JP2020132640A - Oral solid composition, production method thereof, and oral tablet obtained by the production method - Google Patents

Abstract

To provide tablets having excellent elution, stability, and hardness.SOLUTION: Provided are an oral solid composition containing (a) progestin, (b) starches, (c) sodium starch glycolate, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof, the content of (c) being 0.1 to 8 mass% of the total mass of the oral solid composition; a production method; and an oral tablet obtained by the production method.SELECTED DRAWING: Figure 2

Description

The present invention relates to an oral solid composition such as progestin, which is excellent in elution and stability and has good hardness. The present invention also relates to a method for producing the solid composition. Further, the present invention relates to an oral tablet produced by the production method.

Progestin refers to artificially synthesized progesterone, but natural progesterone and synthetic pharmaceutical preparations are often collectively referred to as progestin preparations. Various progestin preparations have unique characteristics, and depending on the dose, low-dose drugs can be used for diagnosis and treatment of functional uterine bleeding, endometriosis treatment, low-dose oral contraception (OC), menstrual difficulty treatment, hormone replacement therapy. As (HRT), high-dose drugs are mainly used for amenorrhea, luteal activation, emergency contraception and the like.

Among the oral solid compositions, tablets have different disintegration and elution properties depending on the amount of water at the time of administration. In addition, the orally disintegrating (OD) tablet is a dosage form that easily disintegrates and is easy to take, but generally has a low tablet hardness.

A progestin-containing preparation containing 60% by mass of an ionic disintegrant and a hydrophilic, water-insoluble nonionic excipient as an oral tablet containing a medicinal ingredient such as progestin (Patent Document 1). ), Tablets containing levonorgestrel, sodium croscarmellose, etc. (Patent Document 2) are known.

In addition, a pharmaceutical composition containing drospirenone and ethinyl estradiol together with methylene chloride having a very low residual level has also been reported (Patent Document 3). The pharmaceutical composition has a high dissolution profile, which is achieved by solubilizing the amorphous drug in methylene chloride, a volatile solvent.

Aripiprazole solid preparation for the treatment of schizophrenia (Patent Document 4) is an excipient in which aripiprazole is turbid in an aqueous solution of a water-soluble polymer such as hydroxypropyl cellulose (HPC) and is in a fluid state. It is obtained by spraying and granulating. Patent Document 5 relates to an easily disintegrating and easily absorbable compression molded product of a poorly soluble drug, and manufactures the compression molded product by a fluidized bed granulation method using a suspension containing the poorly soluble drug and HPC and the like. Patent Document 6 describes a tablet containing a composite granule containing a sugar or sugar alcohol, a swelling type binder, a disintegrant and a highly absorbent excipient, and a medicinal ingredient.

However, conventional oral tablets are not satisfactory in terms of dissolution, stability, and hardness, and further improvement has been desired.

Japanese Patent No. 5649305 Special Table 2005-516904 Special Table 2008-509195 Japanese Patent No. 6007169 Japanese Unexamined Patent Publication No. 56-110612 Japanese Patent No. 5897196

In pharmaceutical compositions containing levonorgestrel, progestin such as norethisterone, and other medicinal ingredients having a hormone-like action, particularly pharmaceutical compositions used for emergency contraception, etc., high initial dissolution property is ensured and dissolution delay prevention is prevented. And ensuring stability such as maintaining hardness is a very important issue.
In addition, in general, a disintegrant is added to improve the elution of the medicinal ingredient in the pharmaceutical composition, but if a large amount of the disintegrant is added, it causes a decrease in hardness, and various components such as the disintegrant Depending on the amount added and the combination with the medicinal ingredient, it may cause insufficient elution performance or delay in elution.
An object of the present invention is to provide an oral solid composition containing progestin and the like with further improved dissolution property, stability, and hardness.

As a result of diligent studies to solve the above problems, the present inventors have found that, in addition to starches, specific amounts of sodium starch glycolate, carmellose, low-degree-of-substitution hydroxypropyl cellulose (L-HPC), crospovidone, and It has been found that an oral solid composition containing a component selected from the combination thereof is excellent in elution and stability as well as hardness. Further, an alcohol suspension or a solution composed of a medicinal ingredient and alcohol is sprayed on a specific first additive or the like in a fluid state to obtain a wet granulated product, and a specific second additive is added to the granulated product. It has been found that an oral solid composition having excellent dissolution property, stability and hardness can be obtained by adding the agent, and the present invention has been completed.
Furthermore, we have included starches as the first disintegrant, and specific amounts of sodium starch glycolate, carmellose, low degree of substitution hydroxypropyl cellulose (L-HPC) as the second disintegrant. , Crospovidone, and an oral solid composition containing a component selected from a combination thereof, have found that an oral solid composition having excellent dissolution property, stability, and hardness can be obtained, and have completed the present invention. It was.

That is, the present invention has the following aspects.
[1]
(A) Progestin and
(B) Starches and
(C) An oral solid composition comprising sodium starch glycolate, carmellose, low degree of substitution hydroxypropyl cellulose (L-HPC), crospovidone, or a combination thereof.
An oral solid composition having a content of (c) of 0.1 to 8% by mass based on the total mass of the oral solid composition.
[2]
The oral solid composition according to [1], which is in the form of a tablet.
[3]
The oral solid composition according to [1] or [2], wherein the progestin is selected from levonorgestrel and norethisterone.
[4]
The oral solid composition according to any one of [1] to [3], wherein (c) is selected from the group consisting of sodium starch glycolate, carmellose, crospovidone, and a combination thereof.
[5]
The oral solid composition according to any one of [1] to [4], wherein (c) is sodium starch glycolate.
[6]
The oral solid composition according to any one of [1] to [5], wherein the cumulative 90% particle size of the progestin is 15 μm or less.
[7]
The oral solid composition according to any one of [1] to [5], wherein the cumulative 90% particle size of the progestin is 10 μm or less.
[8]
The oral solid composition according to any one of [1] to [7], wherein the starches are corn starch.
[9]
(I) A step of spraying an alcohol suspension or a solution composed of a medicinal ingredient and an alcohol onto a first additive in a fluid state to obtain a wet granulated product.
(Ii) A method for producing an oral solid composition, which comprises a step of adding a second additive to the obtained granulated product, mixing the mixture, and then tableting.
The group consisting of the first additive being starches and the second additive being sodium starch glycolate, carmellose, low-degree-of-substitution hydroxypropyl cellulose (L-HPC), crospovidone, and a combination thereof. A method for producing an oral solid composition, which is more selected.
[10]
The production method according to [9], wherein the second additive is selected from the group consisting of sodium starch glycolate, carmellose, crospovidone, and a combination thereof.
[11]
The production method according to [10], wherein the second additive is sodium starch glycolate.
[12]
The production method according to any one of [9] to [11], wherein the alcohol suspension or the solution is an ethanol suspension.
[13]
The production method according to any one of [9] to [12], wherein the cumulative 90% particle size of the medicinal ingredient is 15 μm or less.
[14]
The production method according to any one of [9] to [13], wherein the cumulative 90% particle size of the medicinal ingredient is 10 μm or less.
[15]
The production method according to any one of [9] to [14], wherein the content of the second additive in the oral solid composition is 0.1 to 8% by mass.
[16]
The production method according to any one of [9] to [15], wherein the medicinal ingredient is progestin.
[17]
The production method according to [16], wherein the medicinal ingredient is selected from levonorgestrel and norethisterone.
[18]
An oral tablet obtained by the production method according to any one of [9] to [17].

According to the production method of the present invention, an oral solid composition having excellent elution and stability and having good hardness can be produced.

FIG. 1 shows the dissolution test of the tablet of Example 1 after storage under severe test (25 ° C./90% RH) for 0 months (square) and severe test (25 ° C./90% RH) for 1 month (triangle). The dissolution property is shown from the start to 360 minutes after the start of the dissolution test. Hereinafter, "0 months under severe test (25 ° C / 90% RH) conditions" is simply "0 months", and "after 1 month storage under severe test (25 ° C / 90% RH) conditions" is simply "after 1 month storage". ". FIG. 2 shows the dissolution property of the tablet of Example 2 after storage for 0 months (square) and 1 month (triangle) from the start of the dissolution test to 360 minutes after the start of the dissolution test. FIG. 3 shows the dissolution property of the tablet of Example 3 after storage for 0 months (square) and 1 month (triangle) from the start of the dissolution test to 360 minutes after the start of the dissolution test. FIG. 4 shows the dissolution property of the tablet of Example 4 after storage for 0 months (square) and 1 month (triangle) from the start of the dissolution test to 360 minutes after the start of the dissolution test. FIG. 5 shows the dissolution property of the tablet of Comparative Example 1 after storage for 0 months (square) and 0.5 months (triangle) from the start of the dissolution test to 360 minutes after the start of the dissolution test. FIG. 6 is a photograph showing the appearance of tablets obtained by storing the tablets of Example 7 under severe test (25 ° C./90% RH) conditions for 1 month. As a control, the appearance of tablets of Example 2 stored under the same conditions for 1 month is also shown. FIG. 7 shows the dissolution property of the tablet (circle) of Example 10 at 0 months and the tablet (square) of Example 11 at 0 months from the start of the dissolution test to 360 minutes after the start of the dissolution test.

Hereinafter, the present invention will be described in detail.

One embodiment of the present invention comprises (a) progestin, (b) starches, (c) sodium starch glycolate, carmellose, low-degree-of-substitution hydroxypropyl cellulose (L-HPC), crospovidone, or a combination thereof. The present invention relates to an oral solid composition comprising the above, wherein the content of (c) is 0.1 to 8% by mass of the total mass of the oral solid composition.

(A) Examples of progestin include levonorgestrel, norethisterone, dezogestrel, dienogestrel, drospirenone, chlormaginone acetate, ydrogesterone and the like. More desirable. Progestin also includes its salt, its hydrate, its solvate, its prodrug and the like. Further, two or more kinds of progestins may be used in combination.
Further, as the medicinal ingredient of the present invention, medicinal ingredients other than progestin, for example, medicinal ingredients classified into hormone drugs, hormone substitutes, antihormonal drugs, autacoids and the like can also be used. Two or more kinds of medicinal ingredients may be used in combination.

In the present invention, the content of the medicinal component in the oral solid composition is not particularly limited, but is preferably 0.01 to 8% by mass, preferably 0.1 to 6% by mass, based on the total mass of the oral solid composition. It is more preferable that the amount is 1 to 5% by mass.
When levonorgestrel is used as a medicinal ingredient, the content is not particularly limited, but is preferably 0.5 mg to 2 mg. When a progestin different from levonorgestrel is used, it can be adjusted to a concentration equivalent to that value based on relative efficacy or activity (eg, Kuhl, H., Drugs 51 (2): 188-215 (1996). ); Philibert, D., et al., Gynecol. Endocrinol. 13: 316-326 (1999); Lundeen, S., et al., J. Steroid Biochem. Molec. Biol. 78: 137-143 (2001) See Dickey, RP, "Contraceptive Therapy," OBG Management Supplement (October 2000), pp. 2-6).

In the present specification, the additive in a fluid state in which the alcohol suspension or the solution is sprayed in the method for producing an oral solid composition of the present invention is conveniently referred to as a "first additive" and is wet-produced. The additive that will be added to the granulated product after the granules are obtained is referred to as a "second additive" for convenience.

The component (b) or the first additive of the present invention is used as a disintegrant, an excipient, a binder and the like, and its use is not particularly limited, but it is preferably used as a disintegrant.
Examples of starches as the component (b) or the first additive of the present invention include starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch and the like.

The component (c) or the second additive of the present invention is used as a disintegrant, an excipient, a binder and the like, and its use is not particularly limited, but it is preferably used as a disintegrant. As the component (c) or the second additive of the present invention, sodium starch glycolate, carmellose, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, and combinations thereof are preferable, and sodium starch glycolate and carmellose are preferable. , Crospovidone, and combinations thereof are more preferred, and sodium starch glycolate is even more preferred.
Examples of cross popidone include corridon (registered trademark) CL, corridon (registered trademark) CL-SF (above, BASF Japan), polyplusdon (registered trademark) (ISP Japan), cross povidone (DSP Gokyo Food & Chemical), etc. Insoluble polyvinylpyrrolidone is preferred. The L-HPC preferably has a hydroxypropoxy group substitution degree of 7 to 16%, and more preferably 10 to 13%.

The content of the component (b) or the first additive is preferably 0.5 to 30% by mass, more preferably 3 to 15% by mass, still more preferably 4 to 10% by mass, based on the total mass of the oral solid composition.
The content of the component (c) or the second additive is 0.1 to 8% by mass, preferably 0.5 to 8% by mass, and more preferably 1 to 8% by mass of the total mass of the oral solid composition. It is mass%, more preferably 1 to 7% by mass, more preferably 1 to 6% by mass, more preferably 1 to 5% by mass, still more preferably 1 to 3% by mass. If the content of the component (c) or the second additive is less than 0.1% by mass, the disintegration property is not exhibited, while if it exceeds 8% by mass, the tablet properties such as disintegration property and stability may deteriorate. ..

In addition to the above component (b) and the above component (c), the above oral solid composition further contains a disintegrant, an excipient, a binder and the like other than those listed as the above component (b) and the component (c). You may be. Examples of disintegrants other than those listed as the above component (b) and component (c) include carmellose calcium, croscarmellose sodium, crystalline cellulose / carmellose sodium, methyl cellulose, hydroxypropyl cellulose (HPC), and hydroxypropyl. Examples include starch, sodium alginate, agar powder, and talc.
Examples of excipients include lactose, crystalline cellulose, D-mannitol, sucrose, sucrose, and glucose.
Examples of the binder include polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, powdered cellulose, crystalline cellulose and sodium carmellose.
Two or more of these disintegrants, excipients, binders and the like may be used in combination.

The oral solid composition may further contain a fluidizing agent, a lubricant and the like.
Examples of the fluidizing agent include light anhydrous silicic acid.
Examples of the lubricant include magnesium stearate, glycerin fatty acid ester, sucrose fatty acid ester, light anhydrous silicic acid, and hydrous silicon dioxide.
Two or more of these fluidizing agents, lubricants and the like may be used in combination.

The form of the oral solid composition is preferably a tablet, more preferably an uncoated tablet, but a tablet with a normal skin coating, an orally disintegrating tablet, or the like may be used.

In the above-mentioned oral solid composition of the present invention, a mixture of a medicinal ingredient such as progestin and an alcohol is sprayed onto a first additive in a fluid state to obtain a wet granulated product, and then the obtained granulated product is obtained. It is produced by adding a second additive to a product, mixing it, and then tableting it with a tableting machine by a conventional method.

Examples of the wet granulation method include a fluidized bed granulation method and a stirring granulation method. In particular, the wet granulation method using fluidized bed granulation provides more stable elution property than the direct striking method, and is superior in workability in that the granulation and drying steps can be performed on the same machine as compared with stirring granulation. ing.

The medicinal ingredient used in the production method of the present invention is preferably a fine powder. Since the particle size of the fine powder affects the elution of the medicinal component, the cumulative 90% particle size is preferably 15 μm or less, and more preferably 10 μm or less. Further, it is preferable that the cumulative 10% particle diameter is 5 μm or less, the cumulative 50% particle diameter is 8 μm or less, and the cumulative 90% particle diameter is 15 μm or less. Further, it is more preferable that the cumulative 10% particle diameter is 3 μm or less, the cumulative 50% particle diameter is 5 μm or less, and the cumulative 90% particle diameter is 10 μm or less. In the present invention, the "cumulative 90% particle diameter" means a particle diameter at which the cumulative amount is 90% in a curve obtained by accumulating the percentages in order from the particle diameter on the horizontal axis and the small particles on the vertical axis. ..

In the fluidized bed granulation method, when the medicinal ingredient is contained in the spray liquid, the dissolved liquid in which the medicinal ingredient is dissolved is generally used as the spray liquid. However, when the medicinal ingredient is poorly soluble, a large amount of solvent is required to dissolve the medicinal ingredient, and in some cases, heating is required for dissolution, which complicates the work. Further, when the solvent is a flammable solvent such as alcohol, there is a problem in work such as inducing a dust explosion by a heating operation.
On the other hand, when the medicinal ingredient is used as a suspension without being dissolved as a spray liquid, there are advantages such as no pretreatment is required and the amount of solvent can be reduced, but on the other hand, the content of the medicinal ingredient in the final composition is uniform. There are problems such as the inability to ensure the sex and dissolution of medicinal ingredients.

However, in the present invention, it is finally obtained not only when a solution in which the medicinal ingredient is dissolved in alcohol but also when a wet granulated product is produced using a suspension in which the medicinal ingredient is dispersed in alcohol. For the first time, the present inventors have found that high dissolution and stability can be ensured in an oral solid composition. The ability to use an alcohol suspension is extremely beneficial in terms of the use of sparingly soluble medicinal ingredients, reduction of solvent amount, avoidance of dust explosion, shortening of work process, and the like.

The "alcohol suspension or solution composed of a medicinal component and alcohol" as used in the present invention means a suspension or solution composed of a medicinal component and alcohol. The medicinal ingredient is not particularly limited, and examples thereof include the above-mentioned progestins such as levonorgestrel, norethisterone, dezogestrel, dienogest, drospirenone, chlormadinone acetate, and ydrogesterone. Progestin includes its salt, its hydrate, and its solvate. , The prodrug, etc. are also included. Further, as the medicinal ingredient, not only the medicinal ingredient having high solubility in alcohol but also the medicinal ingredient in which the amount of solvent required to dissolve 1 g of the solute is 30 ml or more, that is, the 17th revised Japanese Pharmacopoeia general rule. Medicinal ingredients belonging to "slightly insoluble", "difficult to dissolve", "extremely insoluble", and "almost insoluble" can also be used.
The alcohol may be a mixture of alcohol and water, in which case the alcohol concentration is 70 v / v% (alcohol / water = 70/30) or more, preferably 90 v / v% or more, more preferably 95 v / v% or more. preferable.

As the alcohol, a lower alcohol is preferable. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, or a mixture thereof can be mentioned, and ethanol and isopropanol are preferable, and ethanol is more preferable.

The concentration of the medicinal ingredient in the alcohol suspension or the solution is preferably 001 to 10% by mass. For example, the concentration of levonorgestrel in the alcohol suspension or solution is preferably 0.01 to 8% by mass, more preferably 0.1 to 5% by mass, and 0.5 to 2% by mass. It is more preferably%. The concentration of norethisterone in the alcohol suspension or solution is preferably 0.01 to 10% by mass, more preferably 0.02 to 5% by mass, and 0.5 to 5% by mass. Is more preferable.

When preparing the alcohol suspension or the solution, if necessary, it may be heated according to the poor solubility of the medicinal ingredient. However, attention must be paid to the melting temperature to avoid a dust explosion.

The first additive and the second additive that can be used in the present invention are as described above. Further, in addition to the first additive, other disintegrants, excipients, binders and the like not contained in the first additive may be further added, and in addition to the second additive, the above-mentioned flow Agents, lubricants and the like may be further added.

The oral solid composition obtained by the production method of the present invention has excellent elution and stability.

In addition, the oral solid composition obtained by the production method of the present invention can maintain good hardness in addition to excellent elution and stability.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

An example of tablet production is shown below. In addition, the elution and stability of the resulting tablets and the hardness were tested.

I. Production of Tablets The tablets of Examples 1 to 4 were produced by the following production methods according to the formulations shown in Table 1.
(1) Pre-mixing Lactose hydrate (200M), which is component B in Table 1, corn starch (Nihon Shokuhin Kako), which is component C, and povidone (K-30), which is component D, are mixed in a V-type mixer (5L, Mixed at Tokuju Kosakusho Co., Ltd.).
(2) Granulation / drying The powder mixed by the premixing of (1) is put into a fluidized bed granulator (FD-MP-01D, manufactured by Paulec Co., Ltd.), and 95% with component A1 (levonorgestrel). An ethanol suspension composed of ethanol was sprayed at an air volume of 0.3 m / min, an air supply temperature of 60 ° C., a spray volume of 14 g / min, and a spray air volume of 55 L / min, granulated, and then dried. As the component A1 (levonorgestrel), a component having a cumulative 10% particle diameter of 1 μm, a cumulative 50% particle diameter of 4 μm, and a cumulative 90% particle diameter of 7 μm was used.
It was confirmed that the amount of residual ethanol in the dried powder was less than or equal to the concentration limit value described in the 17th revised Japanese Pharmacopoeia "Residual Solvent".
(3) Primary mixing The powder dried in (2) and components E, F, and G were mixed with a locking mixer (RM-10-2, manufactured by Aichi Electric Co., Ltd.). Carmellose (NS-300) (Nichirin Chemical Industry Co., Ltd.) as component F1, sodium starch glycolate (Primogel®) (DMV Fontera Ixipientz Co., Ltd.) as F2, and low-substituted hydroxypropyl as F3. Cellulose (LH-11) (Shin-Etsu Chemical Co., Ltd.) and crospopidone (Corridon (registered trademark) CL-SF) (BASF) were used as F4.
(4) Secondary mixing The powder mixed in the primary mixing of (3) and component H were mixed with a locking mixer (RM-10-2, manufactured by Aichi Electric Co., Ltd.).
(5) Tableting The powder mixed by the secondary mixing of (4) is subjected to a tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 7 kN, a tablet diameter of 7.0 mm, and a mass of 140 mg. I locked it like this.

Examples 5-7
Tablets having the formulations shown in Table 1 were produced in the same manner as in Example 2 except that the content of sodium starch glycolate was changed as the component F.

Example 8
In the above (2) granulation / drying step, tablets having the formulations shown in Table 1 were produced in the same manner as in Example 2 except that an ethanol solution was used instead of the ethanol suspension. When producing the component A1 (levonorgestrel) solution, a heating operation was appropriately performed.

Example 2-2
In the above (2) granulation / drying step, tablets having the formulation shown in Table 1 are prepared in the same manner as in Example 2 except that an ethanol suspension in which the amount of component A1 (levonorgestrel) added is 3.0 mg is used. Manufactured.

Example 9
In the above (2) granulation / drying step, an ethanol solution having an added amount of component A2 (norethisterone) of 0.75 mg was used instead of component A1 (levonorgestrel) in the same manner as in Example 2. Tablets with the formulations shown in Table 1 were produced. As the component A2 (norethisterone), a component having a cumulative 10% particle diameter of 0.4 μm, a cumulative 50% particle diameter of 2.3 μm, and a cumulative 90% particle diameter of 6.3 μm was used.

Example 9-2
In the above (2) granulation / drying step, tablets having the formulations shown in Table 1 were prepared in the same manner as in Example 9 except that an ethanol suspension in which the amount of component A2 (norethisterone) was added was 7.5 mg was used. Manufactured.

Comparative Example 1
Tablets were produced in the same manner as in Example 2 except that component F was not added.

Reference Example As a reference example, a tablet of Aska Pharmaceutical Co., Ltd. "Norrevo Tablets 1.5 mg" (approval number 22700AMX01035, lot number LX082F) was used. This tablet contains 1.5 mg of levonolgestrel in one tablet, lactose hydrate, corn starch, povidone, light anhydrous silicic acid, and magnesium stearate as additives, but the component (c) of the present invention, or the first tablet. It is a formulation that does not contain the two additives, sodium starch glycolate, carmellose, low-substituted hydroxypropyl cellulose (L-HPC), or crospovidone.

[Test method for all related substances / elution / hardness]
(1) All related substances / test method / 17th revised Japanese Pharmacy Law "Liquid Chromatography", liquid chromatography device (HPLC system (e2695, manufactured by Japan Waters Tokyo Office), UV / VIS detector (2489) , Japan Waters Co., Ltd.) and data processing software (Empower3, Japan Waters Co., Ltd.) were used to measure the total amount of related substances in one tablet of each sample.
・ Stability preservation test (temperature and humidity severe test)
Each unwrapped sample placed in an open petri dish was set to temperature: 60 ° C ± 2 ° C and humidity: 80% RH ± 5% RH for 0.5 months or with equipment (LH21-15M, manufactured by Nagano Science Co., Ltd.). Stored for 1 month.

(2) Dissolution Test equipment (Fully automatic dissolution tester (RT-3, manufactured by Dainippon Seiki Co., Ltd.)) in accordance with the "dissolution test method" and "liquid chromatography" of the 17th revised Japanese Pharmacy. , Data processing software (RT-3, manufactured by Dainippon Seiki Co., Ltd.), liquid chromatography device (HPLC system (e2695, manufactured by Nippon Waters Co., Ltd.), UV / VIS detector (2489, manufactured by Nippon Waters Co., Ltd.) or PDA Using a detector (2998, manufactured by Nippon Waters Co., Ltd.) and data processing software (Empower3, manufactured by Nippon Waters Co., Ltd.), the average value of dissolution of 6 tablets of each sample was calculated. The dissolution test was performed by the Japanese Pharmacopoeia. The paddle method, which is a general test method, was used. Sampling was performed from immediately after the start of the dissolution test (0 minutes) to 360 minutes after the start of the test.
Liquid chromatography analysis conditions:
Column: Inertsil ODS-3 3mm x 7.5cm 3μm (GL Sciences Co., Ltd.)
No. 154
Flow rate: 0.6 mL / min: Mobile phase: 70% methanol
Column temperature: 35 ° C, sample cooler temperature: 25 ° C
Detection wavelength: 244 nm.
・ Stability preservation test (humidity severe test)
Each unwrapped sample placed in an open petri dish was set to temperature: 25 ° C ± 2 ° C and humidity: 90% RH ± 5% RH for 0.5 months or with equipment (LH21-15M, manufactured by Nagano Science Co., Ltd.). Stored for 1 month.

(3) Hardness The tablet hardness of each sample was measured using a tablet hardness tester (KHT-20N, manufactured by Fujiwara Seisakusho Co., Ltd.), and the average value was calculated.
・ Stability preservation test (humidity severe test)
Each unwrapped sample placed in an open petri dish was stored for 1 month in a device (LH21-15M, manufactured by Nagano Science Co., Ltd.) set at a temperature of 25 ° C. ± 2 ° C. and a humidity of 90% RH ± 5% RH.

(4) Results For each tablet of Examples 1 to 4, Comparative Example 1 and Reference Example, 0 months (square) under severe test (25 ° C./90% RH) conditions and severe test (25 ° C./90% RH). Tables 2 to 7 and FIGS. 1 to 5 show the dissolution rates from the start of the dissolution test (0 minutes) to 360 minutes after the start of the dissolution test after storage under the conditions for 1 month (triangle). In this example, 0 months under the severe test (25 ° C / 90% RH) condition is referred to as "0 month", and after 1 month storage under the severe test (25 ° C / 90% RH) condition is referred to as "after 1 month storage". .. In addition, Table 8 shows the difference between the dissolution rate of the tablet at 0 months and the dissolution rate of the tablet after storage for 1 month as the dissolution rate fluctuation value (%).

From FIGS. 1 to 5 and Tables 2 to 8, the tablets of Examples 1 to 4 containing the component F were compared with the tablets of Comparative Example 1 or the reference example not containing the component F, particularly immediately after the start of the dissolution test (start of the dissolution test). It can be seen that the dissolution property (from to 30 minutes) is improved. Further, among the examples to which the component F was added, in particular, the tablet of the example 2 using the component F2 (sodium starch glycolate) contained the components F1 (carmellose), F3 (L-HPC), and F4 (crosspovidone). It can be seen that the change in dissolution rate after the rigorous test is lower and the stability is higher than that of the tablets used.

Table 9 shows changes over time in the total amount of related substances of the tablets of Examples 1 to 4, Comparative Example 1, and Reference Example.

Dissolution rate is the difference between the dissolution rate of 0-month tablets and the dissolution rate of tablets after 1-month storage of the tablets produced in Examples 2 to 7 in which the amount of sodium starch glycolate added as component F was changed. Table 10 shows the fluctuation value (%). Table 11 shows changes in the total amount of related substances.
Specifically, Table 10 shows Comparative Example 1 (without addition of the second additive), Example 2 (addition amount of sodium starch glycolate in tablets 1%), and Example 5 (in tablets of sodium starch glycolate). Elution rate fluctuation value (addition amount 0.5%), Example 6 (addition amount of sodium starch glycolate in tablets 5%), Example 7 (addition amount of sodium starch glycolate in tablets 20%) %) Is shown. In addition, Table 11 shows the amount of increase in the total related substances in the tablets of Comparative Example 1 and Examples 2 and 5-7.

For the tablets of Examples 1 to 7, the appearance of the tablets after storage under severe test (25 ° C./90% RH) conditions for 1 month was visually confirmed. No shape change was observed in the tablets of Examples 1 to 6, but the tablets of Example 7 had high hygroscopicity, so that fungi were generated on the surface of the tablets, causing a shape change (FIG. 6). As a control, the appearance of the tablet of Example 2 in which no shape change was observed is also shown.

Table 12 shows the fluctuation value (%) of the elution rate when a solution consisting of the active ingredient and 95% ethanol was used in the (2) granulation / drying step of paragraph [0039], and the fluctuation of the total amount of related substances. Is shown in Table 13.
Specifically, Table 12 shows the elution rate fluctuation value (%) in each tablet of Example 8 (levonorgestrel lysate) and Example 9 (norethisterone lysate). Since the elution rate of Example 9 reached 95%, the measurement was completed 120 minutes after the start of sampling. Table 13 shows the amount of increase in total related substances in Examples 8 and 9.

Table 14 shows the fluctuation value (%) of the dissolution rate in each tablet of Example 2-2 (levonorgestrel suspension) and Example 9-2 (norethisterone suspension), and Table 15 shows the fluctuation of the total amount of related substances. Shown in.

Example 10
The tablets of Example 10 were produced according to the production method of Example 2. However, as the setting conditions of the fluidized bed granulator (FD-MP-01D, manufactured by Paulec Co., Ltd.) in the (2) granulation / drying process of paragraph [0039], the air volume is 0.5 m / min and the air supply temperature is 60 ° C. The spray amount was 9 g / min and the spray air amount was 34 L / min. As component A1 (levonorgestrel), a drug substance having the same particle size as in Examples 1 to 8, that is, a drug substance having a cumulative 10% particle size of 1 μm, a cumulative 50% particle size of 4 μm, and a cumulative 90% particle size of 7 μm was used. ..

Example 11
(2) In the granulation / drying step, tablets were produced in the same manner as in Example 10. However, as component A1-2 (levonorgestrel), a component having a cumulative 10% particle diameter of 1 μm, a cumulative 50% particle diameter of 6 μm, and a cumulative 90% particle diameter of 17 μm was used.

For reference, the cumulative 10% particle size (d (10)), the cumulative 50% particle size (d (50)), and the cumulative 90% particle size (d (90)) in the drug substance used in Examples 1 to 11 The measured values of are shown in Table 16.

Table 17 shows the dissolution rate (%) of the tablets of Examples 10 and 11 from the start of the dissolution test for "0 months" to 360 minutes after the start of the dissolution test.

From Table 17 and FIG. 7, it can be seen that when the drug substance particle diameter (d (90)) is 15 μm or less, the dissolution property is improved as compared with the case where d (90) is 17 μm.

Table 18 shows the time course of the hardness of the tablets of Example 2, Example 2-2, Example 9-2 and Example 7, and Reference Example. The sample one month after the harsh test of Example 7 could not maintain its hardness due to moisture absorption and could not be measured.

The oral solid composition of the present invention has good hardness in addition to excellent elution and stability.

Claims (18)

(A) Progestin and
(B) Starches and
(C) An oral solid composition comprising sodium starch glycolate, carmellose, low degree of substitution hydroxypropyl cellulose (L-HPC), crospovidone, or a combination thereof.
An oral solid composition having a content of (c) of 0.1 to 8% by mass based on the total mass of the oral solid composition. The oral solid composition according to claim 1, which is in the form of a tablet. The oral solid composition according to claim 1 or 2, wherein the progestin is selected from levonorgestrel and norethisterone. The oral solid composition according to any one of claims 1 to 3, wherein (c) is selected from sodium starch glycolate, carmellose, crospovidone, or a combination thereof. The oral solid composition according to any one of claims 1 to 4, wherein the (c) is sodium starch glycolate. The oral solid composition according to any one of claims 1 to 5, wherein the cumulative 90% particle size of the progestin is 15 μm or less. The oral solid composition according to any one of claims 1 to 5, wherein the cumulative 90% particle size of the progestin is 10 μm or less. The oral solid composition according to any one of claims 1 to 7, wherein the starches are corn starch. (I) A step of spraying an alcohol suspension or a solution composed of a medicinal ingredient and an alcohol onto a first additive in a fluid state to obtain a wet granulated product.
(Ii) A method for producing an oral solid composition, which comprises a step of adding a second additive to the obtained granulated product, mixing the mixture, and then tableting.
The group consisting of the first additive being starches and the second additive being sodium starch glycolate, carmellose, low-degree-of-substitution hydroxypropyl cellulose (L-HPC), crospovidone, and a combination thereof. A method for producing an oral solid composition, which is more selected. The production method according to claim 9, wherein the second additive is selected from the group consisting of sodium starch glycolate, carmellose, crospovidone, and a combination thereof. The production method according to claim 10, wherein the second additive is sodium starch glycolate. The production method according to any one of claims 9 to 11, wherein the alcohol suspension or the solution is an ethanol suspension. The production method according to any one of claims 9 to 12, wherein the cumulative 90% particle size of the medicinal ingredient is 15 μm or less. The production method according to any one of claims 9 to 13, wherein the cumulative 90% particle size of the medicinal ingredient is 10 μm or less. The production method according to any one of claims 9 to 14, wherein the content of the second additive in the oral solid composition is 0.1 to 8% by mass. The production method according to any one of claims 9 to 15, wherein the medicinal ingredient is progestin. The production method according to claim 16, wherein the medicinal ingredient is selected from levonorgestrel and norethisterone. An oral tablet obtained by the production method according to any one of claims 9 to 17.