WO2017082577A1

WO2017082577A1 - Amorphous solifenacin-containing solid preparation for oral use and preparation method therefor

Info

Publication number: WO2017082577A1
Application number: PCT/KR2016/012490
Authority: WO
Inventors: 임호택; 권택관; 윤승빈; 김용일; 박재현; 우종수
Original assignee: 한미약품 주식회사
Priority date: 2015-11-11
Filing date: 2016-11-02
Publication date: 2017-05-18
Also published as: CN108348617A; BR112018009413A2; PH12018500980A1; MX2018005848A; EA201890896A1; KR20170055211A

Abstract

An aspect of the present invention provides a solid preparation for oral administration, containing: amorphous solifenacin or a pharmaceutically acceptable salt thereof; and a stabilizer selected from the group consisting of alkane celluloses, antioxidants, and any combination thereof.

Description

Amorphous solifenacin-containing oral solid preparation and preparation method thereof

The present invention relates to an oral solid preparation containing amorphous solifenacin and a method for preparing the same. More specifically, an amorphous solipenacin-containing oral solid preparation having a significantly reduced tendency to form amorphous materials and the formation of a flexible substance and its preparation It is about a method.

Solifenacin is a quinoline derivative having the structure of Formula 1 below, and its chemical name is (1R, 3'R) -3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-iso Quinolinecarboxylate is:

[Formula 1]

The solifenacin or a pharmaceutically acceptable salt thereof has excellent selective antagonistic action on muscarinic M ₃ receptors, such as neuropathy, neurogenic bladder, nocturia, unstable bladder, bladder spasms or chronic cystitis, etc. It has been reported to be useful as a prophylactic agent for respiratory diseases such as urinary diseases, chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis (EP 0 801 067 A).

Crystalline solvenacin succinate has a problem in that the crystal form is changed to amorphous during the wet granulation process, and the softening material increases over time to reduce the stability of the tablet.

On the other hand, amorphous solifenacin has a pharmacokinetic advantage which is high in solubility compared to crystalline solifenacin. The amorphous solifenacin also has a problem in that the crystal form of the main component changes according to storage conditions because it changes to a crystalline solifenacin over time. However, the method for stabilizing the crystalline solifenacin is not effective in improving the stability of amorphous solifenacin. Therefore, there is a need for the development of oral preparations of amorphous solifenacin that can maintain the stability of the active ingredient over time.

It is an object of the present invention to provide an amorphous solid solvenacin-containing oral solid preparation having excellent stability of the active ingredient.

Another object of the present invention is to provide a method for preparing an oral solid preparation containing amorphous solifenacin having excellent stability of an active ingredient.

One aspect of the invention

Amorphous solifenacin or a pharmaceutically acceptable salt thereof; And it provides a solid preparation for oral administration comprising a stabilizer.

One aspect of the present invention provides at least 90% amorphous solifenacin or a pharmaceutically acceptable salt thereof; And a stabilizer selected from the group consisting of alkane celluloses, antioxidants, and any combination thereof.

Another aspect of the invention

Solifenacin or a pharmaceutically acceptable salt thereof; And spray drying a mixed solution of a stabilizer selected from the group consisting of alkancelluloses, antioxidants, and any combination thereof to produce amorphous solifenacin powder.

Solidifying the amorphous solifenacin powder with a pharmaceutically acceptable additive;

The stabilizer provides a method for producing an oral solid preparation according to an aspect of the present invention, which is selected from alkancelluloses, neutral antioxidants, and any combination thereof.

In accordance with an aspect of the present invention, the amorphous solvenacin-containing oral solid preparation contains hypromellose or hydroxypropyl cellulose, which not only maintains its amorphous form over time, but also significantly lowers the generation of flexible substances. As such, the solid preparation has high stability over time of the active ingredient. Thus, the oral solid preparation may enable effective oral administration of amorphous solifenacin.

1 to 4 are XRD graphs after four weeks of storage of a solid preparation for oral solifenacin according to Examples 1 to 4 of the present invention at 60 ° C. under severe storage conditions of HDPE bottles.

5 to 7 are XRD graphs after 4 weeks of storage of a solid preparation for oral solifenacin according to Comparative Examples 1 to 3 at 60 ° C. under severe storage conditions of HDPE bottles.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. In addition, numerical values described in this specification are considered to include the meaning of "about", even if not specified. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

The present invention provides amorphous solifenacin or a pharmaceutically acceptable salt thereof; And it provides a solid preparation for oral administration comprising a stabilizer.

In one aspect, the invention provides amorphous solifenacin or a pharmaceutically acceptable salt thereof; And stabilizers,

The stabilizer provides a solid dosage form for oral administration, which is selected from the group consisting of alkancelluloses, antioxidants, and any combination thereof.

In another aspect of the present invention,

Amorphous solifenacin or a pharmaceutically acceptable salt thereof; And stabilizers,

The amorphous solifenacin or the pharmaceutically acceptable salt thereof is 90% by weight or more based on the total weight of the solifenacin or the pharmaceutically acceptable salt thereof,

The stabilizer provides a solid dosage form for oral administration that is selected from the group consisting of alkancelluloses, antioxidants, and any combination thereof.

The alkane cellulose may be selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose, ethyl cellulose, phthalic acid hydroxypropyl cellulose, and any combination thereof. .

In one embodiment, the alkane cellulose may be hypromellose, hydroxypropyl cellulose or a combination thereof.

The antioxidant may be a neutral antioxidant.

In one embodiment of the present invention, the neutral antioxidant may be an antioxidant including a phenol derivative. More specifically, the neutral antioxidant may be selected from butylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol, and any combination thereof. In one embodiment, the neutral antioxidant can be selected from butylhydroxytoluene, butylhydroxyanisole, propyl gallic acid and any combination thereof.

Pharmaceutically acceptable salts of solifenacin include acid addition salts or quaternary ammonium salts, and the acid addition salts include inorganic or organic acid salts.

The inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and the like. The organic acid salts are formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartarate, carbonate, picrate, methanesulfonate, ethane Sulfonate, glutamate, and the like, but are not limited thereto.

In one embodiment, the pharmaceutically acceptable salt of solifenacin is solifenacin succinate.

As used herein, "stabilization" of an active ingredient means inhibiting any change in the active ingredient by increasing the stability of the active ingredient, and includes inhibiting the change in the crystal form of the active ingredient or the formation of a flexible substance.

The term "stabilizer" means any pharmaceutically acceptable additive that can increase the stability of the active ingredient and includes amorphous crystalline inhibitors and antioxidants of the active ingredient.

The term "stabilizer" means any pharmaceutically acceptable additive that is effective in inhibiting the oxidation of the active ingredient.

In one embodiment, the stabilizer is hypromellose, hydroxypropyl cellulose; And antioxidants selected from butylhydroxytoluene, butylhydroxyanisole, and combinations thereof.

The present inventors have diligently studied for the development of a solid formulation having high stability of amorphous solifenacin, and when the solid formulation is prepared by containing alkane cellulose such as hypromellose or hydroxypropyl cellulose, Compared with other polymers, it is possible to block the amorphous crystallization remarkably, and to prepare a solid preparation by containing an antioxidant such as butylhydroxytoluene, butylhydroxyanisole, propyl gallate, or tocopherol It has been found that the increase in lead can be significantly reduced compared to other antioxidants. Specifically, when solvenacin succinate is prepared by spray-drying powders with various high molecular compounds and then solidified, when alkane celluloses such as hypromellose or hydroxypropyl cellulose are contained, amorphous solvenacin While succinate remains amorphous even in severe storage conditions for a long time, it was confirmed that the succinate is changed to a crystalline form when other polymers are contained (see Test Example 2). In addition, when solvenacin succinate is prepared by spray-drying powder with various antioxidants and then solidified, amorphous solvena when butylhydroxytoluene, butylhydroxyanisole, gallic acid propyl, or tocopherol is contained Succinic acid salt was found to be significantly lower than the case of containing other antioxidants under accelerated storage conditions (see Test Example 1).

In one embodiment, the hypromellose may be, but is not limited to, hypromellose having 16.5 to 30% of methoxyl groups and 4 to 32% of hydroxypropoxyl groups. In one embodiment, the hypromellose may be hypromellose 1828, hypromellose 2208, hypromellose 2906, or hypromellose 2910.

The alkane cellulose may be present in an amount of 0.1 to 5.0 parts by weight, more specifically 0.5 to 3.0 parts by weight with respect to 1 part by weight of the amorphous solifenacin or a pharmaceutically acceptable salt thereof. If the content does not reach the content, the crystallization blocking effect of suppressing the crystallization of amorphous solifenacin may not be sufficiently exhibited. If the content exceeds the content, the viscosity may be high, which may cause a problem in process setting.

The antioxidant selected from butylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol and any combination thereof may be used in an amount of 0.005 to 1.0 weight based on 1 part by weight of the amorphous solifenacin or its pharmaceutically acceptable salts. Parts, more specifically, 0.01 to 0.1 parts by weight. If the content is less than the stabilization effect may not appear sufficiently, if the content is exceeded, the degree of improvement of the stabilization effect may be very insignificant.

The oral solid preparation may be formulated, for example, as pellets, capsules, tablets, powders, granules, or dry syrups, but is not limited thereto. More specifically, the oral solid preparation may be in the form of a capsule or tablet. When the composite formulation of the present invention is a capsule, the capsule may be in the form of a powder, granules, tablets, dry syrup, pellets and the like therein.

In one embodiment, the amorphous solifenacin or a pharmaceutically acceptable salt thereof, and the stabilizer may be included in the oral solid preparation in the form of a spray-dried powder of their mixed solution. The "in the form of a spray-dried powder may be included in the oral solid preparation" is a spray-dried powder is included as it is, filled into a capsule, or included in the form of granules prepared using a spray-dried powder, It is interpreted to mean that it is included as a state in which the property of a powder is not maintained as it is by an additional process, such as tableting and tableting it into the granule.

The solvent for preparing the mixed solution may be used amorphous solifenacin or a pharmaceutically acceptable salt thereof, and any pharmaceutically acceptable solvent that can dissolve all of the stabilizers, for example ethanol and It is a mixed solvent of water. In one embodiment, the mixed solvent is a mixture of ethanol and purified water, more specifically, the mixture of ethanol and purified water may be a volume ratio of ethanol: water of 1 to 9: 9 to 1, for example, the volume ratio of ethanol: water About 5: 5, but is not limited thereto.

In one embodiment, the solid preparation is a tablet, may be a tablet by a direct compression method for tableting the raw material mixture, or may be a tablet by a granulation compression method for tableting after granulation of the raw material mixture. In one embodiment, the tablet may be a tablet by direct compression method.

The pharmaceutically acceptable additives included in the oral solid preparations according to the present invention may be any additives that the oral solid preparations typically include, for example, diluents, binders, disintegrants, glidants, and these It can be selected from the group consisting of any combination of.

The diluent is used for increasing and may be selected from the group consisting of lactose or its hydrate, microcrystalline cellulose, mannitol, starch, sucrose, lactose, sorbitol, xylitol, glucose, calcium dihydrogen phosphate, and any combination thereof. It is not limited to this.

The binder may be selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone, macrogol, hard silicic anhydride, and any combination thereof, but is not limited thereto.

The disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, pregelatinized starch, And any combination thereof, but is not limited thereto.

The glidants include stearic acid, stearic acid metal salts (e.g. calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes, glyceryl fatty acid esters, glycerol dibehenate, And it may be selected from the group consisting of any combination thereof, but is not limited thereto.

In one embodiment, the oral solid preparation may contain about 2.5 to 10 mg of free active solvenacin or its pharmaceutically acceptable salt per unit dosage form, more specifically about 5 to 10 mg. It may contain mg.

The oral solid preparation may be administered to a mammal, including a person having any indication of solifenacin or a pharmaceutically acceptable salt thereof. Thus, the oral solid preparations can be used for the treatment or prevention of any disease that is effective in good selective antagonistic action on muscarinic M ₃ receptors. The diseases include urinary diseases such as neuronal urinary, neurogenic bladder, enuresis, irritable bladder, bladder spasm, or chronic cystitis; Respiratory diseases such as, but not limited to, sex obstructive pulmonary disease, chronic bronchitis, asthma, or rhinitis. In one embodiment, the oral solid preparations can be used to treat overactive bladder.

In another aspect of the present invention,

The stabilizer is hypromellose, hydroxypropyl cellulose; Antioxidants selected from butylhydroxytoluene, butylhydroxyanisole, propyl gallic acid and any combination thereof; And it is selected from any combination thereof, provides a method for producing an oral solid preparation according to one aspect of the present invention.

Details of the method for preparing oral solid preparations according to this aspect may be applied to the description of the oral solid preparations according to one aspect of the present invention.

In one embodiment, the step of solidifying may be performed according to any method known in the art of formulating a solid solvenacin powder as the raw material, into a solid preparation, for example pellets, capsules It may be carried out according to any known method for formulating into a formulation, tablet, powder, granule, or dry syrup.

In one embodiment, the step of solidifying may be a method of mixing the amorphous solifenacin powder with a pharmaceutically acceptable additive and then preparing a tablet by tableting. The tableting may be an indirect tableting method of preparing and then granulating the granules, or may be a direct tableting method of mixing and then tableting with other pharmaceutically acceptable additives without preparing the granules. In one embodiment, the tableting is a direct tableting method.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

EXAMPLE

실시예Example 1: 무정형의 1: amorphous 솔리페나신숙신산염Solifena Succinate 정제의 제조 Manufacture of tablets

To the composition as shown in Table 1, first, solvenasin succinate, hypromellose and butylhydroxytoluene dissolved in a mixture of ethanol and purified water (ethanol: water = 5: 5) by spray-drying the amorphous solvena Succinate spray dried powder was obtained. It was dried at 60 ° C., sieved to 30 mesh, and then all the remaining ingredients were added to prepare a mixture. Then, the mixture was compressed into tablets using a rotary punching machine (GRC-18; Sejong Machinery, Korea) using a round punch having a diameter of 8.0 mm to prepare solifenacin succinate tablets having a hardness of about 5 to 12 kp. Then, the solvena succinate succinate tablet prepared as described above was coated with a solution in which Opadry Pink was dispersed in purified water.

TABLE 1

실시예Example 2 내지 8 : 무정형의 2 to 8: amorphous 솔리페나신숙신산염Solifena Succinate 정제의 제조 Manufacture of tablets

Instead of the contents of hypromellose and butylhydroxytoluene of Example 1, solvena succinate succinate tablets were prepared in the same manner as in Example 1 with the contents of Examples 2 to 8 shown in Table 1. In Example 7, butylhydroxyanisole was used instead of butylhydroxytoluene, and in Example 8, gallic acid propyl was used instead of butylhydroxytoluene.

비교예 1 : 무정형의 솔리페나신숙신산염 정제의 제조Comparative Example 1 Preparation of Amorphous Solfenasuccinic Acid Tablet

To the composition as shown in Table 2, first, solvenacin succinate, lactose hydrate and butyl hydroxytoluene dissolved in a mixed solvent of ethanol and purified water (ethanol: water = 5: 5) by spray-drying the amorphous solipenacin Succinate spray dried powder was obtained. It was dried at 60 ° C., stipulated as 30 mesh, and mixed with the remaining ingredients. The mixture was prepared by sieving at 30 mesh and then adding all the remaining ingredients. Then, the mixture was compressed into tablets using a rotary punching machine (GRC-18; Sejong Machinery, Korea) using a round punch having a diameter of 8.0 mm to prepare solifenacin succinate tablets having a hardness of about 5 to 12 kp. Then, the solvena succinate succinate tablet prepared as described above was coated with a solution in which Opadry Pink was dispersed in purified water.

TABLE 2

비교예 2 내지 7 : 무정형의 솔리페나신숙신산염 정제의 제조Comparative Examples 2 to 7: Preparation of amorphous solifenacin succinate tablets

In Comparative Example 1, D-mannitol, povidone, or hypromellose instead of the lactose hydrate, butylhydroxytoluene, sodium edetate, sodium thiosulfate, or tartaric acid in place of the butylhydroxytoluene is shown in Table 2 above. In the same manner as in Comparative Example 1 with a content of 2 to 7 to prepare solifenacin succinate tablets.

시험예 1: 가속 보관 안정성 시험Test Example 1: Accelerated Storage Stability Test

After storing the amorphous solifenacin succinate tablets obtained in Examples 1 to 7 and Comparative Examples 4 to 7 under the following accelerated conditions, the degree of generation of the soft substance of solifenacin succinate salt under the analysis conditions of the flexible substance described below Analyzed.

Storage condition: HDPE bottle packaging at 40 ℃, 75%

Test Points: Initial, 3 and 6 Months

Analysis target: solifenacin succinate

Equipment: HPLC (Hitachi 5000 series, Japan)

Detector: UV absorbance photometer (wavelength: 210 nm)

Column: A column filled with silica gel for liquid chromatograph with a particle diameter of 5 μm in a stainless steel pipe with an inner diameter of about 4.6 mm and a length of about 15 cm (Develosil ODS Column)

Mobile phase-potassium phosphate buffer (pH 6.0): acetonitrile = 70: 30

Phosphate buffer (pH 6.0): Dissolve 8.7 g of anhydrous dipotassium hydrogen phosphate in 1 L of water, and add phosphoric acid to pH 6.0.

Flow rate: 1.3 mL / min

Column temperature: 40 ℃

The production pattern of solifenacin analogues measured under the analytical conditions is shown in Table 3 below.

TABLE 3

As shown in the measurement results of the analogous substances in Table 3, Examples 1 to 8 are different from those in which the amount of the flexible substance generated over time includes butylhydroxytoluene, butylhydroxyanisole, or gallic acid propyl as an antioxidant. It was found to be significantly less compared to Comparative Examples 4-7, including antioxidants.

시험예 2: 가혹 보관 조건에서 결정형 확인Test Example 2: Form Crystallization in Severe Storage Conditions

The amorphous solifenacin succinate spray dried powders obtained in Examples 1 to 4 and Comparative Examples 1 to 3 were stored under the following severe conditions, and then crystalline changes were analyzed by XRD.

Storage condition: HDPE bottle packaged at 60 ℃

Test Points: Initial, 2 and 4 weeks

Analysis target: amorphous solifenacin succinate

Equipment: XRD (Bruker D8 ADVANCE, Germany)

The crystalline changes of amorphous solifenacin succinate measured under the above conditions are shown in Table 4 below. In addition, the XRD results of Examples 1 to 4 after 4 weeks are shown in FIGS. 1, 2, 3, and 4, and the XRD results of Comparative Examples 1 to 3 after 2 weeks are shown in FIGS. 5, 6, and 7, respectively. Indicated.

TABLE 4

As can be seen from the XRD analysis results of Table 4 and FIGS. 1 to 7, when hypromellose or hydroxypropyl cellulose is contained, amorphous solifenacin succinate remains amorphous even in long-term harsh storage conditions. In the case of containing other polymer, it was confirmed to change into crystalline form.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims

Amorphous solifenacin or a pharmaceutically acceptable salt thereof; And a stabilizer, wherein the stabilizer is selected from the group consisting of alkancelluloses, antioxidants, and any combination thereof.
The solid preparation for oral use according to claim 1, wherein at least 90% of the total weight of solifenacin or a pharmaceutically acceptable salt thereof is amorphous.
The method of claim 1, wherein the alkanes cellulose

A solid preparation for oral administration, which is selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxypropylethyl cellulose, methyl cellulose, ethyl cellulose, phthalic acid hydroxypropyl cellulose, and any combination thereof.
The method of claim 1, wherein the alkanes cellulose

Hypromellose, hydroxypropyl cellulose or a combination thereof is a solid preparation for oral administration.
The solid preparation for oral administration according to claim 1, wherein the antioxidant is a neutral antioxidant.
6. The solid dosage form of claim 5, wherein the neutral antioxidant is selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol, and any combination thereof.
7. The solid dosage form of claim 6, wherein the neutral antioxidant is selected from butylhydroxytoluene, butylhydroxyanisole, propyl gallic acid, and any combination thereof.
The solid preparation for oral administration according to claim 1, wherein the alkancellulose is included in an amount of 0.1 to 5.0 parts by weight relative to 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof.
The solid preparation for oral administration according to claim 8, wherein the alkane cellulose is contained in an amount of 0.5 to 3.0 parts by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof.
The solid preparation for oral administration according to claim 5, wherein the neutral antioxidant is included in an amount of 0.005 to 1.0 parts by weight relative to 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof.
The solid preparation for oral administration according to claim 10, wherein the neutral antioxidant is included in an amount of 0.01 to 0.1 parts by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof.
The solid preparation of claim 1, wherein the amorphous solifenacin or a pharmaceutically acceptable salt thereof is amorphous solifenacin succinate.
The oral solid preparation according to claim 1, wherein the amorphous solvenacin or a pharmaceutically acceptable salt thereof, the alkancelluloses and the antioxidant are contained in the form of a spray-dried powder of a mixed solution thereof. .
The oral solid preparation of claim 1, wherein the solid preparation is selected from the group consisting of pellets, powders, granules, dry syrups, tablets, and capsules.
The oral solid preparation according to claim 1, wherein the amorphous solifenacin or the pharmaceutically acceptable salt thereof is contained in an amount of 2.5 to 10 mg per unit dosage form as a free base.
The oral solid preparation according to claim 1, which is for the treatment of overactive bladder.
Solifenacin or a pharmaceutically acceptable salt thereof; And spray drying a mixed solution of a stabilizer selected from the group consisting of alkancelluloses, antioxidants, and any combination thereof to produce amorphous solifenacin powder.

Solidifying the amorphous solifenacin powder with a pharmaceutically acceptable additive;

The stabilizing agent is selected from alkane celluloses, antioxidants and any combination thereof, the method for producing an oral solid preparation according to any one of claims 1 to 16.
18. The method of claim 17, wherein the step of solidifying comprises mixing the amorphous solifenacin powder with a pharmaceutically acceptable additive and then preparing the tablet by tableting.
The method of claim 18, wherein the tableting is a direct tableting method.