hydrochloride.
326 g of the obtained uncoated tablet was put into a coating machine (manufactured by POWREC, Doria Coater DRC-300), and 88 g of hydroxypropylmethylcellulose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5R) was dissolved in 1169.2 g of purified water. After that, a film solution prepared by adding 22 g of titanium oxide (trade name, titanium oxide, manufactured by Wako Pure Chemical Industries, Ltd.) and uniformly dispersing with a homomixer is sprayed in a film coating machine to obtain a film layer weight of 10 mg. A film tablet having a tablet weight of 70 mg per tablet was obtained. The obtained film tablet is dissolved in a sugar coating liquid (hydroxypropylmethylcellulose 2208 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, SB-4)) in a sugar coating machine (manufactured by Kikusui Seisakusho), and then sucrose (new) 630 g of Mitsui Sugar Co., Ltd., trade name, AA) is added and dissolved, and 350 g of precipitated calcium carbonate (trade name, precipitated calcium carbonate, manufactured by Bihoku Flour Kogyo Co., Ltd.) is further added and prepared with sufficient agitation at about 3 ml / time. The solution was dripped to uniformly coat the sugar coating liquid. Then, air supply (temperature: 60 ° C.) was added and the tablet was dried for 3 minutes. This operation was repeated until the dose was increased by 30 mg per tablet to form a sugar coating layer. Continuously, a sugar solution (prepared by dissolving 470 g of purified water in 700 g of white sugar (trade name, AA) manufactured by Shin Mitsui) was added dropwise at about 3 ml / time to coat the sugar solution uniformly. Then, air supply (temperature: 60 ° C.) was added and the tablet was dried for 3 minutes. This operation was repeated until the dose was increased by 20 mg to give a sugar-coated tablet having a tablet weight of 120 mg per tablet.

[Example 3-2]
360 g of milnacipran hydrochloride (manufactured by Pierre Fabre) was dissolved in 201.6 g of purified water, and 907.2 g of porous anhydrous calcium hydrogen phosphate produced by a spray drying method (trade name, manufactured by Fuji Chemical Industry Co., Ltd.) Fujicalin) was sprayed using a fluidized bed granulator at a supply air temperature of 40 ° C. After the spraying was completed, the supply air temperature was raised to 70 ° C. and dried until the exhaust temperature reached 40 ° C. Thereafter, the powder was taken out from the fluidized bed granulator and passed through a 710 μm mesh to obtain an adsorption powder. 12056 g of carmellose calcium (trade name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) is added to 1056 g of this adsorbed powder, mixed for 10 minutes with a V-type mixer, and further magnesium stearate (trade name, manufactured by Taihei Chemicals, magnesium stearate). 24 g was added and mixed for 5 minutes to obtain a tableting powder. This was tableted with a mortar with a diameter of 6 mm and 4.5 R to obtain 100 mg tablets (uncoated tablets) per tablet containing 25 mg of milnacipran hydrochloride.
500 g of the obtained uncoated tablet is put into a coating machine (manufactured by POWREC, Doria Coater DRC-300), and 40 g of hydroxypropylmethylcellulose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5R) is dissolved in 531.6 g of purified water. After that, a film solution prepared by adding 60 g of titanium oxide (trade name, titanium oxide, manufactured by Wako Pure Chemical Industries, Ltd.) and uniformly dispersing with a homomixer is sprayed in a film coating machine to have a film layer weight of 5 mg. A film tablet having a tablet weight of 105 mg per tablet was obtained.
The obtained film tablet was dissolved by adding 1050 ml of purified water to a sugar coating liquid (hydroxypropylmethylcellulose 2208 (trade name, SB-4, manufactured by Shin-Etsu Chemical Co., Ltd.) in a coating machine (manufactured by POWREC, Doria Coater DRC-300). Next, 630 g of sucrose (manufactured by Shin Mitsui Sugar, trade name, AA) is added and dissolved, and 350 g of precipitated calcium carbonate (trade name, precipitated calcium carbonate, manufactured by Bihoku Flour Kogyo Co., Ltd.) is added and prepared with sufficient stirring. Spraying was performed at about 3 ml / min for 2 minutes to uniformly coat the sugar coating liquid without supplying air. Then, air supply (temperature: 70 ° C.) was added and the tablets were dried for 3 minutes. This operation was repeated until the dose was increased by 30 mg per tablet to form a sugar coating layer. Next, spray sugar solution (prepared by adding 470 g of purified water to 700 g of white sugar (manufactured by Shin Mitsui Sugar Co., Ltd., trade name, AA)) at a rate of about 3 ml / min for 2 minutes to uniformly coat the sugar solution without air supply. It was. Then, air supply (temperature: 70 ° C.) was added and the tablets were dried for 3 minutes. This operation was repeated until the dose was increased by 20 mg to give a sugar-coated tablet with a tablet weight of 155 mg per tablet.

[Comparative Example 3-1]
175 g of milnacipran hydrochloride (Pierre Fabre), finely divided anhydrous calcium hydrogen phosphate (trade name, anhydrous calcium hydrogen phosphate GS) 204.4 g, carmellose calcium (product name of Gotoku Pharmaceutical, trade name) ECG-505) 16.1 g was put into a high-speed mixer (Fukae Pautech), mixed for 3 minutes at a blade rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm, and 30 g of 50% ethanol aqueous solution was added to the blade rotation speed. The mixture was granulated with stirring for 3 minutes at the same rotational speed as when mixing with the cross screw. This is put into a fluidized bed granulator (made by Paulec, LAB-1), dried at an air supply temperature of 80 ° C., taken out when the exhaust temperature reaches 50 ° C., and sized through a mesh with an opening of 850 μm. I did it. Carmelose calcium (trade name, ECG-505, 16.1 g) and light anhydrous silicic acid (Freund Sangyo, trade name, Adzolida-101) 1.4 g are added to this granulated powder, and V-type mixing is performed. Then, 8 g of magnesium stearate (trade name, magnesium stearate, manufactured by Taihei Kagaku) was added and mixed for 5 minutes to obtain a tableting powder. This was tableted using a mortar with a diameter of 5 mm and 3.5 R to obtain 60 mg tablets (uncoated tablets) containing 25 mg of milnacipran hydrochloride.
300 g of the obtained uncoated tablet was put into a coating machine (manufactured by POWREC, Doria Coater DRC-300), and 60 g of hydroxypropylmethylcellulose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5R) was dissolved in 1050 ml of purified water. Later, a film solution prepared by adding 15 g of titanium oxide (trade name, titanium oxide, manufactured by Wako Pure Chemical Industries, Ltd.) and uniformly dispersing with a homomixer is sprayed in a film coating machine to have a film layer weight of 10 mg A film tablet having a tablet weight per tablet of 70 mg was obtained.
The obtained film tablet was dissolved by adding 1050 ml of purified water to a sugar coating liquid (hydroxypropylmethylcellulose 2208 (trade name, SB-4, manufactured by Shin-Etsu Chemical Co., Ltd.) in a coating machine (manufactured by POWREC, Doria Coater DRC-300). Next, 630 g of sucrose (manufactured by Shin Mitsui Sugar, trade name, AA) is added and dissolved, and 350 g of precipitated calcium carbonate (trade name, precipitated calcium carbonate, manufactured by Bihoku Flour Kogyo Co., Ltd.) is added and prepared with sufficient stirring. Spraying was performed at about 3 ml / min for 2 minutes to uniformly coat the sugar coating liquid without supplying air. Then, air supply (temperature: 70 ° C.) was added and the tablets were dried for 3 minutes. This operation was repeated until the dose was increased by 30 mg per tablet to form a sugar coating layer. Next, spray sugar solution (prepared by adding 470 g of purified water to 700 g of white sugar (manufactured by Shin Mitsui Sugar Co., Ltd., trade name, AA)) at a rate of about 3 ml / min for 2 minutes to uniformly coat the sugar solution without air supply. It was. Then, air supply (temperature: 70 ° C.) was added and the tablets were dried for 3 minutes. This operation was repeated until the dose was increased by 20 mg to give a sugar-coated tablet having a tablet weight of 120 mg per tablet.

[Comparative Example 3-2]
175 g of milnacipran hydrochloride (Pierre Fabre) and 441 g of anhydrous calcium hydrogen phosphate (Kyowa Chemical, trade name, anhydrous calcium hydrogen phosphate GS) are charged into a high-speed mixer (Fukae Powtech) and blade The mixture was mixed for 3 minutes at a rotation speed of 670 rpm and a cross screw rotation speed of 2000 rpm, 40 g of a 50% ethanol aqueous solution was added thereto, and both the blade rotation speed and the cross screw rotation speed were granulated with stirring for 3 minutes at the same rotation speed. This is put into a fluidized bed granulator (made by Paulec, LAB-1), dried at an air supply temperature of 80 ° C., taken out when the exhaust temperature reaches 50 ° C., and sized through a mesh with an opening of 850 μm. I did it. To this granulated powder, 70 g of carmellose calcium (product name, ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) is added, and mixed for 15 minutes with a V-type mixer, and further magnesium stearate (product name, magnesium stearate, manufactured by Taihei Chemical). ) 14 g was added and mixed for 5 minutes to obtain a tableting powder. This was tableted with a mortar with a diameter of 6 mm and 4.5 R to obtain 100 mg tablets (uncoated tablets) per tablet containing 25 mg of milnacipran hydrochloride.
550 g of the obtained uncoated tablet is put into a coating machine (manufactured by POWREC, Doria Coater DRC-300), and 48 g of hydroxypropylmethylcellulose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, TC-5R) is dissolved in 637.8 g of purified water. After that, a film solution prepared by adding 72 g of titanium oxide (trade name, titanium oxide, manufactured by Wako Pure Chemical Industries, Ltd.) and uniformly dispersing with a homomixer is sprayed in a film coating machine to have a film layer weight of 5 mg. A film tablet having a tablet weight of 105 mg per tablet was obtained.
The obtained film tablet is dissolved in a sugar coating liquid (hydroxypropylmethylcellulose 2208 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name, SB-4)) in a sugar coating machine (manufactured by Kikusui Seisakusho), and then sucrose (new) 630 g of Mitsui Sugar Co., Ltd., trade name, AA) is added and dissolved, and 350 g of precipitated calcium carbonate (trade name, precipitated calcium carbonate, manufactured by Bihoku Flour Kogyo Co., Ltd.) is further added and prepared with sufficient agitation at about 3 ml / time. The solution was dripped to uniformly coat the sugar coating liquid. Then, air supply (temperature: 60 ° C.) was added and the tablet was dried for 3 minutes. This operation was repeated until the dose was increased by 30 mg per tablet to form a sugar coating layer. Continuously, a sugar solution (prepared by dissolving 470 g of purified water in 700 g of white sugar (trade name, AA) manufactured by Shin Mitsui) was added dropwise at about 3 ml / time to coat the sugar solution uniformly. Then, air supply (temperature: 60 ° C.) was added and the tablet was dried for 3 minutes. This operation was repeated until the dose was increased by 20 mg to give a sugar-coated tablet with a tablet weight of 155 mg per tablet.

表１に記載の添加剤と塩酸ミルナシプランからなる散剤１ｇを粉体測定用セルに入れ、３０ｍｍコンデンサーレンズを装着した色差計（ＣＬＲ−７１００Ｆ；島津製作所製）を用いて色差（ΔＥ）を測定したところ、保存後でのΔＥはすべて３．０以下であり外観上の変化を認めなかった。 [Example 4-1] relates to a preparation which is prevented from being colored by adding an additive.
[Example 4-1]
10 g of milnacipran hydrochloride (manufactured by Pierre Fabre) and 10 g of additive were mixed for 3 minutes with a chemical grinder to obtain a powder. Table 1 shows changes in the appearance after 1 g of the obtained powder was put in a glass bottle, covered and stored in a sealed state at 60 ° C. for 2 weeks.

1 g of powder consisting of the additives listed in Table 1 and milnacipran hydrochloride was placed in a powder measurement cell, and the color difference (ΔE) was measured using a color difference meter (CLR-7100F; manufactured by Shimadzu Corporation) equipped with a 30 mm condenser lens. When measured, ΔE after storage was 3.0 or less, and no change in appearance was observed.

[Experimental Example 1-1]
The tablets obtained in Example 1-1, Example 1-2, Example 1-3, Example 1-4 and Comparative Example 1-1 were made into a glass having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous solution of potassium nitrate. It was stored in a desiccator for 24 hours at a temperature of 30 ° C. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, the tablet was placed on a smooth glass plate without irregularities, and this was gradually tilted to measure the angle at which the tablet slipped. In addition, the appearance change after storage was also observed. The results are shown in Table 2.
As is clear from the results in Table 2, the tablet obtained by mixing the milnacipran hydrochloride of Comparative Example 1-1 with other additives, granulating, and then tableting is as follows: temperature 30 ° C., relative humidity After storage at 92%, it adhered to the glass plate used for the measurement, and even if the glass plate was tilted from 90 ° to 90 °, it did not slide down.
On the other hand, Example 1-1, Example 1-2 which made pills by adsorbing milnacipran hydrochloride to porous anhydrous calcium hydrogen phosphate produced by a spray drying method, and porous magnesium silicate Example 1-3 in which milnacipran hydrochloride was adsorbed to form a tablet and Example 1-4 in which milnacipran hydrochloride was adsorbed to porous calcium silicate to form a tablet were as in Comparative Example 1-1. In addition, the phenomenon that the tablet adhered to the glass plate was not observed, and all of the tablets slipped off at an inclination angle of 40 ° or less.
Further, in Comparative Example 1-1, changes in appearance such as stickiness of the tablet were confirmed after storage, but in the tablets of Example 1-1, Example 1-2, Example 1-3, and Example 1-4, the appearance was changed. The above change was not confirmed.

[Experimental Example 1-2]
The film-coated tablets obtained in Example 1-5, Example 1-6 and Comparative Example 1-2 were placed in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous potassium nitrate solution at a temperature of 30 ° C. for 24 hours. saved. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, the tablet was placed on a smooth glass plate without irregularities, and this was gradually tilted to measure the angle at which the tablet slipped. In addition, the appearance change after storage was also observed. The results are shown in Table 3.
Tablets obtained by film-coating tablets obtained by mixing tablets of milnacipran hydrochloride of Comparative Example 1-2 with other additives, granulated, and tableted are stored at a temperature of 30 ° C. and a relative humidity of 92%. Later, it adhered to the glass plate used for the measurement, and even if the glass plate was tilted from 90 ° to 90 °, it did not slide down.
In contrast, Example 1-5 and Example 1-6, in which milnacipran hydrochloride was adsorbed on porous anhydrous calcium hydrogen phosphate produced by a spray drying method to form film-coated tablets, Comparative Example 1 As shown in Fig. 2, the phenomenon that the tablet was sticky and strongly adhered to the glass plate was not observed, and all of the tablets slipped off at an inclination angle of 50 ° or less.
Further, in Comparative Example 1-2, changes in appearance such as the tablet sticky after storage and the film peeled off when held with a finger were confirmed, but the film-coated tablets of Example 1-5 and Example 1-6 have an appearance change. No change was confirmed.

[Experimental Example 1-3]
The powder obtained in Example 1-7 and Comparative Example 1-3 was stored at a temperature of 30 ° C. for 2 days in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous solution of potassium nitrate. At this time, the relative humidity in the desiccator is about 92%. Before and after storage, the angle of repose was measured with a three-wheeled cylindrical rotation angle of repose measuring instrument. In addition, the appearance change of the stored powder was also observed. The results are shown in Table 4.
The powder of Example 1-7 has no change in the angle of repose before and after storage at a temperature of 30 ° C. and a relative humidity of 92%, whereas the powder of Comparative Example 1-3 has a temperature of 30 ° C. and a relative humidity of 92%. After storage, the angle of repose clearly increased and the fluidity deteriorated.
In Example 1-7, no change in appearance was confirmed, whereas in Comparative Example 1-3, aggregation was confirmed.

[Experimental Example 1-4]
The capsules obtained in Example 1-8, Example 1-9, and Comparative Example 1-4 were placed in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous potassium nitrate solution at a temperature of 30 ° C. for 2 days. saved. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, a metal disk having a diameter of about 6 mm was used to evaluate whether or not the capsule cracked when a pressure of 5 kg was applied in the minor axis direction of the capsule, and the damage rate of the capsule was determined. In addition, the appearance change after storage was also observed. The results are shown in Table 5. In Examples 1-8 and 1-9, no damage was observed in all 10 capsules, and no change in appearance was confirmed, whereas in Comparative Example 1-4, all 10 capsules The capsule was broken and the stickiness of the capsule was confirmed.

[Experimental Example 1-5]
The capsules obtained in Example 1-10, Example 1-11 and Comparative Example 1-5 were stored at a temperature of 30 ° C. for 8 days in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous potassium nitrate solution. did. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, the capsule was placed on a smooth glass plate without irregularities, and this was gradually tilted to measure the angle at which the capsule fell. In addition, the appearance change after storage was also observed. The results are shown in Table 6.

[Experiment 1-6]
In accordance with the dissolution test method (second method) of the 14th revised Japanese Pharmacopoeia / General Test, the capsules obtained in Example 1-10, Example 1-11 and Comparative Example 1-5 were mixed with 900 ml of water. The dissolution test (using a sinker) was carried out at a paddle rotation speed of 50 rotations per minute. The results of the dissolution rate at this time are shown in Table 7.
Compared to the capsule of Comparative Example 1-5, the capsules of Example 1-10 and Example 1-11 were eluted quickly.

[Experimental example 2-1]
The capsules obtained in Example 2-1 and Comparative Example 2-1 were stored at a temperature of 30 ° C. for 2 days in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous potassium nitrate solution. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, a metal disk having a diameter of about 6 mm was used to evaluate whether or not the capsule cracked when a pressure of 5 kg was applied in the minor axis direction of the capsule, and the damage rate of the capsule was determined. In addition, the appearance change after storage was also observed. The results are shown in Table 8. In Example 2-1, no damage was observed in all 10 capsules, and no change in appearance was confirmed, whereas in Comparative Example 2-1, all capsules in 10 capsules were damaged. No stickiness was confirmed.

[Experimental example 2-2]
The capsules obtained in Example 2-2 and Comparative Example 2-2 were stored at a temperature of 30 ° C. for 8 days in a glass desiccator having a diameter of 15 cm and a depth of 15 cm containing a saturated aqueous potassium nitrate solution. At this time, the relative humidity in the desiccator is about 92%.
Before and after storage, the capsule was placed on a smooth glass plate without irregularities, and this was gradually tilted to measure the angle at which the capsule fell. In addition, the appearance change after storage was also observed. The results are shown in Table 9.

[Experimental Example 3-1]
For each of the 6 sugar-coated tablets obtained in Example 3-1, Example 3-2, Comparative Example 3-1, and Comparative Example 3-2, a dissolution test by the paddle method was performed. For each vessel, a disk with a diameter of about 10 mm, a height of about 6 mm, and a weight of about 1.5 g is submerged in the center of the bottom of the hemisphere of the vessel, and 900 ml of water is used as the test solution, and the paddle rotation speed is 50 rpm. The test was conducted. Table 10 shows the coefficient of variation of the dissolution rate at each time at this time.
The coefficient of variation of the dissolution rate at each time is expressed as a percentage by dividing the standard deviation of the dissolution rate at a given time for each of the 6 sugar-coated tablets by the average dissolution rate at that time. It can be said that the degree of is large.
The sugar-coated tablets of Example 3-1 and Example 3-2 have a smaller coefficient of variation in the dissolution rate at each time than the sugar-coated tablets of Comparative Example 3-1 and Comparative Example 3-2, and variation in dissolution between individual tablets. It was a small dragee.

[Experimental Example 3-2]
For each of the 6 sugar-coated tablets obtained in Example 3-1 and Example 3-2, according to the dissolution test method (second method) of the 14th revised Japanese Pharmacopoeia / General Test, use 900 ml of water as the test solution, and paddle Rotational speed: The dissolution test was performed under two conditions of 50 rpm and 75 rpm. Table 11 shows the coefficient of variation of the dissolution rate at each time at this time.
For the sugar-coated tablets of Example 3-1 and Example 3-2, the dissolution rate from individual tablets greatly varied at the 50 paddle rotation speed per minute during the dissolution test. The variation became smaller at 75 revolutions per minute. As test conditions, a stable elution result can be obtained by using 75 paddle rotations per minute.

The present invention is a milnacipran formulation with improved degradation when stored under high humidity and improved dissolution, and can be used as a stable pharmaceutical product.

Claims (31)

  A milnacipran-containing composition used for producing a milnacipran formulation, wherein milnacipran or a salt thereof is present in a porous carrier.   The composition according to claim 1, wherein the milnacipran or a salt thereof is milnacipran hydrochloride.   The composition according to claim 1 or 2, wherein the porous carrier is a porous carrier made of a pharmaceutically acceptable inorganic substance.   Porous carrier is anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, kaolin, hydrous silicon dioxide, calcium silicate, magnesium silicate, light anhydrous silicic acid, magnesium metasilicate aluminate, diatomaceous earth, synthetic aluminum silicate, dry The aluminum hydroxide gel, magnesium carbonate, calcium carbonate, silicon dioxide, bentonite, calcium sulfate, activated carbon or mesoporous silica is any one type or a combination of two or more types. The composition as described.   The composition according to any one of claims 1 to 4, wherein the porous carrier is a porous carrier containing anhydrous calcium hydrogen phosphate.   The composition according to claim 1 or 2, wherein the porous carrier is a porous carrier comprising a pharmaceutically acceptable organic substance.   The composition according to claim 1, 2, or 6, wherein the porous carrier is starch and granulated product thereof, crystalline cellulose and granulated product thereof, cellulose derivative, dextrin, lactose or lauryl methacrylate.   The composition according to any one of claims 1 to 7, wherein milnacipran or a salt thereof is made to exist in the porous carrier by adding milnacipran or a salt thereof to the porous carrier and then drying. object.   Milnacipran or a salt thereof, a pharmaceutically acceptable additive, and a pharmaceutically acceptable binder are wet-granulated and then dried to make milnacipran or a salt thereof present in the porous carrier. A formulated milnacipran-containing composition.   A stabilized milnacipran formulation comprising the milnacipran-containing composition according to any one of claims 1 to 9.   A milnacipran formulation with improved stickiness, comprising the milnacipran-containing composition according to any one of claims 1 to 9.   A milnacipran formulation comprising the milnacipran-containing composition according to any one of claims 1 to 9, wherein 80% of milnacipran or a salt thereof contained in the entire formulation A milnacipran formulation characterized in that the above is present in a milnacipran-containing composition.   The milnacipran formulation according to claims 10 to 12, wherein the milnacipran formulation is a sugar-coated tablet.   A milnacipran formulation in which the milnacipran-containing composition according to any one of claims 1 to 9 is filled in a capsule.   A milnacipran formulation in which the milnacipran-containing composition according to any one of claims 1 to 9 is filled in a hydroxypropylmethylcellulose (HPMC) capsule.   A pharmaceutically acceptable additive and a pharmaceutically acceptable binder are granulated to form a porous carrier, followed by the addition of a milnacipran solution and drying to form a mill in the porous carrier. A method for producing a milnacipran-containing composition in which nacipran or a salt thereof is present.   A method for stabilizing a milnacipran formulation, characterized in that milnacipran or a salt thereof is present in a porous carrier.   A method for stabilizing the dissolution of a milnacipran sugar-coated tablet, characterized in that milnacipran or a salt thereof is present in a porous carrier.   A method for inhibiting film peeling of a milnacipran tablet, wherein the milnacipran or a salt thereof is present in a porous carrier in the film-coated milnacipran tablet.   A method for suppressing an increase in the adhesion of a milnacipran formulation tablet, characterized in that milnacipran or a salt thereof is present in a porous carrier.   A method for inhibiting a decrease in fluidity of a powder of a milnacipran formulation in powder form, characterized in that milnacipran or a salt thereof is allowed to exist in a porous carrier.   A method for inhibiting stickiness of the surface of a milnacipran capsule preparation, characterized in that a milnacipran-containing composition in which milnacipran or a salt thereof is present in a porous carrier is filled in a capsule.   The method for stabilizing a milnacipran formulation according to any one of claims 18 to 22, wherein the milnacipran or a salt thereof is milnacipran hydrochloride.   Use of a porous carrier for improving the stability of a milnacipran formulation containing milnacipran or a salt thereof.   The use of the porous carrier according to claim 24, wherein the milnacipran or a salt thereof is milnacipran hydrochloride.   A milnacipran formulation characterized in that HPMC capsules are filled with a powder obtained by mixing milnacipran or a salt thereof and a pharmaceutically acceptable carrier.   The method for dissolving milnacipran sugar-coated tablets according to claim 13, wherein the milnacipran sugar-coated tablets are not retained in the center of the bottom of the vessel during stirring in the second method of the Japanese Pharmacopoeia dissolution test.   28. The dissolution test method for milnacipran sugar-coated tablets according to claim 27, wherein a vessel having a convex portion at the center of the bottom of the vessel is used.   28. The dissolution test method for milnacipran sugar-coated tablets according to claim 27, wherein a container in which a disk is allowed to stand is used at the center of the bottom of the vessel.   30. A method for the dissolution test of milnacipran sugar-coated tablets according to claim 27, wherein a rotation speed of 75 rpm or more is used. Milnacipran or a salt thereof and at least one substance selected from the group consisting of D-mannitol, corn starch, partially pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carmellose, and calcium hydrogen phosphate Milnacipran-containing composition.