WO2020122670A1 - Pharmaceutical composition, comprising tolvaptan, for preparation of solid dispersion and preparation method therefor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, comprising tolvaptan, for preparation of a solid dispersion, and a preparation method therefor. Specifically, the present invention relates to a pharmaceutical composition for preparation of a solid dispersion, which comprises: tolvaptan (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine) as an active ingredient; a moisture penetration enhancer; and an organic solvent.

Description

Pharmaceutical composition for preparing solid dispersion containing tolvaptan and method for manufacturing same

The present invention relates to a pharmaceutical composition for preparing a solid dispersion containing tolvaptan and a method for manufacturing the same. Specifically, tolvaptan (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H- as active ingredient Benzoazepine), a water permeation enhancer, and an organic solvent, to a pharmaceutical composition for preparing a solid dispersion.

Tolvaptan is a compound of the formula (I): 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tete Rohydro-1H-benzoazepine, used as a vasopressin antagonist.

[Formula I]

Drugs using tolvaptan as an active ingredient are commercially available as Samsuka tablets, and are clinically significant hypervolemic or euvolemic in patients with heart failure and antidiuretic hormone secretion syndrome (SIADH). The treatment of sodiumemia, or the first administration, corresponds to stages 1 to 3 of chronic renal disease, and the rapid progression of autosomal dominant polycystic kidney disease (ADPKD) delays the formation of cysts and delayed renal function in adult patients. Used for

Tolvaptan is very poorly soluble in water, and when preparing a solid preparation using conventional formulation technology, it has a problem of low solubility and low absorption into the digestive tract, resulting in low bioavailability.

Therefore, various studies have been attempted to improve the solubility or absorption of poorly soluble drugs. Attempts to increase the solubility and absorption by converting crystalline compounds into amorphous or improving them through physical changes that increase the surface area by miniaturization, or by developing as emulsions or microemulsions using surfactants or suitable solvents Yes.

Since the solubility in water is 10-1600 times greater than that in the amorphous form, bioavailability may be significantly increased when converted to the amorphous form. However, the amorphous form has a problem that storage stability is low because it tends to be recrystallized into a crystalline form with low free energy over time.

Attempts to increase the surface area by miniaturizing the particle size may be effective in improving the dissolution rate of a material having a small dissolution rate, but there is a limit that does not change the intrinsic solubility of the material, and there is a hammer mill or jet mill. ), it is refined by using a grinder such as ), and thus is limited in application depending on the energy reactivity of the compound.

Methods for improving solubility by making a microemulsion using a solubilizing agent such as a surfactant are frequently used, but use is limited due to toxicity of a solubilizing agent, an organic solvent, and a surfactant.

Therefore, studies using solid dispersions as another method for improving the solubility of poorly soluble drugs have been attempted. A solid dispersion is a system in which drug particles are dispersed in a solid, water-soluble polymer matrix, which can increase the surface area of the drug particles by reducing the size of the drug particles. In the process of preparing the solid dispersion, the drug is converted to amorphous, partially Or, since it exists in an amorphous state as a whole, it is efficient in terms of increasing the solubility of the drug and storage. As a method for producing a solid dispersion, a spray drying method and a melt extrusion method are known.

The melt extrusion method is a method of forming a solid dispersion by melting a drug and a water-soluble polymer mixture above the melting point of the drug and the glass transition temperature of the polymer mixture, thereby converting the drug into an amorphous state and imparting plasticity to the polymer to extrude it. In order to melt above the transition temperature, there is an disadvantage in terms of energy consumption.

The spray drying method is a method of preparing a solid dispersion by mixing in a suitable solvent according to the properties of a drug and a water-soluble polymer, and there is a problem that it is difficult to find a solvent that can dissolve a poorly water-soluble drug and a water-soluble polymer together.

On the other hand, Japanese Patent Laid-Open No. 1999-21241 discloses a method of powdering by dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent and evaporating and removing the organic solvent. However, due to the residual and low disintegration properties of the organic solvent, Therefore, there are still problems to be solved.

In order to solve this problem, the present inventors have repeatedly studied to improve the disintegration, solubility, and absorbability of tolvaptan, by adding a moisture permeation enhancer and finding an organic solvent capable of effectively dissolving them. By manufacturing, the present invention was completed.

An object of the present invention is to provide a pharmaceutical preparation for improving bioavailability by improving the disintegration, solubility and absorbability of tolvaptan.

Specifically, the present invention is to provide a pharmaceutical composition for the preparation of a solid dispersion and a method for manufacturing the same, comprising tolvaptan, a water permeation enhancer and an organic solvent.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preparing a solid dispersion, comprising tolvaptan or a pharmaceutically acceptable salt thereof, a water permeation enhancer and an organic solvent.

At this time, the moisture penetration enhancer may be polyvinylpyrrolidone. In addition, the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof may be 0.5 or more, preferably 0.5 or more and 1 or less, and more preferably 0.5.

In addition, the organic solvent may include one or more from the group consisting of methylene chloride and ethanol.

In addition, the organic solvent is preferably used in a minimum amount to dissolve the tolvaptan and the moisture permeation enhancer in order to secure the safety and economic efficiency of the process in the manufacture of the solid dispersion. In this case, the weight ratio of the tolvaptan or the pharmaceutically acceptable salt thereof to the organic solvent may be 11 or more, preferably 11 or more and 20 or less, and more preferably 11 or more and 13 or less. In addition, the weight ratio of the methylene chloride to the tolvaptan or a pharmaceutically acceptable salt thereof may be 9 or more and 16 or less, and preferably 9 or more and 11 or less.

In addition, the solid dispersion may be that the solubility of tolvaptan in water may be increased by 10 times or more, preferably 20 times or more, more preferably 22 times or more, compared to the tolvaptan raw material powder.

In addition, the present invention comprises a solid dispersion prepared using the pharmaceutical composition and at least one additive selected from the group consisting of lactose hydrate, starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose and hydroxypropylmethylcellulose It provides a pharmaceutical formulation characterized in that.

The present invention also provides a method for preparing solid dispersion by dissolving tolvaptan or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone in an organic solvent.

The organic solvent may include one or more from the group consisting of methylene chloride and ethanol.

At this time, the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof may be 0.5 or more, preferably 0.5 or more and 1 or less, and more preferably 0.5.

In addition, the weight ratio of the organic solvent to the tolvaptan or a pharmaceutically acceptable salt thereof may be 11 or more, preferably 11 or more and 20 or less, and more preferably 11 or more and 13 or less. At this time, the weight ratio of the methylene chloride to the tolvaptan or a pharmaceutically acceptable salt thereof may be 9 or more and 16 or less, preferably 9 or more and 11 or less.

In addition, the present invention provides a method for preparing a pharmaceutical formulation comprising the following steps:

(1) dissolving tolvaptan or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone in a mixture of methylene chloride and ethanol to prepare a solution;

(2) preparing a mixture by mixing the solution prepared in the step (1) with powder, starch, lactose hydrate, microcrystalline cellulose and low-substituted hydroxypropyl cellulose;

(3) dissolving hydroxypropyl methyl cellulose in purified water to prepare a binding solution;

(4) preparing granules using the mixture of step (2) and the binding solution of step (3); And

(5) Mixing magnesium stearate with the granules prepared in step (4). In this case, the pharmaceutical preparation may be a tablet for oral administration.

The solid dispersion prepared according to the present invention has an effect of significantly increasing the dissolution rate of tolvaptan compared to tolvaptan raw material powder. Therefore, the pharmaceutical preparation prepared using the solid dispersion of the present invention has the effect of increasing the absorbability of the poorly soluble drug tolvaptan and improving the bioavailability.

1 to 4 is a graph showing the dissolution rate according to the pH conditions of the pharmaceutical formulation and the control drug (Samsuka tablet) according to the present invention.

The present invention is tolvaptan (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine ) Or a pharmaceutically acceptable salt thereof, a water permeation enhancer, and an organic solvent.

The "pharmaceutically acceptable salt" of the present invention is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of acid addition salt formed by, but is not limited thereto.

The "moisture penetration enhancer" of the present invention is a component used to accelerate the elution of the active ingredient from the tablet by absorbing moisture, sodium croscarmellose, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, cross Povidone, polyvinylpyrrolidone, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene glycol, collidone CL, alginic acid, sodium alginate, carboxymethylcellulose calcium salt and sodium salt , Colloidal silicon dioxide, guar gum, magnesium aluminum silicate, powdered cellulose and starch may be selected from one or more, but is not limited thereto.

The "organic solvent" of the present invention is one or more selected from the group consisting of alcohols, ketones, methylene chloride, dichloromethane, dichloroethane, chloroform and 2-methyl 2-butene. And may not be limited thereto. The alcohols may be methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, isopentyl alcohol or isopropyl alcohol, and ketones are acetone, methyl ethyl ketone (MEK), methylbutyl ketone (MBK) Or methyl isobutyl ketone (MIBK).

In addition, the present invention comprises a solid dispersion prepared using the pharmaceutical composition and at least one additive selected from the group consisting of lactose hydrate, starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose and hydroxypropylmethylcellulose It relates to a pharmaceutical formulation.

Starch includes, but is not limited to, corn starch, wheat starch, potato starch, and the like. The content of the hydroxypropoxyl group in low-substituted hydroxypropyl cellulose is generally in the range of 5.0 to 16.0% by weight, but is not limited thereto. Hydroxypropylmethylcellulose (hydroxypropylmethylcellulose or hypromellose, "HPMC") is a type of cellulose derivative having a methoxy group (-OCH ₃ ), hydroxypropoxy group (-OCH ₂ CH(CH ₃ )OH) or hydrogen as a substituent. As, there are numbers 1828, 2208, 2906, 2910, etc. depending on the ratio (substitution degree) of the substituent.

In addition, the pharmaceutical compositions and formulations containing tolvaptan of the present invention have the effect of treating hyponatremia or delaying the progression of cyst formation and renal function decline in autosomal dominant polycystic kidney disease (ADPKD).

In order to prepare the pharmaceutical formulation of the present invention, it may further include suitable carriers, excipients, and diluents commonly used.

Carriers, excipients, and diluents that may be included in the formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.

Hereinafter, preferred embodiments are provided to help understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

[Examples 1 to 10]

Preparation of solid dispersion containing tolvaptan

After making a mixed solvent of methylene chloride and ethanol to the content of Table 1, tolvaptan was dissolved. After dissolving polyvinylpyrrolidone as a moisture permeation enhancer in a mixed solvent in which tolvaptan was completely dissolved, an amorphous solid dispersion was prepared by completely evaporating the mixed solvent using a spray dryer (Examples 1 to 10).

As a result, in the case of Examples 1 to 7, all the tolvaptan was dissolved, and when the solid dispersion was observed with an electron microscope, it was confirmed that the tolvaptan was evenly dispersed in the solid dispersion. However, in the case of Examples 8 to 10 in which the content of the mixed solvent was small, the phenomenon that tolvaptan was not completely dissolved occurred.

	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7	Example 8	Example 9	Example 10
Tolvaptan (g)	100	100	100	100	100	100	100	100	100	100
Polyvinylpyrrolidone (K-30, g)	50	50	50	50	50	50	50	50	50	50
Methylene chloride (g)	1670	1390	1250	1110	1040	975	920	835	765	700
Ethanol (g)	420	350	320	280	260	245	220	210	195	180

[Experimental Example 1]

Measurement of the solubility of tolvaptan made of solid dispersion

Among the examples, the solubility was measured for the solid dispersion of Example 7 in which all tolvaptan was dissolved using the smallest amount of organic solvent. After dissolving the raw material of tolvaptan or the solid dispersion of tolvaptan in Example 7 in purified water at the concentrations shown in Table 2 below, each detection amount was analyzed and compared using HPLC.

		Detection amount (Area)		Solubility ratio (tolvaptan solid dispersion/tolvaptan)
		Tolvaptan	Example 7
Tolvaptan concentration (mg/mL)	0.003	3439.5	52729.5	15.33
	0.005	3723.3	97028.3	26.06
	0.01	6293.3	154429.8	24.54
	0.02	9573.8	312601.5	32.65

As shown in Table 2 above, it was confirmed that the solid dispersion of Example 7 exhibited a remarkable increase in solubility of 15 times or more compared to tolvaptan raw material powder.

[Experimental Example 2]

Measurement of the solubility of tolvaptan according to the type of moisture penetration enhancer

To compare the solubility of the tolvaptan solid dispersion according to the type of the water permeation enhancer, in the same manner as in Example 7, in the same manner as polyvinylpyrrolidone, instead of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene glycol is moisture permeated Solid dispersions containing as an enhancer were prepared (Comparative Examples 1 to 3).

The solid dispersions of Examples 7 and Comparative Examples 1 to 3 were measured in the same manner as in Experimental Example 1 to measure the increase in solubility in the raw powder of tolvaptan and are shown in Table 3 below.

	Comparative Example 1	Example 7	Comparative Example 2	Comparative Example 3
Methylene chloride (g)	920
Ethanol (g)	220
Tolvaptan (g)	100
Hydroxypropyl cellulose (HPC-L, g)	50
Polyvinylpyrrolidone (k-30, g)		50
Hydroxypropylmethylcellulose (E4.5, g)			50
Polyethylene glycol (g)				50
Solubility ratio (tolvaptan solid dispersion / tolvaptan)	21.5	23.3	15.6	8.9

As described above, the solid dispersion of Example 7 using polyvinylpyrrolidone as the moisture permeation enhancer is more solid than that of the comparative example using hydroxypropylcellulose, hydroxypropylmethylcellulose or polyethylene glycol as the moisture permeation enhancer. It was found that the solubility of tolvaptan increased significantly.

[Experimental Example 3]

Measurement of the solubility of tolvaptan according to the content of polyvinylpyrrolidone

In order to compare the solubility of the tolvaptan solid dispersion according to the content of polyvinylpyrrolidone as a moisture permeation enhancer, in the same manner as in Example 7, the solid dispersions containing different contents of polyvinylpyrrolidone were used. It was prepared (Examples 11 to 16).

The solid dispersion was measured in the same manner as in Experimental Example 1 to measure the increase in solubility in the raw powder of tolvaptan and is shown in Table 4 below.

	Example 11	Example 12	Example 13	Example 7	Example 14	Example 15	Example 16
Methylene chloride (g)	920
Ethanol (g)	220
Tolvaptan (g)	100
Polyvinylpyrrolidone (k-30, g)	10	20	40	50	100	200	500
Tolvaptan: polyvinylpyrrolidone (weight)	1: 0.1	1: 0.2	1: 0.4	1: 0.5	1: 1	1: 2	1: 5
Solubility ratio (tolvaptan solid dispersion / tolvaptan)	4.8	13.5	21.6	23.3	24.1	22.9	23.5

As described above, when the weight ratio of polyvinylpyrrolidine to tolvaptan is 0.5 or more, it was confirmed that the solubility of the solid dispersion is significantly increased compared to the case where it is less than or less.

[Experimental Example 4]

Dissolution rate test of solid dispersion tablets

Granules were prepared using a mixture of a solid dispersion of Example 7, corn starch, lactose hydrate, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and a binding solution in which hydroxypropyl methyl cellulose was dissolved in purified water. After mixing the granules of Blue No. 2 with aluminum granules, lubricating with magnesium stearate, and tableting with the same tableting hardness as the control drug (samsuka tablets 15 mg, Otsuka Pharmaceutical Co., Ltd.) to obtain tablets having the composition and content of Table 5 below. It was prepared (Example 17).

Example 17
ingredient	Content (mg)
Tolvaptan	15.00
Lactose hydrate	102.32
Corn starch	20.00
Microcrystalline cellulose	20.00
Polyvinylpyrrolidone	7.50
Hydroxypropylmethylcellulose	4.00
Low-substituted hydroxypropyl cellulose	9.00
Blue No. 2 Aluminum Lake	0.18
Magnesium stearate	2.00

For the solid dispersion tablet of the present invention prepared above and the control drug (Samsuka tablets 15mg, Otsuka Pharmaceutical Co., Ltd.), a dissolution test was performed for each pH condition according to the following dissolution test method, and the results are shown in Table 6 and FIG. 1. 4 to 4.

<Elution test method>

Test method: Dissolution test method 2nd method (paddle method)

Elution medium: 900 mL of purified water containing 0.22% sodium lauryl sulfate (SLS)

Stirring speed: 50 rpm

Eluent temperature: 37 ±0.5℃

Dissolution conditions		Dissolution time (minutes)
		0	5	10	15	30	45	60	90	120	180	240	360
pH 1.2	Samskajeong	0	11.0	21.0	28.5	41.0	51.7	59.0	70.3	75.3	-	-	-
	Experimental Example 1	0	16.3	27.4	36.1	50.6	59.9	65.3	72.0	76.7	-	-	-
pH 4.0	Samskajeong	0	12.4	22.3	28.5	44.8	54.5	61.3	69.2	74.1	79.2	82.8	83.7
	Experimental Example 1	0	15.4	29.7	36.0	51.7	60.3	65.5	70.7	74.7	77.8	79.5	80.3
pH 6.8	Samskajeong	0	14.7	24.5	37.2	45.8	54.0	61.9	69.2	73.5	78.6	79.4	83.0
	Experimental Example 1	0	18.7	30.5	43.9	52.5	60.3	65.9	72.1	72.8	77.5	79.7	81.2
DW		Samskajeong	0	12.2	21.3	33.4	42.7	52.1	58.7	67.4	71.6	75.9	79.2	81.6
	Experimental Example 1	0	19.3	32.4	48.0	51.8	63.6	67.8	73.8	76.3	79.9	79.0	82.2

As shown in Table 6 and FIGS. 1 to 4, as a result of the dissolution test, the tablets made of the solid dispersion of the present invention were eluted in a shorter time than the reference drug at all pH conditions.

In the end, when the formulation was prepared using the solid dispersion according to the present invention, improvement in dissolution of the poorly soluble drug tolvaptan was confirmed, and accordingly, the absorption of tolvaptan in the digestive tract and improvement in bioavailability can also be expected.

Claims (15)

1. Tolvaptan or a pharmaceutically acceptable salt thereof, a water permeation enhancer and an organic solvent, the pharmaceutical composition for preparing a solid dispersion.
2. According to claim 1, wherein the moisture permeation enhancer is characterized in that the polyvinylpyrrolidone, pharmaceutical composition for preparing a solid dispersion.
3. The pharmaceutical composition for preparing a solid dispersion according to claim 2, wherein the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof is 0.5 or more.
4. The pharmaceutical composition for preparing a solid dispersion according to claim 3, wherein the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof is 0.5.
5. According to claim 1, The organic solvent is characterized in that it comprises at least one from the group consisting of methylene chloride and ethanol, pharmaceutical composition for preparing a solid dispersion.
6. The pharmaceutical composition for preparing a solid dispersion according to claim 1, wherein the weight ratio of the organic solvent to the tolvaptan or a pharmaceutically acceptable salt thereof is 11 or more.
7. The pharmaceutical composition for preparing a solid dispersion according to claim 6, wherein the weight ratio of the organic solvent to the tolvaptan or a pharmaceutically acceptable salt thereof is 11 or more and 20 or less.
8. The method of claim 1, wherein the organic solvent is a mixture of methylene chloride and ethanol,

   The weight ratio of the organic solvent to the tolvaptan or a pharmaceutically acceptable salt thereof is 11 or more and 20 or less,

   A pharmaceutical composition for preparing a solid dispersion, characterized in that the weight ratio of the methylene chloride to the tolvaptan or a pharmaceutically acceptable salt thereof is 9 or more and 16 or less.
9. The pharmaceutical composition for preparing a solid dispersion according to claim 1, wherein the solid dispersion has a solubility of tolvaptan in water increased by 20 times or more, compared to the raw powder of tolvaptan.
10. Characterized in that it comprises a solid dispersion prepared using the pharmaceutical composition of claim 1 and at least one additive selected from the group consisting of lactose hydrate, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose Pharmaceutical preparations.
11. A method for preparing a solid dispersion by dissolving tolvaptan or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone in a mixture of methylene chloride and ethanol.
12. 12. The method of claim 11, wherein the weight ratio of polyvinylpyrrolidone to the tolvaptan or a pharmaceutically acceptable salt thereof is 0.5 or more.
13. The method of claim 11, wherein the weight ratio of the mixture of methylene chloride and ethanol to the tolvaptan or a pharmaceutically acceptable salt thereof is 11 or more.
14. (1) dissolving tolvaptan or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone in a mixture of methylene chloride and ethanol to prepare a solution;

    (2) preparing a mixture by mixing the solution prepared in the step (1) with powder, starch, lactose hydrate, microcrystalline cellulose and low-substituted hydroxypropyl cellulose;

    (3) dissolving hydroxypropyl methyl cellulose in purified water to prepare a binding solution;

    (4) preparing granules using the mixture of step (2) and the binding solution of step (3); And

    (5) characterized in that it comprises the step of mixing magnesium stearate to the granules prepared in the step (4), the method of manufacturing a pharmaceutical preparation.
15. The method of claim 14, wherein the pharmaceutical preparation is a tablet for oral administration.

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