KR20150102852A - Solid dispersion composition with increased stability comprising amorphous solifenacin or pharmaceutically acceptable salts thereof - Google Patents

Abstract

In a solid dispersion composition comprising solifenacin or a pharmaceutically acceptable salt thereof, disclosed are a solid dispersion body composition and a manufacturing method thereof wherein the composition is configured to comprise only an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to an improved solid dispersion composition containing amorphous soliphenacin or a salt thereof, and a method for producing the same. [0002]

The present invention relates to an improved solid dispersion composition comprising amorphous solifenacin or a salt thereof and a process for preparing the same. Specifically, the present invention relates to a solid dispersion composition comprising substantially amorphous solifenacin or a pharmaceutically acceptable salt thereof and a process for producing the same. More particularly, the present invention relates to a solid dispersant composition comprising amorphous solifenacin or a pharmaceutically acceptable salt thereof, which is prepared by a wet granulation method using water as a solvent, and a process for producing the same.

Quinuclidine derivatives including solifenacin or its salts have an excellent selective antagonistic action on muscarinic M3 receptors and have been shown to be effective in treating urinary disorders such as neurogenic urinary frequency, neurogenic bladder, bladder relaxation or chronic cystitis, It has been reported to be useful as a preventive treatment for diseases, chronic bronchitis, respiratory diseases such as asthma and rhinitis (see European Patent No. 801067)

Solifenacin succinate is currently marketed under the trade name Vesicare and is approved by the FDA for the treatment of irritable cystitis, which is prescribed once a day for 5 mg and 10 mg tablets.

Solifenacin succinate was developed by Yamanouchi Pharmaceutical Co., and is disclosed in U.S. Patent No. 6017927 and U.S. Patent No. 6174896.

The surge TPCOMOOOI 47748D discloses crystals characterized by a powder X-ray diffraction (PXRD) peak at about 3.9, 11.2, 14.3 and has a PXRD peak characteristic of 19.3, 21.1, 23.2, 25.2 + 0.2 < / RTI > 2 &thetas; (Form I).

Such a crystalline compound can be obtained in any form with little remaining solvent in the final agent and can be further purified by crystallization, exhibits high stability in the manufacture of pharmaceuticals, and is easy to handle in a manufacturing factory .

Studies have been made to prepare solifenacinous succinate in the form of crystals, and Korean Patent Publication No. 2011-0016447 discloses a crystalline solifenacin succinate. Specifically, crystals characterized by X-ray powder diffraction peaks And identified the crystal forms by 2θ of 7.24, 12.09, 12.47, 13.91, 14.44, 16.98, 19.55, 20.29, 20.99, 21.71, 23.54, 24.21, 24.81, 26.99, 29.10.

In addition, with respect to the new crystal form of the solifenacin succinate, European Patent No. 2043639 has an X-ray diffraction spectrum with 2θ of 8.6, 11.7, 14.7, 16.2, 18.3, 19.9, 22.3, 23.7, 25.6 (Form II) Discloses crystalline < RTI ID = 0.0 > solifenacinous < / RTI >

As described above, the crystal form of solifenacin exists in various forms, and even if it is the same crystal form, the particle size can exist in various ways.

This substantial physical property is related to the tendency of the powder or granule form and when it is compressed with the tablet, whether or not the crystalline surface and the excipients are in close contact, and also that the drug compounds of such different crystalline forms have different melting points, solubilities and densities These differences can change the absorption rate of the drug when administered in vivo, and the change in the absorption rate of the drug may result in a change in drug concentration in the blood, and even if the same crystal form is used, the dissolution rate Which may lead to difficulties in achieving the same therapeutic effect.

In this connection, in Korean Patent No. 1270908, it is disclosed that the amorphous substance content in the pharmaceutical composition containing solifenacin or its salt gives stability to the product, and the content of the amorphous substance should be limited to 77% or less .

European Patent No. 801067 U.S. Patent No. 6017927 U.S. Patent No. 6174896 Korea Patent Publication No. 2011-0016447 Korea Patent No. 1270908

Solifenacin or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition.

As a solution to the above problems, there is provided a solid dispersion composition comprising amorphous solifenacin or a pharmaceutically acceptable salt thereof and a method for producing the solid dispersion composition.

The solid dispersion composition containing amorphous solifenacin or a salt thereof according to the present invention has high stability because there is no change in crystal form even when stored at high temperature and high humidity for a long period of time. In particular, since the active ingredient is solely of amorphous soliphenacin, the present invention has a remarkable effect that there is no problem in stability even if a raw material having a relatively low purity is used as compared with the conventional preparation containing the crystalline type solifenacin as an active ingredient. Therefore, the present invention has an advantage in that the raw material cost can be reduced as compared with the conventional preparation requiring high-cost raw materials of high purity.

Figure 1. XRD results of solifenacin
Figure 2. XRD results of corn starch
3. XRD results of Examples 1 to 5
Figure 4. XRD results of corn starch, HPMC, Example 7
Figure 5. Beginning of Example 7 ~ Acceleration 24 weeks XRD result (accelerated stability test)
6. From the start of Example 10 to the accelerated 24-week XRD result (accelerated stability test)
Figure 7. XRD results of Starlac and Example 11
8. From the start of Example 11 to the accelerated 24-week XRD result (accelerated stability test)

In a pharmaceutical preparation containing solifenacin or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as " solifenacin ") as an active ingredient, according to the prior art document (Korean Patent No. 1270908), its amorphous form It is known that this is a cause of the temporal decomposition of liquor. In order to ensure the stability of the preparation, an attempt is made to increase the stability by limiting the amorphous form of solifenacin to a specific content or less.

However, according to the study of the present inventors, it has been surprisingly found that when amorphous solifenacin, which is a cause of stability problems in the prior art, is formed into a solid dispersion and formulated using a pharmaceutically acceptable excipient, It was found that the stability increases rapidly even under high humidity conditions.

That is, the present inventors prepared a solid dispersion containing amorphous soliphenacin and at least one hydrophilic polymer in order to solve the problem caused by the difference in crystal form and the particle size that changes the dissolution rate, and the solid dispersion Found that solifenacin was stable without changing the crystal form under high temperature and humidity conditions.

The solid dispersion is a dispersion of solifenacin or a salt thereof in a hydrophilic polymer matrix. The solifenacin or a salt thereof exists amorphous and has no crystal form change.

The present invention also provides a solid composition prepared by a wet granulation method as a solid dispersion containing solifenacin and at least one hydrophilic polymer.

Hereinafter, the present invention will be described in detail.

When designing suitable dosage formulations in the pharmaceutical manufacturing process, it is extremely important that the physical state of the drug substance, ie, whether it is crystalline or amorphous. In general, amorphous is high in solubility, which helps to improve drug efficacy and to exhibit rapid efficacy, but it is unstable, shortening distribution period, and also difficult to control drug release and blood concentration. However, since the crystal form has a large variation depending on the crystal form, it can not be said uniformly. However, since it has low solubility and low bioavailability per unit weight, Crystalline feedstocks are preferred in formulations.

In the process of preparing pharmaceutical preparations containing solifenacin, there is a crystalline form of solifenacin and amorphous solifenacin in the final formulation using any method. In this case, it is a known fact that amorphous ssolifenacin causes a time-dependent degradation of the drug, and therefore, a formulation method has been reported in which amorphous ssolifenacin is not produced as much as possible.

However, the inventors of the present invention have found that when all of the solifenacin present in the preparation is amorphous and present in the form of a solid dispersion, the stability is rather increased, which is the amount of amorphous solifenacin in the preparation Which is contrary to the conventional technical idea of decreasing the number of pixels. This suggests that the concurrent presence of both crystalline and amorphous forms in the final formulation may have some effect on stability in a manner unknown in the past, and the precise mechanism should be clarified later.

The solid dispersion is obtained by uniformly dispersing the dispersion in a dispersion medium. Generally, the solid dispersion is obtained by dispersing an effective component (dispersion) in a state where a polymer (dispersion medium) is dissolved in an organic solvent, and then removing the solvent. As a method for removing the solvent, a spray drying or a fluidized bed granulation method is generally employed. In the present invention, in the course of producing a solid dispersion containing solifenacin, Or more of the hydrophilic polymer (step 1); Step (2) may be adopted in which step 1 is combined with an excipient, followed by drying and drying. By such a method, a preparation containing 100% amorphous solifenacin can be obtained in the final preparation.

Accordingly, in the present invention,

(a) dissolving solifenacin or a pharmaceutically acceptable salt thereof and a hydrophilic polymer in a solvent; And

(b) spray drying and fluidizing the solution of step (a); Or a step of combining the solution of step (a) with a pharmaceutically acceptable excipient to prepare granules. The solid dispersion according to claim 1, wherein the solid dispersion comprises amorphous solifenacin or a pharmaceutically acceptable salt thereof. do.

In the present invention, it is preferable to use water as a solvent in the production process of the solid dispersion. The hydrophilic polymer according to the present invention may be selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, chitosan, alginic acid, carrageenan, methacrylate copolymer, polyethylene oxide, povidone, , But it is not limited thereto, and both hydrophilic polymers can be used.

In the solid dispersion according to the present invention, the solifenacin and the hydrophilic polymer may be mixed at various ratios, and preferably the solifenacin: hydrophilic polymer is mixed at a ratio of 1: 0.1 to 1:10.

The solifenacin solid dispersions prepared according to the present invention were found to be amorphous (see FIG. 3) as a result of a solipenacin X-ray diffraction analysis, (Fig. 5). The results are shown in Fig.

The solid dispersion according to the present invention may be prepared by incorporating at least one pharmaceutically acceptable carrier in addition to the above-described effective ingredients for administration. The pharmaceutically acceptable carrier is an organic or inorganic carrier which can be administered together with the active ingredient, for example, for solid pharmaceutical preparations such as excipients, lubricants, binders and disintegrants, pharmaceutically acceptable additives, For example, coloring agents, sweeteners and the like. Examples of the disintegrant include corn starch, potato starch, carmellose calcium, and carmellose sodium. Examples of the acidulant include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate and the like.

Examples of the artificial sweetener include sodium saccharin, glycyrrhizin potassium, aspartame, stevia, and somatin. Examples of the fragrance include lemon, lemon lime, orange, and menthol. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, and stearic acid.

Examples of the coloring agent include yellow ferric oxide, red ferric oxide, edible yellow No. 4 and No. 5, edible red No. 3, No. 102, and edible blue No. 3. Examples of the buffering agent include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, .

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate. Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.

The composition according to the present invention may be conveniently administered by any route appropriate for the administration, for example, oral administration, topical administration, parenteral administration, inhalation administration, etc., and is preferably administered orally. A suitable formulation of the composition is a tablet, granule or capsule, and the drug may be compressed into solid unit dosage forms such as tablets, tablets, or mixed with a pharmaceutically acceptable carrier and then processed into a capsule.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the invention is not limited by the examples.

≪ Example 1 > Preparation of solid dispersion (wet granule)

10 g of crystalline solifenacin succinate and 10 g of hydroxypropylmethylcellulose were completely dissolved in 40 g of purified water and the solution was added to 80 g of corn starch. The associate water was dried in a drier at 60 DEG C until the dry weight loss became 1.5% or less, and then dried using a 20 mesh sieve.

≪ Examples 2 to 5 >

Granules containing solifenacin succinate solid dispersion were prepared in the same manner as in Example 1 except that only the hydrophilic polymer in Example 1 was changed.

Constituent Content (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Solifenacin succinate 10 10 10 10 10 Hydroxypropylmethylcellulose 10 Methylcellulose 10 Hydroxymethylcellulose 10 Hydroxyethyl cellulose 10 Carboxymethylcellulose 10 Corn starch 80 80 80 80 80 Purified water 40 40 40 40 40

Examples 6 to 9 Content of hydrophilic polymer

The granules containing the solid dispersion of solifenacin succinate were prepared in the same manner as in Example 1 except that only the amount of hydroxypropylmethylcellulose was changed.

Constituent Content (mg) Example 6 Example 7 Example 8 Example 9 Solifenacin succinate 10 10 10 10 Hydroxypropylmethylcellulose 2.5 5 10 20 Corn starch 80 80 80 80 Purified water 40 40 40 40

Example 10 Production of Solid Dispersion (Fluidized Bed Assembly)

Granules were prepared in the fluidized bed granulator (FL-LABO, manufactured by Freund) with the same constituents as in Example 7. In the fluidized-bed granulator, the assembling conditions were sprayed with the bonding liquid at an inlet air temperature of 75 ° C, an inlet air pressure of 0.2 to 0.3 MPa, a spraying rate of 0.25 mL / min, and a spraying / shaking cycle of 30 seconds / 5 seconds to obtain a solifenacin succinate solid dispersion (Table 3). ≪ tb > < TABLE >

Constituent Content (mg) Example 7 Example 10 Solifenacin succinate 10 10 Hydroxypropylmethylcellulose 5 5 Corn starch 80 80 Purified water 40 40

Example 11: Preparation of tablets

10 g of crystalline solifenacin succinate and 5 g of hydroxypropylmethylcellulose were completely dissolved in 40 g of purified water, and then the above solution was added to 252 g of lactose-corn starch (trade name: starlac). The associate water was dried in a drier at 60 DEG C until the dry weight loss became 1.5% or less, and then dried using a 20 mesh sieve. 3 g of magnesium stearate was added to the sizing product, mixed and then compressed.

<Experimental Example 1> Amorphous confirmation test result

A commonly used method for indicating or characterizing a crystalline composition is XRD. XRD (ATX-G, Rigaku) is a very useful means for illuminating the internal microstructure of matter. Crystals in which atoms are arranged regularly scatter strongly in a certain direction as a result of interfering with scattered X-rays by atoms. Structure (see Figures 1, 2 and 3).

It was confirmed that the solid dispersion granules containing solifenacin succinate of Examples 1 to 5 were amorphous as a result of XRD.

<Experimental Example 2> Solubility test

As can be seen in the literature, solifenacin succinate having different crystal forms were found to have different solubilities, and the solid dispersion amorphous granules containing solifenacin succinate of Examples 1 to 5 had a solubility constant (Table 4).

The following test was carried out to examine the solubility of the amorphous soliphene-succinic acid solid dispersion according to the present invention.

(1) Preparation of Standard Solution

25 mg of the solipenacinosuccinate standard was taken in a 50 mL volumetric flask and dissolved in a water / acetonitrile mixture (7: 3) and then drawn.

(2) Preparation of test liquid

10 g of the solid dispersion of solifenacin succinate prepared in Examples 1 to 5 was placed in a 50-mL volumetric flask, and the solution was circulated with purified water, followed by shaking for 12 hours at 37 DEG C in a water bath.

(3) Quantitative analysis

The solubilities of the standards and the solutions prepared in (1) and (2) above were quantitatively analyzed by high performance liquid chromatography (HPLC) under the following conditions.

Detector: Ultraviolet absorptiometer (measuring wavelength: 210 nm)

Column: Develosil ODS-UG-5 (150 mm x 4.6 mm, 5 um)

Mobile phase: 0.05 mol / L potassium phosphate buffer (pH 6.0) / acetonitrile mixture (70:30)

Flow rate: 1.0 mL / min

Literature I Literature II Literature III Example 1 Example 2 Example 3 Example 4 Example 5 620 727 96 873 862 840 866 845

Literature I: Bessecare's Interview foam

Document II: Patent WO2012004264A1

Document III: Selleck Chemicals solifenacin succinate data sheet

<Experimental Example 3> Stability test results according to the amount of hydrophilic polymer

As a result of the accelerated test, it was confirmed that the decomposition products were low in Examples 6 to 9. (Table 5)

Storage conditions: 40 ℃, 75% RH (2, 4, 6 months)

Packing form: sealed glass vial

Test items: Flexible materials

division Example 6 Example 7 Example 8 Example 9 Start 0.07 0.06 0.06 0.06 8 weeks 0.1 0.1 0.08 0.06 16 weeks 0.14 0.12 0.08 0.07 24 weeks 0.14 0.13 0.09 0.07

<Experimental Example 4> Amorphous content test result

The near infrared spectroscopy (NIR) measurement was performed by measuring the spectrum (measurement range: 10000 cm- ¹ to 4000 cm- ¹ ) by a Fourier transform near-infrared spectrometer (Bruker vector / 22 Near-IR Spectrometer) Infrared spectral analysis software (OPUS, Bruker) was used.

As a result of measuring the amorphous content, Example 7 was confirmed to be an amorphous solid dispersion by confirming the 100% amorphous content. (Table 6)

division Example 7 Example 10 Amorphous content (%) 100 100

As a result of XRD measurement, Example 7 showed the same peak as the peak of corn starch, indicating that the solifenacin succinate was amorphous (see Fig. 4). Further, even after storage for up to 6 months of acceleration, It was found that the granular solifenacin succinate containing the succinic acid disaccharide retains amorphousness (see Figures 5 and 6).

Therefore, it can be seen that the solid amorphous solifenacin succinate solid dispersion prepared by the production method according to the present invention has stability because it is not converted into a crystalline form even when it is stored for a long time at high temperature and high humidity (acceleration conditions).

<Experimental Example 5> The stability test result of the tablet (Example 11)

As a result of the accelerated test, it was confirmed that the degradation products were smaller than those of the product Betsy Care, which is also commercially available in tablets. (Table 7)

Storage conditions: 40 ℃, 75% RH (2, 4, 6 months)

Packing Type: PTP Package

Test items: Flexible materials, XRD

division Example 11 Betsy Care Start 0.00 0.17 8 weeks 0.09 0.22 16 weeks 0.11 0.35 24 weeks 0.12 0.37

As a result of XRD measurement, Example 11 showed the same peak as the peak of Starlac, indicating that the solifenacin succinate was amorphous (see Fig. 7). Further, even after storage for up to 6 months of acceleration, the amorphous solifenacin It can be seen that the tablet of solifenacin succinate containing the succinate solid dispersion maintains amorphousness (see FIG. 8).

Therefore, it can be seen that the solid amorphous solifenacin succinate solid dispersion prepared by the production method according to the present invention has stability because it is not converted into a crystalline form even when it is stored for a long time at high temperature and high humidity (acceleration conditions).

Claims (8)

A solid dispersion composition comprising solifenacin or a pharmaceutically acceptable salt thereof, wherein the active ingredient is an amorphous form of solifenacin or a pharmaceutically acceptable salt thereof. The solid dispersion composition according to claim 1, wherein the solid dispersion composition comprises amorphous solifenacin or a pharmaceutically acceptable salt thereof and at least one hydrophilic polymer. The solid dispersion composition according to claim 2, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, corn starch . The solid dispersion composition according to claim 2, wherein the weight ratio of the solifenacin or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is 1: 0.1 to 1:10. A process for preparing the solid dispersion composition as defined in claim 1,
(a) dissolving solifenacin or a pharmaceutically acceptable salt thereof and a hydrophilic polymer in a solvent; And
(b) spray drying and fluidizing the solution of step (a); Or a step of preparing the solution of step (a) with a pharmaceutically acceptable excipient and a wet granule. The solid dispersion according to claim 1, The method of claim 5, wherein the solvent is water. [7] The method according to claim 5 or 6, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, corn starch Gt; The method according to claim 5 or 6, wherein the weight ratio of the solifenacin or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is 1: 0.1 to 1:10.

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