WO2020122244A1

WO2020122244A1 - Tablet and method for producing same

Info

Publication number: WO2020122244A1
Application number: PCT/JP2019/049020
Authority: WO
Inventors: 敦加納; 翔豊永
Original assignee: 富士フイルム株式会社
Priority date: 2018-12-14
Filing date: 2019-12-13
Publication date: 2020-06-18
Also published as: EA202191372A1

Abstract

The present invention provides a tablet including: an amorphous solid dispersion including an amorphous form of at least one pharmaceutical active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives. and a pH-independent cellulosic water-soluble polymer; a disintegrant having a swelling level of less than 10 mL/g; and a salting-out agent. The present invention also provides a method for producing a tablet.

Description

Tablet and manufacturing method thereof

The present disclosure relates to tablets and manufacturing methods thereof.

Among the compound groups selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, orally administrable antiviral agents, particularly human immunodeficiency virus (hereinafter referred to as HIV) infectious disease , Active pharmaceutical ingredients useful as therapeutic agents for hepatitis C and the like are included.
However, at least one compound selected from the group consisting of L-isoleucine derivatives and L-valine derivatives (hereinafter sometimes referred to as a specific active ingredient) is sparingly soluble in water. Therefore, when the specific active ingredient is formulated as a tablet, a means for improving the disintegration property of the tablet and the elution of the specific active ingredient and improving the absorbability of the specific active ingredient in the body is desired.

As one means for improving the dissolution property, for example, in Japanese Patent Publication No. 2017-505306 and Japanese Patent Laid-Open No. 2018-35163, an amorphous solid dispersion containing a pharmaceutically active ingredient and crospovidone which is a water-soluble polymer is disclosed. A tablet containing the body is disclosed.
Japanese Patent Publication No. 2015-517690 discloses a tablet containing an acidic polymer, porosigen as an excipient having an appropriate amount of voids, and a disintegrant.

It may be possible to suppress the disintegration delay by increasing the amount of disintegrant contained in the tablet, but due to the increase in the content of the disintegrant, the size of the tablet becomes large and it becomes difficult to take orally. Due to moisture absorption, storage stability in a high humidity environment may be reduced.
Further, in order to solve the problem of improving the elution of the specific active ingredient, an amorphous solid dispersion is prepared by combining the specific active ingredient with a water-soluble cellulose polymer. This is because by making the specific active ingredient amorphous, it is expected that the tablet size will be reduced and the absorption of the specific active ingredient will be improved.
However, an amorphous solid dispersion containing a pharmaceutically active ingredient and a water-soluble polymer may gel when contacted with water, and there is a concern that the disintegration rate of the tablet may be delayed when gelled.

Tablets containing the active pharmaceutical ingredients and polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA polymer: copovidone) described in JP-A-2017-505306 and JP-A-2018-35163 can delay disintegration due to gelation. Although the property is low, the polymer itself has the property of deliquescent upon exposure to humidity, and thus storage stability in a high humidity environment may be reduced.
In addition, in the pharmaceutical composition described in JP-A-2017-505306, an amorphous solid dispersion containing a polymer having a weak tendency to gel like copovidone and a pharmaceutically active ingredient by adding a salting-out agent. In order to prevent gelation of the body, a certain degree of tablet disintegration delay inhibitory effect can be expected. However, when a polymer having a strong gelation tendency such as a pH-independent cellulosic water-soluble polymer is contained, a sufficient effect of suppressing the disintegration delay of the tablet cannot be obtained, and from the viewpoint of improving the absorption of the active ingredient. Is desired to have a further tablet disintegration delay suppressing effect.

The tablets described in Japanese Patent Publication No. 2015-517690 have insufficient ability to suppress gelation. In addition, since it contains only acidic polymer as a water-soluble polymer, when it is applied to a dissolution test method using an acidic test solution that mimics the gastric environment, dissolution of the acidic polymer does not proceed and the dissolution of the active ingredient decreases. There is. In addition, when applied to a dissolution test method that uses a test solution having a weak buffering capacity and a small amount of liquid, which is performed under conditions simulating the environment in the digestive tract, the test solution is dissolved in a region where some acidic polymers are dissolved. The pH may decrease. In a region where the pH of the test solution is lowered, further dissolution of the acidic polymer becomes difficult to proceed, and the elution of the active ingredient may be reduced.

An object of one embodiment of the present invention is to provide a tablet containing a medicinal active ingredient as an amorphous solid dispersion and suppressing the disintegration delay.
An object of another embodiment of the present invention is to provide a method for producing a tablet, which comprises a medicinal active ingredient as an amorphous solid dispersion and can obtain a tablet with suppressed disintegration delay.

Means for solving the above problems include the following aspects.
<1> An amorphous solid containing an amorphous form of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and a pH-independent cellulosic water-soluble polymer A tablet containing a dispersion, a disintegrating agent having a swelling amount of less than 10 mL (milliliter)/g, and a salting-out agent.

<2> The active ingredient for pharmaceuticals described in <1>, which is at least one selected from the group consisting of ritonavir, lopinavir, cyclosporin A, colistin or a salt thereof, bacitracin A, polymyxin B, daclatasvir, elvasvir, and velpatasvir. Tablets.
<3> The tablet according to <1> or <2>, wherein the medicinal active ingredient is at least one selected from the group consisting of ritonavir and lopinavir.

<4> The amorphous solid dispersion contains 10 to 1000 parts by mass of the pH-independent cellulosic water-soluble polymer with respect to 100 parts by mass of the medicinal active ingredient <1> to <3. > The tablet according to any one of>.
<5> The pH-independent cellulosic water-soluble polymer contains at least one selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose. The tablet according to any one of claims.
<6> The tablet according to any one of <1> to <5>, wherein the pH-independent cellulosic water-soluble polymer contains hypromellose.

<7> The tablet according to any one of <1> to <6>, in which the disintegrant having a swelling amount of less than 10 mL/g contains crospovidone.
<8> The tablet according to any one of <1> to <7>, which contains 0.1 to 50 parts by mass of the disintegrant having a swelling amount of less than 10 mL/g with respect to 100 parts by mass of the tablet.
<9> The tablet according to any one of <1> to <8>, further including a disintegrant having the swelling amount of 10 mL/g or more.
<10> The tablet according to <9>, wherein the disintegrant having a swelling amount of 10 mL/g or more is at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and carmellose calcium.
<11> The tablet according to <9> or <10>, wherein the disintegrant having a swelling amount of 10 mL/g or more is croscarmellose sodium.
<12> The tablet according to any one of <9> to <11>, which contains 0.1 to 50 parts by mass of the disintegrant having a swelling amount of 10 mL/g or more with respect to 100 parts by mass of the tablet.

<13> The salting-out agent contains at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and calcium carbonate <1> to The tablet according to any one of <12>.
<14> The tablet according to any one of <1> to <13>, containing 0.1 to 50 parts by mass of the salting-out agent with respect to 100 parts by mass of the tablet.
<15> The tablet according to any one of <1> to <14>, wherein the volume average particle diameter of the amorphous solid dispersion is in the range of 0.1 μm to 200 μm.

<16> An amorphous solid containing an amorphous form of at least one medicinal active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and a pH-independent cellulosic water-soluble polymer Step A for preparing a dispersion, Step B for preparing a mixture containing the obtained amorphous solid dispersion, a disintegrating agent having a swelling amount of less than 10 mL/g, and a salting-out agent, and the resulting mixture And a step C of obtaining a tablet by compressing.
<17> In the step A, a solution containing the pharmaceutical active ingredient, the pH-independent cellulosic water-soluble polymer, and a solvent is prepared, and the resulting solution is spray-dried to be a spray-dried powder. The method for producing a tablet according to <16>, which comprises obtaining.

<18> Includes an amorphous form of at least one medicinal active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, a pH-independent cellulosic water-soluble polymer, and an acidic polymer A tablet containing an amorphous solid dispersion, a disintegrant, and a salting-out agent.

<19> The tablet according to <18>, wherein the medicinal active ingredient is at least one selected from ritonavir, lopinavir, cyclosporin A, colistin or a salt thereof, bacitracin A, polymyxin B, daclatasvir, elvasvir, and velpatasvir.
<20> The tablet according to <18> or <19>, wherein the medicinal active ingredient is at least one selected from ritonavir and lopinavir.

<21> The amorphous solid dispersion contains 10 parts by mass to 1000 parts by mass in total of the pH-independent cellulosic water-soluble polymer and the acidic polymer with respect to 100 parts by mass of the medicinal active ingredient. The tablet according to any one of <18> to <20>.
<22> The content ratio of the acidic polymer with respect to the total content of the pH-independent cellulosic water-soluble polymer and the acidic polymer contained in the amorphous solid dispersion is more than 0 mass% and 90 The tablet according to any one of <18> to <21>, which is at most% by mass.
<23> The content ratio of the acidic polymer to the total content of the pH-independent cellulosic water-soluble polymer and the acidic polymer contained in the amorphous solid dispersion is 10% by mass to 75% by mass. The tablet according to any one of <18> to <22>.
<24> The pH-independent cellulosic water-soluble polymer contains at least one selected from the group consisting of hypromellose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose. The tablet according to any one of claims.
<25> The tablet according to any one of <18> to <24>, wherein the pH-independent cellulosic water-soluble polymer is hypromellose.
<26> The above-mentioned acidic polymer is a group consisting of hypromellose acetate succinate, carboxymethylethyl cellulose, hypromellose phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer S, and polyvinyl acetate phthalate ester. The tablet according to any one of <18> to <25>, which is at least one selected from the following.
<27> The tablet according to any one of <18> to <26>, wherein the acidic polymer is at least one selected from the group consisting of hypromellose acetate succinate and carboxymethylethyl cellulose.

<28> The tablet according to any one of <18> to <27>, containing 0.1 to 50 parts by mass of the disintegrant with respect to 100 parts by mass of the tablet.
<29> The salting-out agent contains at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and calcium carbonate <18> to The tablet according to any one of <28>.
<30> The tablet according to any one of <18> to <29>, which contains 0.1 to 50 parts by mass of the salting-out agent with respect to 100 parts by mass of the tablet.
<31> The tablet according to any one of <18> to <30>, wherein the volume average particle diameter of the amorphous solid dispersion is in the range of 0.1 μm to 200 μm.

<32> Amorphous substance of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivative and L-valine derivative, pH-independent cellulosic water-soluble polymer, and acidic polymer Step A2 for preparing an amorphous solid dispersion, Step B2 for preparing a mixture containing the obtained amorphous solid dispersion, a disintegrant, and a salting out agent, and tableting the obtained mixture. And a step C2 of obtaining a tablet by a method for producing a tablet.
<33> In the step A2, a solution containing the medicinal active ingredient, the pH-independent cellulosic water-soluble polymer, the acidic polymer, and a solvent is prepared, and the obtained solution is spray-dried. The method for producing a tablet according to <32>, which comprises spraying to obtain a spray-dried powder.

According to one embodiment of the present invention, there is provided a tablet containing a pharmaceutically active ingredient as an amorphous solid dispersion, which suppresses disintegration delay.
According to another embodiment of the present invention, there is provided a method for producing a tablet, which comprises a medicinal active ingredient as an amorphous solid dispersion to obtain a tablet with suppressed disintegration delay.

Hereinafter, the tablet of the present disclosure and the method for producing the tablet will be described with reference to specific examples. However, the present disclosure is not limited to the following embodiments, and can be implemented with appropriate modifications as long as the gist of the present disclosure is not exceeded.

In the present disclosure, the numerical range indicated by using “to” means a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
In the numerical ranges described stepwise in the present disclosure, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the upper limit value or the lower limit value of another stepwise described numerical range. Further, in the numerical range described in the present disclosure, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the values shown in the examples.
In the present disclosure, a combination of two or more preferable aspects is a more preferable aspect.
In the present disclosure, the amount of each component means the total amount of a plurality of types of substances when there are a plurality of types of substances corresponding to each component, unless otherwise specified.
In the present disclosure, a “poorly water-soluble” component refers to a component having a solubility in water at 20° C. of 0.1 mg/mL or less.
In the present disclosure, gelling of the tablet or the amorphous solid dispersion contained in the tablet means that when the tablet or the amorphous solid dispersion contained in the tablet comes into contact with a liquid, a high content of a water-soluble cellulosic polymer or the like. A phenomenon in which a molecular compound takes in a liquid, loses fluidity, and becomes a solid.
A gel formed by gelation of an amorphous solid dispersion is formed by at least a part of a polymer compound forming a crosslinked structure to form a network structure, and a liquid is retained in the network voids. It is considered to have been done. Therefore, it is considered that the formed gel does not become in a fluid state even when stressed or heated, and inhibits absorption of the pharmaceutically active ingredient contained in the amorphous solid dispersion. . The liquid referred to here includes water and liquids containing water, such as saliva, gastric juice, and intestinal fluid.

In the present disclosure, the term “step” is included in the term not only as an independent step but also when it cannot be clearly distinguished from other steps as long as the intended purpose of the step is achieved.
Incidentally, each of the components shown below that may be contained in the tablet of the present disclosure, except for components such as an organic solvent that is removed out of the system in the manufacturing process, even if not particularly stated, all are pharmaceutically acceptable. It goes without saying that it is an ingredient.

[Tablet: First embodiment]
A first aspect of the tablet of the present disclosure is an amorphous form of at least one pharmaceutically active ingredient (specific active ingredient) selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and pH independence. An amorphous solid dispersion containing a cellulosic water-soluble polymer (hereinafter sometimes referred to as a specific polymer), a disintegrating agent having a swelling amount of less than 10 mL/g (hereinafter sometimes referred to as a specific disintegrating agent), And a salting-out agent.
Hereinafter, the tablet of the present disclosure may be simply referred to as “tablet”. Further, the tablet according to the first aspect may be referred to as “tablet (I)” for the purpose of distinguishing it from the tablet according to the second aspect of the present disclosure described below [also referred to as tablet (II)]. Unless otherwise specified, the “tablet of the present disclosure” and “tablet” refer to “tablet (I)”.

The specific active ingredient is a poorly water-soluble ingredient, and is hardly soluble in a solvent, particularly a solvent containing water such as a body fluid (eg, digestive fluid).
Therefore, the specific active ingredient and the cellulose-based water-soluble polymer are dissolved in a solvent and mixed to disperse the specific active ingredient in the water-soluble polymer, and then solidified to be used as an amorphous solid dispersion. In the obtained amorphous solid dispersion, the specific active ingredient exists as an amorphous body having excellent absorbability into the living body, and when the tablet containing the amorphous solid dispersion comes into contact with the liquid, the polymer is dissolved. It is considered that the specific active ingredient also dissolves with the above.
However, according to the studies by the present inventors, it is sufficient to form a mixture by combining an amorphous body of a specific active ingredient which is poorly soluble in water and a cellulosic polymer known as a dissolution improving agent. It was found that the elution improving effect could not be obtained. This is because when the amorphous solid dispersion comes into contact with a solvent containing water, the outer peripheral region of the tablet gels and the permeability of the liquid inside the tablet is impeded, or the tablet disintegration is delayed or the tablet disintegrates. Even in such a case, the particles of the amorphous solid dispersion may be agglomerated with each other due to gelation to cause dissolution delay due to the formation of aggregates, and as a result, elution of the active ingredient may occur. I'm guessing it's being hindered.

Although the action of the tablet of the present disclosure is not clear, it is considered as follows.
The tablet of the present disclosure is a salting-out agent and disintegration with a swelling amount of less than 10 mL/g, with respect to an amorphous solid dispersion containing a specific active ingredient amorphous form and a pH-independent cellulosic water-soluble polymer. Contains an agent. When the swelling amount of the disintegrant is less than 10 mL/g, a water-conducting effect to the inside of the tablet containing the amorphous solid dispersion can be expected. Therefore, the liquid is easily introduced between the amorphous bodies which are dispersoids of the amorphous solid dispersion due to the water-conducting effect of the disintegrant, and the disintegrant swells by absorbing the introduced liquid inside the tablet. The increase in volume promotes tablet disintegration. Further, the salting-out agent suppresses the water absorption of the water-insoluble polymer which is pH-independent, thereby suppressing the gelation of the tablet or the amorphous solid dispersion. It is considered that, together with the above effects, delayed disintegration and gelation of tablets are effectively suppressed.
Furthermore, the pH-independent cellulosic water-soluble polymer in the present disclosure is less likely to cause deliquescence of the tablet due to the polymer, as compared with the case of using a known water-soluble polymer such as polyvinylpyrrolidone, and the stability of the tablet. It is considered that it also has a secondary effect of being excellent.
It is considered that the absorption of the specific active ingredient into the body is improved by improving the elution of the specific active ingredient which is poorly soluble in water, and it is expected that the pharmacological effect of the specific active ingredient in the body is promptly exhibited.
It should be noted that the above description of the mechanism of action is based on estimation, and is not intended to limit the mechanism of action of the tablet of the present disclosure, but is shown as an example of a possible mechanism of estimation.

Hereinafter, each component that may be contained in the tablet of the present disclosure will be described in detail.

[Amorphous solid dispersion]
The tablet of the present disclosure contains an amorphous solid dispersion containing an amorphous form of the specific active ingredient and a pH-independent cellulosic water-soluble polymer.
The amorphous solid dispersion refers to a state in which the amorphous body of the specific active ingredient is uniformly dispersed in a fine solid state in the pH-independent water-soluble cellulose polymer.

<Specific active ingredient>
The tablet of the present disclosure contains at least one amorphous substance (specific active ingredient) selected from the group consisting of L-isoleucine derivatives and L-valine derivatives as a pharmaceutically active ingredient. The specific active ingredient is contained in tablets in the form of an amorphous solid dispersion. It is considered that when the specific active ingredient is in the form of an amorphous solid dispersion, the solubility and dispersibility of the specific active ingredient in the body are improved, and the absorption of the specific active ingredient in the body is better.
Specific active ingredients include ritonavir, lopinavir, Lopinavir, cyclosporin A, colistin or a salt thereof, bacitracin A, polymyxin B, Daclatasvir, elbassvir, velpatas virpat and the like.
The tablet of the present disclosure preferably contains at least one kind of the compounds exemplified above, and more preferably contains at least one kind selected from ritonavir and lopinavir.

The tablet may contain only one type of specific active ingredient, or may use two or more types in combination.
For example, ritonavir is known as a protease inhibitor having an antiretroviral effect, and since it has an effect of suppressing the decomposition of other protease inhibitors used in combination, it is often used in combination with other protease inhibitors. For example, a drug containing ritonavir and lopinavir is on the market.
When two or more specific active ingredients are used in combination, a combination system of ritonavir and lopinavir, a combination system of ritonavir and lamivudine, a combination system of ritonavir, lopinavir and lamivudine and the like can be mentioned as preferred embodiments.

The specific active ingredient may be obtained by synthesis or can be obtained as a commercial product.
For example, ritonavir and a method for producing the same are described in US Pat. No. 5,542,206 and US Pat. No. 5,648,497, and for lopinavir, US Pat. No. 5,914,332. As described in the specification, the synthesis of the specific active ingredient can be referred to, for example, these descriptions.
In addition, ritonavir, lopinavir and the like are commercially available from Sigma-Aldrich and the like.

The content of the specific active ingredient in the tablet can be appropriately set within the pharmaceutically acceptable range according to the purpose of treatment or prevention. For example, depending on whether the content that achieves the required drug efficacy is included in one tablet, or dispersed into two or more tablets, or how many times a day the required amount is taken to achieve the desired effect The content of the specific active ingredient per tablet is appropriately selected.
Generally, the content of the specific active ingredient in a tablet can be set to an amount for an adult, which is a dose of 0.1 mg to 1000 mg, and a dose of 0.1 mg to 500 mg. The amount is preferably set in the range, and more preferably set in the range of 0.1 mg to 300 mg.
Considering ease of taking, it is preferable that the weight of each tablet is 2000 mg or less.

<pH-independent cellulosic water-soluble polymer: specific polymer>
The amorphous solid dispersion contains a pH-independent cellulosic water-soluble polymer.
The pH-independent cellulosic water-soluble polymer in the present disclosure means a cellulosic water-soluble polymer whose solubility in water does not depend on the pH of water. That is, the specific polymer according to the present disclosure dissolves in water not only in the acidic region where the pH of water is less than 4 and the alkaline region where the pH exceeds 9, but also in the neutral region where the pH of water is 4 to 9. sell.
Here, that the specific polymer “dissolves in water” means that the specific polymer has a solubility of 10 mg/mL or more after being added to water at 20° C. and stirred.

Examples of the specific polymer include cellulosic water-soluble polymers exemplified below. The numbers in parentheses are the abbreviations of the respective compounds, and hereinafter, in the present disclosure, the abbreviations given together with the names of the respective compounds may be used.
Methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl hydroxyethyl cellulose (MHEC) and the like. Note that HPMC is also called "hypromellose" and is widely used as an additive for medicines and foods.
Among them, the amorphous solid dispersion preferably contains, as the specific polymer, at least one selected from the group consisting of HPMC (hypromellose), HPC, MC, HEC, and MHEC, and more preferably HPMC. ..

The molecular weight of the specific polymer is preferably 500 or more and 500,000 or less, more preferably 1000 or more and 150,000 or less, still more preferably 10,000 or more and 100,000 or less.
The molecular weight of the specific polymer can be measured by gel permeation chromatography (GPC).
For example, the molecular weight of the specific polymer can be determined by using GPC as a value of polystyrene (PST) conversion or pullulan conversion weight average molecular weight. When this method is applied to measure the weight average molecular weight of a specific polymer, when PST is dissolved in the eluent for measurement, it is measured by PST conversion, and when pullulan is dissolved in the eluent, pullulan is used. It may be measured by conversion.
When a commercial product is used as the specific polymer, the catalog value of the commercial product is adopted as the molecular weight.

The viscosity of a 2% by mass aqueous solution of the specific polymer at 20° C. [17th Revised Japanese Pharmacopoeia (first method of viscosity test)] is, for example, 100 mPa·s from the viewpoint that the effect of suppressing dissolution delay is better. The following is preferable, 50 mPa·s or less is more preferable, and 25 mPa·s or less is further preferable.
The “viscosity” in the present disclosure refers to the viscosity measured at 20° C. by the method described in the 17th revised Japanese Pharmacopoeia (first method of viscosity test).
The lower limit of the viscosity of a 2% by mass aqueous solution of the specific polymer at 20° C. [17th Revised Japanese Pharmacopoeia (first method of viscosity test)] is not particularly limited, but is preferably 1 mPa·s or more, for example.

HPMC is commercially available. As commercially available HPMC, for example, TC-5 (registered trademark) E [trade name, Shin-Etsu Chemical Co., Ltd.: substitution degree type: 2910, molecular weight (catalog value): 16,000, viscosity: 3 mPa·s], TC-5 (registered trademark) M [trade name, Shin-Etsu Chemical Co., Ltd.: substitution degree type: 2910, molecular weight (catalog value): 22,000, viscosity: 4.5 mPa·s], TC-5 (registered trademark) R [trade name, Shin-Etsu Chemical Co., Ltd.: substitution degree type: 2910, 6 mPa·s, molecular weight (catalog value): 36,000, viscosity: 6 mPa·s], TC-5 (Registered trademark) S [trade name, Shin-Etsu Chemical Co., Ltd.: substitution degree type: 2910, molecular weight (catalog value): 60,000], METOLOSE (registered trademark) 60SH-50 [trade name, Shin-Etsu Chemical Co., Ltd.] : Substitution degree type: 2910, molecular weight (catalog value): 768,000], METOLOSE (registered trademark) 90SH-100SR [trade name, Shin-Etsu Chemical Co., Ltd.: substitution degree type: 2208], Methocel (registered trademark) E5 Premiun LV [trade name, Dow Chemical Company: HPMC substitution degree type: 2910, viscosity: 5 mPa·s], VIVAPHARM (registered trademark) HPMC E5 [trade name, JRS Pharma: HPMC substitution degree type: 2910, viscosity: 5 mPas .S] and the like, and TC-5 (registered trademark) E, TC-5 (registered trademark) M, TC-5 (registered trademark) R [all are trade names, Shin-Etsu Chemical Co., Ltd.] and the like are preferable. ..
The molecular weights of commercially available products of the specific polymers are all in the range of 500 to 500,000, and the viscosities are all in the range of 1 mPa·s to 100 mPa·s.

The amorphous solid dispersion may contain only one type of the specific polymer or may contain two or more types of the specific polymer.
The content of the specific polymer in the amorphous solid dispersion is not particularly limited.
From the viewpoint that the elution of the specific active ingredient from the amorphous solid dispersion is better, the content of the specific polymer is 10 parts by mass to 1000 parts by mass with respect to 100 parts by mass of the specific active ingredient. Is more preferable, 50 parts by mass to 500 parts by mass is more preferable, and 100 parts by mass to 300 parts by mass is further preferable.

<Preparation of amorphous solid dispersion>
The preparation method of the amorphous solid dispersion is not particularly limited, and a known preparation method such as a spray drying method or a melt kneading extrusion method can be appropriately applied.
Among them, from the viewpoint of further improving the stability of the specific active ingredient and reducing the content of the specific polymer in the tablet useful for amorphizing the specific active ingredient, the specific active ingredient and the specific polymer are combined. A preferred method is to prepare a mixed solution dissolved in a suitable solvent and spray-dry the obtained mixed solution. Details of the method for preparing the amorphous solid dispersion will be described later.
The volume average particle diameter (D50) of the amorphous solid dispersion is preferably 0.1 μm to 200 μm, and more preferably 0.1 μm to 100 μm, from the viewpoint that the productivity of tablets, dry granules and the like will be better. Is more preferable, and the range of 1 μm to 50 μm is even more preferable.
When the volume average particle diameter of the amorphous solid dispersion is within the above range, the spray-dried powder is sufficiently dried, the generated spray-dried powder can be collected efficiently, and the amorphous solid dispersion is amorphous. The yield of solid dispersion is better.
The volume average particle diameter of the amorphous solid dispersion can be measured by a laser diffraction/scattering method (also referred to as a microtrack method). More specifically, the volume average particle diameter of the dry powder can be measured by a laser diffraction/scattering particle size distribution measuring device, for example, LS 13 320 manufactured by Beckman Coulter.

The amorphous solid dispersion in the present disclosure refers to a state in which an amorphous body of a specific active ingredient is present in a specific polymer uniformly dispersed in a fine solid state, and the specific active ingredient is solid in the specific polymer. When present as a dispersion, it is considered that the specific active ingredient becomes an amorphous body and the absorbability in the body is further improved.
As will be described later, it is considered that the specific active ingredient becomes an amorphous body in the process of preparing an amorphous solid dispersion of the specific active ingredient.

It should be noted that the presence of the specific active ingredient in the amorphous state in the tablet of the present disclosure means that the specific active ingredient which is the drug substance in the tablet is determined by powder X-ray diffraction (PXRD). It can be confirmed by not showing a clear peak derived from the crystal of the component and showing a halo pattern.
More specifically, since the tablet usually contains additives other than the specific active ingredient, first, individual peak patterns of the additives other than the specific active ingredient are confirmed in advance. Then, the peak obtained by subtracting the peak derived from the additive other than the specific active ingredient confirmed in advance from the peak obtained by PXRD of the tablet was observed, and a clear peak derived from the crystal of the specific active ingredient appeared in the tablet. First, it is a method of confirming that a halo pattern is shown.

[Disintegrant with swelling amount less than 10 mL/g: specific disintegrant]
The tablet of the present disclosure contains a disintegrant having a swelling amount of less than 10 mL/g.
By including the specific disintegrant in the tablet, the water-conducting effect of the liquid into the amorphous solid dispersion is further improved, the disintegration of the tablet after administration is made easier, and the specific active ingredient is efficiently released and eluted. It is thought that it is possible to
Specific disintegrants include starch such as corn starch and potato starch, partially pregelatinized starch, carmellose, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch and the like.
The swelling amount of a typical specific disintegrant is described below.
Corn starch (swelling amount: 1.5 mL/g)
Partially pregelatinized starch (swelling amount: 8.0 mL/g)
Carmellose (Swelling amount: 2.5 mL/g)
Crospovidone (swelling amount: 4.3 mL/g)
Low-substituted hydroxypropyl cellulose (swelling amount: 1.5 mL/g)
Among them, the tablet of the present disclosure preferably contains crospovidone as the specific disintegrant.

When the amount of swelling of the disintegrant in water can be confirmed from the literature value, the literature value is adopted. When a commercially available disintegrant is used and the catalog value of the swelling amount can be confirmed, the catalog value is adopted.
In the present disclosure, the amount of swelling of the disintegrant in water can also be measured by the following method.
In a room temperature (25° C.) environment, 1.0 g of a disintegrant to be measured is weighed as a sample. The weighed disintegrant is put in a graduated cylinder, and the volume (mL) of 1.0 g of the disintegrant before swelling is read.
75 mL of purified water is put into a beaker, 1.0 g of the above disintegrant is added little by little while stirring with a stirrer, and after all disintegrants are added, the mixture is stirred for 3 minutes.
The suspension is transferred to a 100 mL graduated cylinder, and after measuring up to 100 mL, the suspension is left standing for 16 hours, and the volume (mL) of the disintegrant settled at the bottom of the graduated cylinder is read. The measurement is performed at room temperature (25°C).
For 1.0 g of the disintegrant to be measured, the volume of the disintegrant settled at the bottom of the graduated cylinder (that is, the disintegrant after swelling with water) before the disintegration before being added to water (that is, the disintegration before swelling) The value obtained by dividing the volume of the agent) is taken as the swelling amount (mL/g) when absorbing water per 1.0 g of the disintegrant.

As the specific swelling agent, a commercially available product may be used, and examples of the commercially available product of crospovidone (crosslinked polyvinylpyrrolidone) include Kollidon (registered trademark) CL-SF and Kollidon (registered trademark) CL [above, trade name: BASF Company], Polyplasdone (registered trademark) XL, Polyplasdone (registered trademark) XL-10, Polyplasdone Ultra, Polyplasdone (registered trademark) Ultra-10 [above, product name: Ashland, Inc.] and the like.

The tablet of the present disclosure may include only one type of specific disintegrant or may include two or more types.
The content of the specific disintegrant in the tablet of the present disclosure is not particularly limited and is appropriately selected depending on the dosage form of the tablet, the purpose of use of the tablet, the required disintegration property, and the like.
Among them, without increasing the size of the tablet too much, and that the effect of suppressing the disintegration delay can be sufficiently obtained, from the viewpoint of the balance between the size of the tablet and the disintegration delay suppressing effect, the content of the specific disintegrant is: The amount is preferably 0.10 parts by mass to 50 parts by mass, more preferably 1 part by mass to 30 parts by mass, and further preferably 1 part by mass to 20 parts by mass, relative to 100 parts by mass of the tablet. .

[Salting-out agent]
The tablet of the present disclosure contains a salting-out agent.
Examples of the salting-out agent include at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and calcium carbonate. The salting-out agent preferably contains at least one selected from the group consisting of the compounds described above.

The tablet of the present disclosure may include only one type of salting-out agent, or may include two or more types of salting-out agent.
The content of the salting-out agent in the tablet of the present disclosure is not particularly limited and may be appropriately selected depending on the dosage form of the tablet, the purpose of use of the tablet, the required disintegration property, and the like.
Among them, the content of the salting-out agent is preferably 0.1 parts by mass to 50 parts by mass with respect to 100 parts by mass of the tablet, from the viewpoint of the balance between the tablet size and the disintegration delay suppressing effect. The amount is more preferably 1 part by mass to 30 parts by mass, further preferably 1 part by mass to 20 parts by mass.

<Other ingredients>
The tablet of the present disclosure can contain, in addition to the specific active ingredient, the specific polymer, the specific disintegrant, and the salting-out agent, other components as necessary, as long as the effects are not impaired.
The other components are not particularly limited as long as they are components that can be used as a pharmaceutical additive.
As the other component, a disintegrating agent other than the specific disintegrating agent, that is, a disintegrating agent having a swelling amount of 10 mL/g or more (hereinafter sometimes referred to as other disintegrating agent), a binder, a lubricant, an excipient , Antioxidants, stabilizers, colorants, flavoring agents, sweeteners, corrigents, pH adjusters, fluidization accelerators and the like.
Examples of other components include various compounds described in paragraphs 0109 to 0115 of JP-A-2016-525579 and various compounds described in paragraph 0024 of WO 2015/053227.

(Other disintegrants)
The tablet of the present disclosure can further contain at least one other disintegrant in addition to the specific disintegrant.
It is believed that the tablets of the present disclosure further include other disintegrants to facilitate tablet disintegration. That is, when the amorphous solid dispersion contains another disintegrant, the liquid containing water is introduced into the amorphous solid dispersion by the function of the specific disintegrant as described above, and the liquid containing the introduced water. Quickly reach other disintegrants. Since other disintegrants have a larger swelling amount when contacted with water than the specific disintegrant, it is considered that tablet disintegration is promoted as compared with the case of containing only the specific disintegrant. Therefore, by further containing other disintegrant, the disintegration rate of the tablet and the accompanying dissolution of the specific active ingredient are further improved.

Other disintegrants that can be used in the tablet of the present disclosure include, for example, croscarmellose sodium (swelling amount: 13.5 mL/g), sodium starch glycolate (swelling amount: 23.6 mL/g), and carmellose calcium. It is preferably at least one selected from the group consisting of (swelling amount: 10.0 mL/g), and more preferably croscarmellose sodium.

When the tablet of the present disclosure contains other disintegrant, it may contain only one kind of the other disintegrant or two or more kinds thereof.
When the tablet contains another disintegrant, the content of the other disintegrant is not particularly limited, and the content can be appropriately selected depending on the dosage form of the tablet and the purpose.
As the content when the tablet contains another disintegrant, the content of the other disintegrant is 0.10 parts by mass relative to 100 parts by mass of the tablet, from the viewpoint that the effect of suppressing the disintegration delay is higher. It is preferably from 50 parts by mass to 50 parts by mass, more preferably from 1 part by mass to 30 parts by mass, still more preferably from 1 part by mass to 20 parts by mass.
Further, the content ratio of the specific disintegrant and the other disintegrant is not particularly limited. Generally, the weight ratio of the specific disintegrant to the other disintegrant contained in the tablet may be 1:1 to 1:4, preferably 1:1.5 to 1:2.

(Excipient)
The tablets of the present disclosure can further include at least one excipient.
The "excipient" is generally used for the purpose of diluting and stabilizing a specific active ingredient before ingestion.
Excipients include monosaccharides, sucrose, lactose, disaccharides such as lactose monohydrate, polysaccharides such as cellulose, sugar alcohols such as xylitol, sorbitol, maltitol, and mannitol, silicified microcrystalline cellulose, calcium carbonate. Alternatively, sodium carbonate, dicalcium phosphate, tricalcium phosphate, dehydrated dibasic calcium phosphate dehydrate, etc. may be mentioned.
A commercially available product may be used as the excipient. Examples of commercially available excipients include Parteck M100 [trade name, Merck Millipore: D-mannitol], PROSOLV (registered trademark) SMCC 90 [trade name, manufactured by JRS PHARMA: silicified microcrystalline cellulose] and the like. Is mentioned.

(Glidant)
The tablets of the present disclosure can include at least one glidant.
When the tablet contains a glidant, the flow property during compression when tableting the tablet can be improved, and the caking effect can be further improved.
Examples of the flow promoter include at least one selected from colloidal silicon dioxide, light anhydrous silicic acid, talc, fumed silica, hydrous silicon dioxide, and bentonite.
A commercially available product may be used as the glidant. Examples of commercially available glidants include Aerosil 200 [trade name, Nippon Aerosil Co., Ltd.: Light anhydrous silicic acid] and the like.

(lubricant)
The tablets of the present disclosure can include at least one lubricant.
Lubricants are generally added to the powder to be compressed during the tabletting process in order to prevent the compressed powder mass from sticking to the surface of a mold or the like for compression. Used. By using a lubricant, the tablet can be more efficiently discharged from the mold after tableting at the time of tablet molding.
Examples of the lubricant include magnesium stearate, silica, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc and the like. Further, fatty acids which are solid at room temperature, such as fatty acids having 8 to 20 carbon atoms such as stearic acid, lauric acid and oleic acid, can be used as lubricants.

(Surfactant)
The tablets of the present disclosure can include at least one surfactant.
When the tablet contains a surfactant, the surface tension between the liquid and the solid can be lowered to improve the wettability of the specific active ingredient and the elution of the specific active ingredient.
As the pharmaceutically acceptable surfactant, a pharmaceutically acceptable nonionic surfactant is preferably used.
The surfactant can affect the emulsification of the eluted specific active ingredient, and can be expected to prevent precipitation of the specific active ingredient in fluid such as gastric juice and intestinal fluid in the digestive tract.

Examples of surfactants are shown below.
Polyoxyethylene alkyl ethers such as polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ether, For example, polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether or polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acid ester such as PEG-200. Monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearic acid or PEG-300 dioleic acid; alkylene glycol fatty acid monoesters such as propylene glycol monolaurate (Lauroglycol®). Sucrose fatty acid esters such as sucrose monostearate, sucrose distearate, sucrose monolaurate or sucrose dilaurate; sorbitan monolaurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span®) 40) or sorbitan fatty acid monoesters such as sorbitan stearate; polyoxyethylene castor oil derivatives such as polyoxyethylene glycerol triricinolate or polyoxyl 35 castor oil (Kolliphor® EL; BASF AG); polyethylene glycol Polyoxyethylene glycerol oxystearate such as 40 hydrogenated castor oil (Kolliphor® RH40) or polyethylene glycol 60 hydrogenated castor oil (Kolliphor® RH60); polyoxyethylene polyoxypropylene block copolymer or poly Block copolymers of ethylene oxide and propylene oxide known as oxyethylene polypropylene glycols, for example, Kolliphor® 124, Kolliphor® 188, Kolliphor® 237, Kolliphor® 388 or Kolliphor®. 407 (BASF); polyoxyethylene (20) sorbitan monofatty acid ester, for example, polyoxyethylene (20) ) Sorbitan monooleate (Tween (registered trademark) 80), polyoxyethylene (20) sorbitan monostearate (Tween (registered trademark) 60), polyoxyethylene (20) sorbitan monopalmitate (Tween (registered trademark) 40) ), polyoxyethylene (20) sorbitan monolaurate (Tween (registered trademark) 20); and the like.
The above "Kolliphor" is a registered trademark of BASF. The "Tween" is a registered trademark of Croda.
Among them, BASF's Kolliphor (registered trademark) series, specifically, for example, Kolliphor P407 is preferable.

(Other water-soluble polymers)
The tablet of the present disclosure can further include at least one kind of pH-dependent water-soluble polymer (hereinafter, appropriately referred to as “other water-soluble polymer”) other than the specific polymer.
Other water-soluble polymers are not particularly limited as long as they are pH-dependent, pharmaceutically acceptable and orally water-soluble polymers. Examples of other water-soluble polymers include acidic polymers and basic polymers for pharmaceutical use.

-Acidic polymer-
The acidic polymer is a polymer compound having a pH of 6.0 or less at 20° C. in a saturated aqueous solution, and is a polymer compound which dissolves in water at a pH around neutrality (specifically, pH 5 to 8). ..
From the standpoint of availability, use as a pharmaceutical additive, and the like, examples of the acidic polymer include a cellulosic polymer having a carboxy group and a cellulose skeleton in the molecule, and a (meth)acrylic group having a carboxy group in the molecule. A polymer or a vinyl polymer having a carboxy group in the molecule is suitable.

Specific examples of the acidic polymer include hypromellose acetate succinate (HPMCAS), carboxymethylethyl cellulose (CMEC), hypromellose phthalate (HPMCP), cellulose acetate phthalate (generic name: ceracetoate), Methacrylic acid copolymer L, methacrylic acid copolymer S, polyvinyl acetate phthalate ester and the like can be mentioned, and at least one selected from the group consisting of hypromellose acetate succinate, carboxymethylethyl cellulose, hypromellose phthalate, and ceracephate. It is particularly preferable that it is at least one selected from the group consisting of hypromellose acetate succinate and carboxymethylethyl cellulose.
The name written in the alphabet in parentheses that is written together with the name of each compound is an abbreviation or another name of each compound.

-Basic polymer-
The basic polymer for pharmaceutical use is a polymer used as a gastric-soluble coating agent, and is a polymer compound that dissolves under acidic conditions of pH 1.2 to 3.5, which is the pH of gastric juice, but does not dissolve near neutrality. Point to. Gastric solubility refers to a physical property that dissolves in the low pH region of the stomach and does not dissolve in the neutral pH region of the intestine.
Examples of the basic polymer include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate.
The basic polymer is also available as a commercially available product, and as the commercially available product of the aminoalkyl methacrylate copolymer E, Eudragit E100, Eudragit EPO (trade name, above, Evonik), and as the commercially available product of polyvinyl acetal diethylaminoacetate, AEA is available. (Trade name, Mitsubishi Chemical Co., Ltd.) and the like.

The molecular weight of the other water-soluble polymer is not particularly limited.
The molecular weight of the other water-soluble polymer is, for example, preferably 500 or more and 500,000 or less, more preferably 1000 or more and 150,000 or less, still more preferably 10,000 or more and 100,000 or less.
The molecular weight of the other water-soluble polymer can be measured by the same method as the molecular weight of the above-mentioned specific polymer, and when a commercially available product is used, the catalog value of the commercially available product can be adopted.

[Production method of tablets]
The method for producing the tablet of the present disclosure is not particularly limited, and it can be produced by a known method.
As a manufacturing method for manufacturing the tablet of the present disclosure, for example, from the viewpoint that the tablet of the present disclosure can be easily manufactured, it is preferably manufactured by the method of manufacturing the tablet of the present disclosure described below.

The method for producing a tablet according to the present disclosure includes at least one pharmaceutically active ingredient (specific active ingredient) selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and a pH-independent cellulosic water-soluble polymer. Step A for preparing an amorphous solid dispersion containing, a mixture containing the obtained amorphous solid dispersion, a disintegrating agent of, and a salting out agent at a swelling amount of less than 10 mL/g. Step B and step C of tableting the obtained mixture to obtain a tablet.

Hereinafter, the manufacturing method of the present disclosure will be described, but description of items common to the tablets described above, for example, details of components contained in the tablets will be omitted.

<Process A>
Step A is a step of preparing an amorphous solid dispersion containing the above-mentioned specific active ingredient, specific polymer and solvent. The method for preparing the amorphous solid dispersion is arbitrary, and known preparation methods such as a spray drying method and a melt-kneading extrusion method can be appropriately applied.
The solvent is not limited as long as it is inert to the specific active ingredient and can dissolve at least a part of the mixture of the specific active ingredient and the specific polymer. The solvent may be determined in consideration of the solubilities of the specific active ingredient and the specific polymer. Specific examples of the solvent include organic solvents.

Among them, from the viewpoint of the stability of the specific active ingredient, the step A is to prepare a solution containing the specific active ingredient, the specific polymer, and the solvent, and spray-dry the obtained solution to obtain a spray-dried powder. It is preferable to include a step.
The spray-dried powder obtained here, ie, is the amorphous solid dispersion prepared in step A.

(Organic solvent)
The organic solvent used in the preferred embodiment of step A is any solvent that is inert to the specific active ingredient and can dissolve at least a part of the mixture of the specific active ingredient and the water-soluble polymer. Can also be used.
For the preparation of the mixture, only one organic solvent may be used, or two or more organic solvents may be used in combination.
Examples of the organic solvent that can be used in step A include acetone, tetrahydrofuran (THF), dichloromethane, ethanol (anhydrous or aqueous), methanol and the like.
In step B described below, it is preferable that the organic solvent be removed from the system as quickly as possible. From the viewpoint of good removability from the mixture, the boiling point of the organic solvent used for preparing the mixture is preferably 150°C or lower, and more preferably 100°C or lower.
Specifically, for example, when HPMC is used as the specific polymer, the organic solvent is preferably a mixture of THF and methanol, more preferably a mixture of THF and methanol in a volume ratio of 1:1.
The content of the organic solvent is adjusted to such an amount that the specific active ingredient and the specific polymer are dissolved, and the resulting mixture (solution) has a viscosity capable of being sprayed at the time of spray drying, which is a preferable step to be performed subsequently. Preferably.
Specifically, the amount of the organic solvent in the mixed solution is preferably such that the solid content concentration in the mixed solution is in the range of 30% by mass to 0.1% by mass, and the solid content concentration is in the range of 30% by mass to 30% by mass. An amount in the range of 2% by mass is more preferable.
The amount of the organic solvent used in the mixed solution is such that the solid content concentration is in the above range, the solubility of the specific active ingredient is good, and the viscosity of the mixed solution is maintained in an appropriate range. Therefore, the productivity of the spray-dried powder, which is an amorphous solid dispersion containing the specific active ingredient, becomes better.

Examples of the method for preparing the solution include a method in which a mixture containing the specific active ingredient, the specific polymer, and the organic solvent is sufficiently stirred and mixed.
By uniformly dispersing the specific active ingredient in the specific polymer to form a solid dispersion, the specific active ingredient becomes an amorphous substance, and an amorphous solid dispersion is obtained.
In step A, the mixed solution may contain optional components such as an excipient, a surfactant, a disintegrating agent, a fluidization accelerator, and an antacid, if necessary.
The device used for mixing is not particularly limited as long as the specific active ingredient and the specific polymer can be mixed substantially uniformly, and a known device can be appropriately selected and used.
Examples of the apparatus include a stirrer used for the purpose of preparing a solution, such as a magnetic stirrer, a high stirrer, and a paddle mixer.
In the step A, it is preferable to mix the specific active ingredient and the water-soluble cellulose-based polymer previously dissolved in an organic solvent, from the viewpoint that a more uniform mixed solution can be prepared.

The solvent can be removed from the obtained solution by spray drying to obtain an amorphous solid dispersion which is a spray-dried powder containing the specific active ingredient and the specific polymer.
In step A, a solution obtained by dissolving the specific polymer and the specific active ingredient in an organic solvent is preferably dried by a spray drying method.
According to the spray drying method, the obtained solution is sprayed in a gas and dried rapidly to obtain an amorphous solid dispersion which is a dry powder.
Specifically, the spray drying method is carried out by spraying a heated gas into the spray drying device from the top, the side, or the bottom of the device to form a hot air stream, which is obtained in step A in the hot air stream. It is a method of spraying the solution. The rapid evaporation of the solvent from the sprayed droplets of the solution gives an amorphous solid dispersion which is a dry powder.
In the spray drying method, by adjusting the evaporation rate of the solvent from the solution, so-called "flash evaporation", the poorly water-soluble active ingredient in the obtained dry powder has low crystallinity or does not have crystallinity. It can be in a state (that is, an amorphous body). Here, the evaporation rate of the solvent from the solution can be controlled by the flow rate and temperature of the heated gas flowing in the spray dryer.

There is no limit to the gas supplied into the spray dryer. Examples of the gas supplied into the spray dryer include air, an inert gas such as nitrogen and argon, and air enriched with nitrogen.

As a spray drying device that can be used in the spray drying method in the present disclosure, a spray dryer manufactured by GEA, for example, Pharma-SD type PSD-1, Pharma-SD type PSD-2, Pharma-SD type PSD-3, Pharma- is used. Examples include SD type PSD-4, Pharma-SD type PSD-5, Buchi spray dryer B-290 (Nippon Büch Co., Ltd.) and the like.

Spray dried powders can be obtained by evaporating the solvent from the droplets of the solution in the device and collecting the resulting dry solid dispersion in powder form, for example in a cyclone.
The temperature of the gas is appropriately selected depending on the scale of the device, manufacturing conditions, and the like. The temperature of the gas is selected such that each component contained in the mixed solution is difficult to crystallize and the organic component such as the organic solvent is not decomposed. The temperature of the gas can generally be about 40° C. to about 300° C. at the gas inlet in the spray dryer. The temperature of the gas for flash evaporation of the solvent from the solution is also preferably adjusted within the above range.

The volume average particle size of the amorphous body of the specific active ingredient obtained through the process A is preferably in the range of 0.1 μm to 200 μm, more preferably 0.1 μm to 100 μm, and 1 μm to 50 μm. Is more preferable.
The volume average particle diameter of the amorphous material can be measured by the method described above, that is, the laser diffraction/scattering method (microtrack method).

<Process B>
Step B is a step of preparing a mixture containing the amorphous solid dispersion obtained in Step A, a specific disintegrant, and a salting-out agent.
The method for preparing the mixture in step B is not particularly limited. The method for preparing the mixture is preferably such that, with respect to the amorphous solid dispersion as a spray-dried powder, a specific disintegrant, a salting-out agent and, if desired, at least one pharmaceutically acceptable other component. A method for preparing a mixture by simply adding and mixing the additive to be prepared, a specific disintegrating agent, a salting-out agent, and, if desired, at least one pharmaceutical agent which is another component to the amorphous solid dispersion. A method of preparing a granulated product by adding a chemically acceptable additive and granulating.
Granulation includes dry granulation and wet granulation, and both can be used.
Known wet granulation methods such as a fluidized bed granulation method, a high speed stirring granulation method, and an extrusion granulation method can be applied to the wet granulation.
Among them, dry granulation is preferable from the viewpoint that the problem of recrystallization of the specific active ingredient due to the use of the solvent hardly occurs. That is, the granulation in the granule preparation step is preferably dry granulation.

A method for preparing a granulated product that can be performed in step B will be described.
In step B, it is preferable to add at least one pharmaceutically acceptable additive to the mixed powder obtained in the mixed powder preparation step and dry granulate to prepare a dry granulated product.
Dry granulation in step B (also referred to as dry granulating) refers to the process of forming granules without further use of solution. Dry granulation refers to powder formulations prepared by the dry granulation process.
Hereinafter, a method for preparing a dry granulated product, which is a preferred embodiment, will be described. However, as described above, the granulation in step B is not limited to dry granulation.

Examples of the dry granulation method include a compacting method and a slugging method, and the compacting method is more preferable.
Examples of the compacting method include a method of producing a compression molded product using a roller compactor and crushing the product to obtain a granular material that is a dry granulated product.
In the tablet production method of the present disclosure, when the production scale is small, a tableting machine can be used for dry granulation, and a compression molded product for crushing with a tableting machine to obtain a dry granulated product. May be manufactured.

As an apparatus used for the compacting method which is a dry granulation, a roller compactor TF-LABO, TF-MINI (above, Freund Industrial Co., Ltd.) and the like can be mentioned.

Examples of the additive added as necessary in step B include the above-described other disintegrants, binders, excipients, lubricants, disintegrants, fluidizing agents, and the like. One or more species can be selected and used.
In the tablet manufacturing method of the present disclosure, it is preferable to use at least one selected from the group consisting of a disintegrant, an excipient, and a lubricant in step B.
The content of the additive is not particularly limited. Generally, the additive is used in the range of 5% by mass to 99% by mass with respect to the total mass of the tablet.

(Process C)
Step C is a step of introducing the mixture or dry granulation product obtained in step B into the mold of a tableting machine and compressing it to form tablets.
When forming tablets, if necessary, the mixture or dry granulation is mixed with other components selected from binders, lubricants, excipients, other disintegrants, etc., and the resulting mixture May be introduced into the mold of a tableting machine and compressed into tablets.
In step C, a dry granulation product is prepared in advance in step B, and the obtained dry granulation product and optional components such as a binder, an excipient, a lubricant, another disintegrant, and a fluidizing agent are added. Are preferably mixed. The content of the other components is not particularly limited and may be appropriately selected and used according to the required dosage form.

The device used for tableting is not particularly limited, and a known device can be used.
Examples of the apparatus used for tableting include a rotary tablet making machine HT-AP series (Hata Iron Works Co., Ltd.), a table-top rotary tabletting machine PICCOLA (RIVA), a tabletop tablet making machine HANDTAB (Ichihashi Seiki Co., Ltd.). Co., Ltd.), a single-shot tablet press Tab Flex (Okada Seiko Co., Ltd.), and the like.
The tableting pressure at the time of forming a tablet, the size of the tablet, that is, the size of the compression mold and the like are appropriately selected according to the purpose of use of the tablet.

[Tablet: Second Mode]
Next, the second aspect as another preferred embodiment of the tablet of the present disclosure will be described. Hereinafter, the tablet according to the second aspect may be referred to as "tablet (II)".
The tablet (II) of the present disclosure comprises an amorphous form of at least one pharmaceutically active ingredient (specific active ingredient) selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and pH-independent cellulose. An amorphous solid dispersion containing a water-soluble polymer (specific polymer) and an acidic polymer, a disintegrating agent, and a salting-out agent.

Although the action of the tablet (II) of the present disclosure is not clear, it is considered as follows.
The tablet (II) of the present disclosure contains an amorphous solid dispersion containing an acidic polymer in addition to the specific polymer with respect to the amorphous body of the specific active ingredient. By using the specific polymer and the acidic polymer in combination, the content of the specific polymer can be relatively reduced, the effect of gelation due to the specific polymer can be reduced, and compared with the case where the acidic polymer is used alone. In addition, acidification by an acidic polymer in an atmosphere having a low buffering capacity is less likely to occur. In addition, the compatibility between the specific polymer and the acidic polymer is good, and the decrease in stability due to phase separation during the preparation of the amorphous solid dispersion hardly occurs.
Therefore, by including a salting-out agent and a disintegrating agent, the disintegrating agent promotes the disintegration of the tablet containing the amorphous solid dispersion, and the effect of the coexisting salting-out agent is combined with the disintegrating agent of the tablet. It is believed that retardation and gelation are effectively suppressed.
In addition, the acidic polymer has good stability, and there is no concern about deliquescent or melting of the tablet due to the water-soluble polymer to be contained, and there is also a secondary effect that the stability of the tablet becomes good.
It is considered that the disintegration delay of the tablet is suppressed and the dissolution of the specific active ingredient which is poorly soluble in water is improved, so that the absorbability of the specific active ingredient into the body is improved, and the efficacy of the specific active ingredient in the body is improved. Rapid expression can be expected.
It should be noted that the above description of the mechanism of action is based on estimation, and is not intended to limit the mechanism of action of the tablet of the present disclosure, but is shown as an example of a possible mechanism of estimation.

Hereinafter, each component contained in the tablet (II) of the present disclosure will be described.

[Specific active ingredient]
The tablet (II) of the present disclosure contains a specific active ingredient.
The specific active ingredient and the amorphous form thereof in the tablet (II) of the present disclosure are the same as the specific active ingredient and the amorphous form thereof in the tablet (I) of the present disclosure described above, and the preferable range is also the same. ..
That is, the specific active ingredient is preferably at least one selected from ritonavir, lopinavir, cyclosporin A, colistin or a salt thereof, bacitracin A, polymyxin B, daclatasvir, ervasvir, and velpatasvir, and selected from ritonavir and lopinavir. More preferably, it is at least one kind.
The preferable content of the specific active ingredient in the tablet (II) is also the same as in the tablet (I).

[Specific polymer]
The tablet (II) of the present disclosure contains a specific polymer.
The specific polymer in the tablet (II) of the present disclosure is the same as the specific polymer in the tablet (I) of the present disclosure described above, and the preferable range is also the same.
That is, the specific polymer preferably contains at least one selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose, and more preferably hypromellose.
The amorphous solid dispersion may contain only one type of the specific polymer or may contain two or more types of the specific polymer.

[Acidic polymer]
Tablet (II) of the present disclosure comprises an acidic polymer.
As mentioned above, the acidic polymer is a polymer compound in which the pH of the saturated aqueous solution at 20° C. is 6.0 or less, and is dissolved in water when the pH is near neutral (specifically, pH 5 to 8). Refers to a polymer compound.
The acidic polymer is the same as the acidic polymer mentioned as an optional component of the tablet (I) of the present disclosure described above, and among them, for example, a cellulosic polymer having a carboxy group and a cellulose skeleton in the molecule, A (meth)acrylic polymer having a carboxy group or a vinyl polymer having a carboxy group in the molecule is suitable.

Specific examples of the acidic polymer include hypromellose acetate succinate (HPMCAS), carboxymethylethyl cellulose (CMEC), hypromellose phthalate (HPMCP), cellulose acetate phthalate (generic name: ceracetoate), Methacrylic acid copolymer L, methacrylic acid copolymer S, polyvinyl acetate phthalate ester and the like can be mentioned, and at least one selected from the group consisting of hypromellose acetate succinate, carboxymethylethyl cellulose, hypromellose phthalate, and ceracephate. Is preferable, at least one selected from the group consisting of hypromellose acetate succinate and carboxymethylethyl cellulose is more preferable, and hypromellose acetate succinate is more preferable.

The acidic polymer may be obtained by synthesis or can be obtained as a commercial product.
Examples of commercially available products of hypromellose acetate succinate include Shin-Etsu AQOAT (registered trademark) LF, Shin-Etsu AQOAT (registered trademark) MF, and Shin-Etsu AQOAT (trade names, manufactured by Shin-Etsu Chemical Co., Ltd.). (Registered trademark) HF, Shin-Etsu AQOAT (registered trademark) LG, Shin-Etsu AQOAT (registered trademark) MG, Shin-Etsu AQOAT (registered trademark) HG, MARCOAT (registered trademark) 125 and MARCOAT (registered trademark) of Shrac Co. 125N etc. are mentioned.
Examples of commercially available products of carboxymethylethyl cellulose include Freund Sangyo's trade name: CMEC (registered trademark).
Examples of the hypromellose phthalate ester include trade name: HPMCP (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd.
Examples of cellulose acetate phthalate include trade name: AQUATERIC (registered trademark) manufactured by FMC.

The amorphous solid dispersion in the tablet (II) may contain only one kind of acidic polymer or two or more kinds thereof.

(Contents of specific polymer and acidic polymer)
The content of the specific polymer and the acidic polymer in the amorphous solid dispersion is not particularly limited.
From the viewpoint of better elution of the specific active ingredient from the amorphous solid dispersion, the total content of the specific polymer and the acidic polymer is 10 parts by mass to 1000 parts by mass with respect to 100 parts by mass of the specific active ingredient. The amount is preferably 50 parts by mass, more preferably 50 parts by mass to 500 parts by mass, further preferably 100 parts by mass to 300 parts by mass.

The content ratio of the specific polymer and the acidic polymer contained in the amorphous solid dispersion exceeds 0% by mass as the total content of the specific polymer and the acidic polymer, that is, the content of the acidic polymer with respect to the total amount of the polymer, and 90 It may be not more than 10% by mass, preferably 10% by mass to 90% by mass, more preferably 10% by mass to 75% by mass, and further preferably 10% by mass to 50% by mass.
When the content of the acidic polymer with respect to the total content of the polymer is in the above range, the effect of suppressing the disintegration delay of the tablet is higher than that in the case of using the specific polymer alone. Further, even in the dissolution test conditions using an acidic test solution, it is difficult to suppress the elution of the specific active ingredient due to the acidic polymer, and even under an atmosphere with a low buffering capacity, the suppression of the elution of the specific active ingredient due to the acidic polymer is suppressed. It produces better effects such as less likely to occur. The conditions for the atmosphere having a low buffer capacity include a small amount of the test solution and a low buffer capacity of the test solution itself.

[Disintegrant]
The tablet (II) of the present disclosure contains a disintegrant. The disintegrant in the tablet (II) is not particularly limited, and any disintegrant used in a pharmaceutical composition can be used without particular limitation.
As the disintegrant, for example, the disintegrant described as the specific disintegrant (disintegrant having a swelling amount of less than 10 mL/g) and the other disintegrant (disintegrator having a swelling amount of 10 mL/g or more) in the tablet (I) is Either can be used.

As the disintegrant, more specifically, starch such as corn starch, potato starch, partially pregelatinized starch, carmellose, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, croscarmellose sodium, starch. Examples thereof include sodium glycolate and carmellose calcium.
Of these, crospovidone, croscarmellose sodium and the like are preferable.

Examples of commercially available products of crospovidone include Kollidon CL series (BASF), Polyplasdone Ultra series (Ashland), and the like, which are appropriately selected from the series of commercially available products in consideration of the relationship with the combination component. Can be used.

The amorphous solid dispersion may contain only one disintegrant or two or more disintegrants.
When two or more disintegrants are combined, a combination of croscarmellose sodium and carmellose calcium, croscarmellose sodium and sodium starch glycolate, croscarmellose sodium and carmellose, croscarmellose sodium and low-substituted hydroxymethylcellulose, etc. And the like are preferable.

The content of the disintegrant in the tablet (II) of the present disclosure is not particularly limited and is appropriately selected depending on the dosage form of the tablet, the purpose of use of the tablet, the required disintegration property, and the like. The content of the disintegrant is the total content of two or more disintegrants.
Among them, the size of the tablet is not too large, and the effect of suppressing the disintegration delay can be sufficiently obtained, from the viewpoint of the balance between the size of the tablet and the effect of suppressing the disintegration delay, the content of the disintegrant is a tablet. (II) With respect to 100 parts by mass, it is preferably 0.10 parts by mass to 50 parts by mass, more preferably 1 part by mass to 30 parts by mass, and further preferably 1 part by mass to 20 parts by mass. More preferable.

[Salting-out agent]
The tablet (II) of the present disclosure contains a salting-out agent.
As the salting-out agent, the same salting-out agent disclosed in the above-mentioned tablet (I) can be used. Specific examples include at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and calcium carbonate. Preferably contains at least one selected from the group consisting of the above compounds as a salting-out agent.

The tablet (II) of the present disclosure may include only one type of salting-out agent, or may include two or more types of salting-out agent.
The content of the salting-out agent in the tablet (II) of the present disclosure is not particularly limited, and is appropriately selected depending on the dosage form of the tablet, the purpose of use of the tablet, the required disintegration property, and the like.
Above all, from the viewpoint of the balance between the tablet size and the disintegration delay suppressing effect, the content of the salting-out agent is 0.1 parts by mass to 50 parts by mass with respect to 100 parts by mass of the tablet (II). Is more preferred, 1 part by mass to 30 parts by mass is more preferred, and 1 part by mass to 20 parts by mass is even more preferred.

[Other ingredients]
The tablet (II) of the present disclosure can contain, in addition to the specific active ingredient, the specific polymer, the acidic polymer, the disintegrating agent, and the salting-out agent, other components as necessary, as long as the effects are not impaired.
The other components are not particularly limited as long as they are components that can be used as a pharmaceutical additive.
Other components include binders, lubricants, excipients, antioxidants, stabilizers, colorants, flavoring agents, sweeteners, corrigents, pH adjusters, fluidization accelerators, and the like. ..
As examples of other components, various compounds described in paragraphs 0109 to 0115 of JP-T-2016-525579 and various compounds described in paragraph 0024 of WO 2015/053227 can be mentioned.

[Method for producing tablet (II)]
Hereinafter, a method for producing the tablet (II) of the present disclosure will be described.
The method for producing the tablet (II) of the present disclosure comprises a step A2 of preparing an amorphous solid dispersion containing an amorphous body of a specific active ingredient, a specific polymer and an acidic polymer, and the obtained amorphous The method includes a step B2 of preparing a mixture containing a solid dispersion, a disintegrant, and a salting-out agent, and a step C2 of tableting the obtained mixture to obtain a tablet.
Here, the step A2 may include preparing a solution containing a specific active ingredient, a specific polymer, an acidic polymer, and a solvent, and spray-drying the obtained solution to obtain a spray-dried powder. preferable.
The volume average particle size of the amorphous solid dispersion obtained in step A2 is preferably in the range of 0.1 μm to 200 μm, more preferably in the range of 0.1 μm to 100 μm, and in the range of 1 μm to 50 μm. Is more preferable.

The step A2 in the method for producing the tablet (II) of the present disclosure is the production of the tablet (I) except that an acidic polymer is used in addition to the specific polymer in the step A in the method for producing the tablet (I) described above. It is the same as step A in the method, and the preferred embodiments are also the same.
In step B2, the amorphous solid dispersion obtained in step A2 is used, and the type of the disintegrant is not limited to the disintegrant having a swelling amount of less than 10 mL/g. It is the same as step B in the manufacturing method, and the preferred embodiments are also the same.
Step C2 is the same as Step C in the method for producing the tablet (I) of the present disclosure described above, except that the mixture obtained in Step B2 is used.

[Method of treatment]
The present disclosure includes, as another embodiment, a therapeutic method including orally administering the above-described tablet of the present disclosure containing a specific active ingredient as an active ingredient to an application subject to be treated.
When the tablet of the present disclosure uses lopinavir and ritonavir as the specific active ingredient in combination, for example, for adults, 400 mg (lopinavir) and 100 mg (ritonavir) once a day as lopinavir and ritonavir, or 1 Examples of administration include oral administration of 800 mg (lopinavir) and 200 mg (ritonavir) once a day.
For administration to children (3 months to 16 years old), orally administered twice daily as lopinavir/ritonavir, body weight 7 kg or more and less than 15 kg, 12 mg/3 mg/kg body weight, 15 kg or more/40 kg or less, body weight 1 kg/kg The dose can be adjusted to 10 mg/2.5 mg. The highest doses are lopinavir: 400 mg and ritonavir: 100 mg.
For example, administration examples such as lopinavir and ritonavir, which are 400 mg (lopinavir) and 100 mg (ritonavir), are orally administered twice a day to a child weighing 40 kg or more.

Hereinafter, the present disclosure will be described in more detail with reference to examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. In the following examples, "%" is based on mass unless otherwise specified.
The volume average particle diameter of the particles or powder in the examples is the value measured by the method described above.

<Examples 1 to 4, Comparative Examples 1 and 2>
[Production of tablets]
2.0 mass% of ritonavir which is a specific active ingredient, 0.5 mass% of lopinavir and 5.0% of HPMC [Hypromellose TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.] which is a specific polymer. % By mass, 0.25% by mass of poloxamer P407 which is a surfactant, and 100% by mass of a mixed solvent of tetrahydrofuran (THF) and methanol which are organic solvents prepared in advance at a volume ratio of 1:1. To prepare a solution.
The resulting solution was spray-dried using a spray dryer Mini Spray Dryer B-290 (trade name: Nippon Büchi Co., Ltd.) under a nitrogen atmosphere at a supply temperature of 100° C., and then at room temperature (20° C.). 2) for 24 hours to obtain a spray-dried powder which is an amorphous solid dispersion. [Process A]
When the volume average particle diameter of the spray-dried powder was measured by the method described above, the volume average particle diameter was 35 μm.

According to the formulation shown in Table 1 below, the spray-dried powder obtained in step A, the excipient D-mannitol (Merck & Co., Parteck M100), light anhydrous silicic acid, sodium chloride as a salting-out agent, specific disintegration Copovidone (Kollidon CL) as an agent, croscarmellose sodium which is another disintegrating agent and stearyl sodium fumarate which is a lubricant are mixed, and the mixture is dry granulated to obtain a granular dry granulated product. It was [Step B]

Sodium stearyl fumarate was mixed with the obtained dry granulation product to obtain a mixture.
The mixture was used to make small size tablets for disintegration testing as follows. The mass of each component contained in each small size tablet is 1/5 of the amount described in Table 1 below.
"Blank" in the content column of each component in Table 1 below indicates that the component is not contained.

(Small tablets)
The obtained mixture was weighed according to 1/5 amount of the formulation shown in Table 1 below and tabletted with a tableting pressure of about 10.0 kN using a single radius punch having a diameter of 9 mm to obtain a small size for disintegration test. A round size tablet was obtained [Step C].

The obtained tablets were measured by powder X-ray diffractometry (PXRD) using a fully automatic multi-purpose X-ray diffractometer SmartLab (Rigaku Co., Ltd.). It was confirmed that ritonavir and lopinavir were amorphous because no clear peaks derived from any crystals of lopinavir appeared and a halo pattern was shown.
It was confirmed that the tablets produced in the examples according to the present disclosure all contained ritonavir and lopinavir in an amorphous form.

[Tablet disintegration test]
In the tablet disintegration test, the obtained small size tablet was used as a test object, and a disintegration tester (NT-2HF Toyama Sangyo Co., Ltd.) was used based on the disintegration test method of the Japanese Pharmacopoeia (16th revision). The first liquid of the Japanese Pharmacopoeia Disintegration Test was used to measure the time from the tablet was put into the disintegration tester until the disintegration. [In each table below, "tablet disintegration time" is described. ]
If the time until disintegration is within 10 minutes, it is within an acceptable range, preferably within 5 minutes, and within 3 minutes, it is evaluated that the disintegration is excellent. The results are shown in Table 1 below.

Details of each component used in Examples and Comparative Examples are as follows.
-Specific active ingredient-
・Lopinavir [Lopinavir Sigma-Aldrich]
・Ritnavir (Ritnavir Sigma-Aldrich)

-Specific polymer-
TC-5 (registered trademark) E [trade name, Shin-Etsu Chemical Co., Ltd.: HPMC, substitution degree type: 2910, indicated viscosity (viscosity of 2% by mass aqueous solution at 20° C.; Japanese Pharmacopoeia): 3.0 mPa·s , Molecular weight (catalog value): 16,000]

-Specific disintegrant-
・Kolidon (registered trademark) CL-SF [trade name, BASF: crospovidone]
・Kolidon (registered trademark) CL [trade name, BASF: crospovidone]
-Other disintegrants-
Ac-Di-Sol SD-711 [trade name, FMC BioPolymer: croscarmellose sodium]
・Primojel (registered trademark) [trade name, DFE Pharma: sodium starch glycolate]
-Carmelose Ca E. G. C-505 [trade name, Gotoku Yakuhin Co., Ltd.: carboxymethyl cellulose calcium]
・Carmellose NS-300 [trade name, Gotoku Yakuhin: carboxymethyl cellulose]
・L-HPC LH-21 [trade name, Shin-Etsu Chemical Co., Ltd.: low-substituted hydroxypropyl cellulose]
-lubricant-
・PRUV [trade name, JRS Pharma: Stearyl Na fumarate]

-Excipient-
・Aerosil 200 [trade name, Nippon Aerosil Co., Ltd.: Light anhydrous silicic acid]
・Parteck M100 [trade name, Merck Millipore: D-mannitol]
PROSOLV (registered trademark) SMCC 90 [trade name, manufactured by JRS PHARMA: silicified microcrystalline cellulose]
-Other polymers-
・Shin-Etsu AQOAT (registered trademark) LG [trade name, Shin-Etsu Chemical Co., Ltd.: hypromellose acetate succinate (HPMCAS): acidic polymer]

From the results in Table 1, all of the tablets of the present disclosure showed tablet disintegration, which has no practical problem. Among them, Examples 1 to 3 in which sodium chloride was used as the salting-out agent showed more excellent tablet disintegration property.
On the other hand, in Comparative Examples 1 and 2 containing no salting-out agent, it can be seen that the tablet disintegration delay is remarkable.

<Examples 5 to 10>
For the disintegration test of Examples 5 to 10 in the same manner as in Example 1 except that the type and content of the salting-out agent added in step B were changed as shown in Table 2. A small size tablet was prepared and the tablet disintegration time was measured in the same manner as in Example 1.
The results are shown in Table 2. As a control example, Table 2 also shows the evaluation results of Example 1.

From the results of Table 2, it is found that the tablets of Examples 5 to 10 have a disintegration time of a level that practically causes no problems, because the delay of tablet disintegration is suppressed even when the type and amount of the salting out agent are changed. I understand.
From the viewpoint of the type of salting-out agent, it can be seen from the comparison of Examples 1, 6 and 7 that sodium chloride and potassium chloride are preferable, and from the comparison of Examples 1 and 6, sodium chloride is the most preferable.
From the viewpoint of the content of the salting-out agent, Examples 1, 9 and 10 in which the content of sodium chloride is in the range of 30 parts by mass to 60 parts by mass relative to 100 parts by mass of the specific active ingredient are out of this range. It can be seen that the effect of suppressing the disintegration delay of the tablet is higher in comparison with the content of Example 8.

<Examples 11 to 14, Comparative Examples 3 to 5>
Examples 11 to 11 were carried out in the same manner as in Example 1 except that the type and content of the specific disintegrant and the other disintegrant added in step B were changed as shown in Table 5. Small size tablets for the disintegration test of Example 14 and Comparative Examples 3 to 5 were prepared, and the tablet disintegration time was measured in the same manner as in Example 1. In addition, in Example 11, Example 12 and Example 14 in which the tablet disintegration time was better, the dissolution test was performed using the normal size tablets (tablet for dissolution test) prepared as described below.
The results are shown in Table 5.

(Tablet for dissolution test)
The obtained mixture was weighed according to the formulation shown in Table 5 below, and tableted at a tableting pressure of about 10.0 kN using a 20 mm×10 mm oval-type punch to obtain tablets for dissolution test [ Step C].
The content of each component in the tablet is as shown in Table 5. The numerical values shown in Table 5 below are masses (unit: mg) of each component contained in one tablet of normal size.

[Dissolution test]
The dissolution test was carried out under the conditions shown in Table 3 below, using a normal-size tablet for dissolution test obtained by the above-described manufacturing method as a test sample.

(Analysis of test solution)
The samples were taken 30 minutes and 120 minutes after the start of the test. The obtained sampling solution was filtered with a 0.45 μm membrane filter.
The sampling liquid (5 mL) after filtration was diluted with a 60 mass% methanol aqueous solution, and the active ingredient was quantified using HPLC under the conditions shown in Table 4 below.
The dissolution rate of the active ingredient is based on the amount of the active ingredient contained in the sample tablet, and the standard amount is divided by the quantitative value obtained by the above method, and this is multiplied by 100. ..
The dissolution rate of the active ingredient was determined by the above method.

*1: The ultraviolet (UV) wavelength suitable for detecting the specific active ingredient is set to 215 nm in Table 2 above, but the wavelength differs depending on the active ingredient and is selected according to the active ingredient.
In the above A: phosphate buffer, 4.1 g of potassium dihydrogen phosphate was placed in a beaker, 1 L of water was weighed and added with a measuring cylinder, dissolved, and then adjusted to pH 4.0±0.05 with phosphoric acid. obtain.

(Measurement result)
The dissolution rate of Ritonavir, which is a specific active ingredient, after 30 minutes from the start of the test is shown as D30 in the table, and the dissolution rate of Ritonavir after 120 minutes from the start of the test is shown as D120 in the table.
From the viewpoint of the elution property of the active ingredient, it is evaluated that the D120 elution rate is preferably 70% or more, and more preferably 85% or more. The measurement results are also shown in Table 5 below.
In addition, "-" in the column of dissolution rate in Table 5 below indicates that the dissolution test was not performed. (The same applies to the tables below.)

From the results shown in Table 5, the tablets of Examples 11 to 14 are suppressed in delay of tablet disintegration even when the amount of the specific disintegrant and the other disintegrant used in combination are changed, and the tablets have practically no problem. You know it's time. Among them, Example 11 in which the content of the specific disintegrant is 80 parts by mass relative to 100 parts by mass of the specific active ingredient and Example 14 in which the specific disintegrant and the other disintegrant are used in a mass ratio of 1:2, It can be seen that the tablet has a higher effect of suppressing the disintegration delay.
In addition, as for the results of the dissolution test for Examples 11, 12, and 14, in each case, the dissolution rate after 120 minutes was high, the specific active ingredient was well dissolved, and the disintegration time was particularly long. In Example 11 and Example 14, which were good, the dissolution rate after 30 minutes was good, and it can be expected that the effect of the specific active ingredient is promptly exhibited.
On the other hand, in Comparative Examples 3 to 5 in which at least one of the salting out agent and the specific disintegrating agent is not contained, it can be seen that the delay of tablet disintegration is remarkable.

<Example II-1 to Example II-7>
[Production of tablets]
2.0 mass% of ritonavir which is a specific active ingredient, 0.5 mass% of lopinavir, and 3.75 mass of HPMC [Hypromellose TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.] which is a specific polymer. %, HPMCAS [Hypromellose Acetate Succinate: Shin-Etsu AQOAT (registered trademark) LG, Shin-Etsu Chemical Co., Ltd.], which is an acidic polymer, and 0.25% by mass of the surfactant Polyxamer P407. 25% by mass was dissolved in a mixed solvent having 100% by mass of a mixed solvent of tetrahydrofuran (THF) and methanol, which was prepared in advance, at a volume ratio of 1:1 to prepare a solution. Using the obtained solution, a spray-dried powder was prepared in the same manner as in Example 1. [Process A]
A dry granulated powder was prepared in the same manner as in Example 1 except that the content of mannitol as an excipient was 1.5% by mass [step B], and the dry granulated powder obtained was used. The tablet of Example II-1 was prepared in the same manner as in Example 1. [Step C]
A small size tablet for disintegration test of Example II-2 to Example II-7 was prepared in the same manner as in Example II-1, except that the types and amounts shown in Table 6 below were used for the ingredients contained in the tablets. Tablets were made.

[Tablet evaluation]
For each of the obtained tablets, the tablet disintegration time was measured in the same manner as in Example 1. The results are also shown in Table 6. As for the tablets of Example II-7 in which the tablet disintegration time was better, the tablets of the normal size for the dissolution test were prepared, and the dissolution of ritonavir after 30 minutes and 120 minutes was performed by the method described above. The rate was measured and the results are shown in Table 6.
As a control, Table 6 also shows the formulations and evaluation results of the tablets of Example 1 and Comparative Example 5.

From the results of Table 6, the tablets of Example II-1 to Example II-7, which are tablets (II) of the present disclosure, suppress the delaying effect of tablet disintegration regardless of the type of disintegrant, which is a practical problem. It can be seen that the disintegration time is at a level that does not occur, and that the effect of suppressing tablet disintegration delay equivalent to that of the tablet of Example 1 can be obtained.
Further, the results of the dissolution test of the tablets of Example II-7 show that good dissolution properties of the specific active ingredient were achieved due to the effect of suppressing the disintegration delay.

<Example III-1 to Example III-8>
[Production of tablets]
Example II-1 is the same as Example II-1 except that the types and amounts of the ingredients contained in the tablets are shown in Table 7 below. Small size tablets were made for the disintegration test.

[Tablet evaluation]
For each of the obtained tablets, the tablet disintegration time was measured in the same manner as in Example 1. In addition, a tablet of a normal size for dissolution test was prepared with the same composition ratio as the obtained tablets of Example III-1 to Example III-8, and after 30 minutes and 120 minutes by the method described above. The dissolution rate of ritonavir was measured.
The above results are shown in Table 7.
Note that Example III-1 is an example relating to the tablet (I) of the present disclosure containing no acidic polymer, and Examples III-2 to III-8 are related to the tablet (II) of the present disclosure. It is an example.

From the results of Table 7, the tablet (I) of the present disclosure, Example III-1 and the tablet (II) of the present disclosure, Example III-2 to Example III-8, the content of the acidic polymer Despite the above, it can be seen that the tablet disintegration delaying effect is suppressed, the disintegration time is at a level at which there is practically no problem, and the tablet disintegrating delay suppressing effect is obtained in each case.
Further, from the results of the dissolution test of ritonavir contained in the tablets, the content of the acidic polymer with respect to the total amount of the cellulosic polymer contained in the amorphous solid dispersion is preferably in the range of 10% to 75%, and the content of the acidic polymer is preferably Is more preferably in the range of 10% to 50%.
It can be seen that both the tablet (I) and the tablet (II) of the present disclosure have a good effect of suppressing the disintegration delay, and that a good dissolution property of the specific active ingredient was achieved due to the effect of suppressing the disintegration delay. ..

The disclosure of Japanese Patent Application 2018-234690 filed on Dec. 14, 2018 is incorporated into the present disclosure by reference.
All references, patent applications, and technical standards mentioned in this disclosure are to the same extent as if each individual document, patent application, and technical standard were specifically and individually noted to be incorporated by reference. Incorporated by reference in the disclosure.

Claims

An amorphous solid dispersion containing an amorphous form of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives, and a pH-independent cellulosic water-soluble polymer.
A tablet containing a disintegrant having a swelling amount of less than 10 mL/g and a salting-out agent.
The tablet according to claim 1, wherein the pharmaceutically active ingredient is at least one selected from the group consisting of ritonavir, lopinavir, cyclosporin A, colistin or a salt thereof, bacitracin A, polymyxin B, daclatasvir, ervasvir, and velpatasvir.
The tablet according to claim 1 or 2, wherein the pharmaceutically active ingredient is at least one selected from the group consisting of ritonavir and lopinavir.
The amorphous solid dispersion contains 10 parts by mass to 1000 parts by mass of the pH-independent cellulosic water-soluble polymer with respect to 100 parts by mass of the medicinal active ingredient. The tablet according to Item 1.
5. The pH-independent cellulosic water-soluble polymer contains at least one member selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose. The tablet according to the item.
The tablet according to any one of claims 1 to 5, wherein the pH-independent cellulosic water-soluble polymer is hypromellose.
The tablet according to any one of claims 1 to 6, wherein the disintegrant having a swelling amount of less than 10 mL/g is crospovidone.
The tablet according to any one of claims 1 to 7, wherein the disintegrant having a swelling amount of less than 10 mL/g is contained in an amount of 0.1 part by mass to 50 parts by mass with respect to 100 parts by mass of the tablet.
The tablet according to any one of claims 1 to 8, further comprising a disintegrant having a swelling amount of 10 mL/g or more.
10. The tablet according to claim 9, wherein the disintegrant having a swelling amount of 10 mL/g or more contains at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and carmellose calcium.
The tablet according to claim 9 or 10, wherein the disintegrant having a swelling amount of 10 mL/g or more is croscarmellose sodium.
The tablet according to any one of claims 9 to 11, wherein the disintegrant having a swelling amount of 10 mL/g or more is contained in an amount of 0.1 part by mass to 50 parts by mass with respect to 100 parts by mass of the tablet.
13. The salting out agent contains at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, and calcium carbonate. The tablet according to any one of 1.
The tablet according to any one of claims 1 to 13, wherein the salting-out agent is contained in an amount of 0.1 to 50 parts by mass based on 100 parts by mass of the tablet.
The tablet according to any one of claims 1 to 14, wherein the volume average particle diameter of the amorphous solid dispersion is in the range of 0.1 µm to 200 µm.
An amorphous solid dispersion containing an amorphous body of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivatives and L-valine derivatives and a pH-independent cellulosic water-soluble polymer. Step A of preparing,
Step B of preparing a mixture containing the obtained amorphous solid dispersion, a disintegrating agent having a swelling amount of less than 10 mL/g, and a salting-out agent,
A method for producing a tablet, comprising the step C of compressing the obtained mixture to obtain a tablet.
In the step A, a solution containing the medicinal active ingredient, the pH-independent cellulosic water-soluble polymer, and a solvent is prepared, and the resulting solution is spray-dried to obtain a spray-dried powder. The method for producing a tablet according to claim 16, comprising:
Amorphous compound containing an amorphous form of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivative and L-valine derivative, a pH-independent cellulosic water-soluble polymer, and an acidic polymer Solid dispersion,
A tablet containing a disintegrant and a salting-out agent.
The tablet according to claim 18, wherein the medicinal active ingredient is at least one selected from ritonavir, lopinavir, cyclosporine A, colistin or a salt thereof, bacitracin A, polymyxin B, daclatasvir, ervasvir, and velpatasvir.
The tablet according to claim 18 or 19, wherein the pharmaceutically active ingredient is at least one selected from ritonavir and lopinavir.
19. The amorphous solid dispersion contains 10 parts by mass to 1000 parts by mass in total of the pH-independent cellulosic water-soluble polymer and the acidic polymer with respect to 100 parts by mass of the medicinal active ingredient. The tablet according to any one of claims 20 to 20.
The content ratio of the acidic polymer with respect to the total content of the pH-independent cellulosic water-soluble polymer and the acidic polymer contained in the amorphous solid dispersion is more than 0 mass% and 90 mass% or less. The tablet according to any one of claims 18 to 21, which is
The content ratio of the acidic polymer to the total content of the pH-independent cellulosic water-soluble polymer and the acidic polymer contained in the amorphous solid dispersion is 10% by mass to 75% by mass. Item 23. The tablet according to any one of items 18 to 22.
The pH-independent cellulosic water-soluble polymer contains at least one member selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose. The tablet according to the item.
The tablet according to any one of claims 18 to 24, wherein the pH-independent cellulosic water-soluble polymer is hypromellose.
The acidic polymer is selected from the group consisting of hypromellose acetate succinate, carboxymethylethyl cellulose, hypromellose phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer S, and polyvinyl acetate phthalate ester. 26. The tablet according to any one of claims 18 to 25, which is at least one kind.
The tablet according to any one of claims 18 to 26, wherein the acidic polymer is at least one selected from the group consisting of hypromellose acetate succinate and carboxymethyl ethyl cellulose.
The tablet according to any one of claims 18 to 27, wherein the disintegrant is contained in an amount of 0.1 part by mass to 50 parts by mass with respect to 100 parts by mass of the tablet.
The salting out agent contains at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and calcium carbonate. The tablet according to any one of 1.
The tablet according to any one of claims 18 to 29, wherein the salting-out agent is contained in an amount of 0.1 to 50 parts by mass based on 100 parts by mass of the tablet.
The tablet according to any one of claims 18 to 30, wherein the volume average particle diameter of the amorphous solid dispersion is in the range of 0.1 µm to 200 µm.
Amorphous substance containing an amorphous form of at least one pharmaceutically active ingredient selected from the group consisting of L-isoleucine derivative and L-valine derivative, a pH-independent cellulosic water-soluble polymer, and an acidic polymer Step A2 of preparing a solid dispersion,
Step B2 of preparing a mixture containing the obtained amorphous solid dispersion, a disintegrant, and a salting-out agent,
A method for producing a tablet, comprising the step C2 of tableting the obtained mixture to obtain a tablet.
In the step A2, a solution containing the medicinal active ingredient, the pH-independent cellulosic water-soluble polymer, the acidic polymer, and a solvent is prepared, and the resulting solution is spray-dried and sprayed. 33. The method of making a tablet of claim 32, comprising obtaining a dry powder.