KR101808963B1 - Stability improved composite particles containing fesoterodine fumarate and oral dosage form comprising the same - Google Patents

Abstract

The present invention relates to a stabilized composite particle containing fesoterodine fumarate, and a formulation for oral administration containing the same. According to the present invention, the composite particle can remarkably improve stability of fesoterodine fumarate in a mixture obtained by mixing specific stabilizers such as xylitol and erythritol and tablets obtained by processing the mixture into a form of tablets, in an attempt to improve stability of fesoterodine fumarate.

Description

[0001] Stability-improving composite particles containing a pesoterodine fumarate salt and an oral dosage form containing the same [0002]

The present invention relates to a stable multiparticulate particle containing a pesoterodine fumarate salt and an oral administration formulation containing the same.

Fesoterodine fumarate is a derivative of 3,3-diphenylpropylamine that inhibits hypertension of the bladder through antimuscarinic action and has indications for irritable bowel syndrome and nocturia among overactive bladder treatments.

The pesoterodine has several mechanisms acting in the body and has the property that the drug is decomposed by oxidation and hydrolysis even under simple storage conditions, not in the body.

Therefore, there is a need to study long-term preservable formulations through the development of new pharmaceutical compositions containing more stable pesoterodine under degradation even under stress conditions.

Thus, the present inventors have found that the stability of pesoterodine fumarate salt is remarkably improved in a mixture obtained by blending a specific stabilizing agent and tablets obtained by tableting it, in order to improve the stability of pesoterodine fumarate salt, thereby completing the present invention.

International Publication No. WO 2012/025941

It is an object of the present invention to provide a composite particle in which the stability of pesoterodine fumarate salt is improved.

It is another object of the present invention to provide an oral dosage form comprising the multiparticulates.

In order to achieve the above object,

The present invention relates to fesoterodine fumaric acid represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And

A stabilizer selected from the group consisting of xylitol, erythritol, pentaerythritol, meso-erythritol and inositol;

≪ / RTI >

[Chemical Formula 1]

The present invention also provides an oral dosage form comprising multiparticulates.

In order to improve the stability of the pesoterodine fumarate salt, the composite particles according to the present invention have markedly improved stability of the pesoterodine fumarate salt in a mixture obtained by blending specific stabilizers (xylitol, erythritol, etc.) .

Fig. 1 shows the results obtained when the tablets prepared in Examples 2-1 to 2-5 and Comparative Example 1 (tablets of pterothelin fumarate) were stored at 60 DEG C and 80% relative humidity for 1, 3, 5 and 10 days, (Non-decomposed) content of the terodine fumarate salt without decomposition.
2 is a graph showing the results of evaluations of the amounts of pesoterodin fumarate salts of Examples 3 and 5 and Comparative Example 2. Fig.

Hereinafter, the present invention will be described in detail.

Pesoterodine Fumarate  Composite particles with improved stability

The present invention relates to fesoterodine fumaric acid represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And

A stabilizer selected from the group consisting of xylitol, erythritol, pentaerythritol, meso-erythritol and inositol;

≪ / RTI >

[Chemical Formula 1]

In the composite particle according to the present invention, the stabilizer serves to prevent the decomposition of phe- theroindane fumaric acid. Preferably, xylitol or erythritol may be used as the stabilizer, and erythritol may be more preferably used.

The composite particle according to the present invention may further comprise an inert excipient such as Xanthan gum, Ludipress, Cellactose, Talc and the like. Here, the inert excipient serves to enhance the stability and the sustained release effect. Preferably, Ludipress or Cellactose may be used as the inert excipient.

In the composite particle according to the present invention, 8 to 10 parts by weight of the stabilizer may be contained relative to 1 part by weight of the pesoterodine fumaric acid or a pharmaceutically acceptable salt thereof, preferably 8.5 to 9.5 parts by weight of the stabilizer, Preferably 9 parts by weight of the stabilizer. If the stabilizer is contained in an amount of less than 8 parts by weight, there may be a problem that the stability improving effect is insignificant. If the stabilizer is contained in an amount exceeding 10 parts by weight, the weight of the tablet may become excessively large, .

In the composite particle according to the present invention, 2-4 parts by weight of an inert excipient relative to 1 part by weight of the total amount of the above-mentioned pesoterodine fumaric acid or a pharmaceutically acceptable salt thereof and a stabilizer may be contained, By weight, particularly preferably 2.8-3.2 parts by weight, of an inert excipient. If the inert excipient is contained in an amount of less than 2 parts by weight, stability may not be sufficiently obtained effectively. If the amount of the inert excipient is more than 10 parts by weight, the weight of the tablet may become excessively large, Can be. However, the inert excipient serves to assist the stabilizer, and may not be included when the stabilizer can achieve the desired stability.

Oral dosage form

The present invention provides an oral dosage form comprising the multiparticulates. Such oral dosage forms may be granules, sustained release tablets, compressed tablets, multiple compression tablets, and the like.

The oral administration formulations may further comprise a pharmaceutically acceptable carrier, additives, etc., alone or in admixture. The carriers and additives may be those generally used in the art in the formulations to be prepared.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

< Example  1-1 to 1-14> Pesoterodine Fumarate and Sugar alcohol  Or preparation of mixtures of inert excipients

Mix 45 mg of sugar alcohols or inert excipients sieved through a 45-well syringe with 5 mg of the pterotrophin fumarate salt , which is sieved through a No. 45 sieve, and put in a glass vial. The sugar alcohols or inert excipients corresponding to each example are shown in Table 1 below. In Table 1, the unit of weight is mg.

1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 One-
10 One-
11 One-
12 One-
13 One-
14 Fesoterodine fumarate 5 Xylitol 45 - - - - - - - - - - - - - Erythritol - 45 - - - - - - - - - - - - Inositol - - 45 - - - - - - - - - - - Ethyl cellulose - - - 45 - - - - - - - - - - Dibutylhydroxytoluene - - - - 45 - - - - - - - - - Butylhydroxyanisole - - - - - 45 - - - - - - - - Hi Prom Melos - - - - - - 45 - - - - - - - Xanthan gum - - - - - - - 45 - - - - - - Rudy Press - - - - - - - - 45 - - - - - Cell Lactose - - - - - - - - - 45 - - - - Talc - - - - - - - - - - 45 - - - Campfitol - - - - - - - - - - - 45 - - Fresh roll - - - - - - - - - - - - 45 - Magnesium stearate - - - - - - - - - - - - - 45 Total (total) 50

Stabilizers: xylitol, erythritol, inositol, campitol, fresh roll, dibutylhydroxytoluene, butylhydroxyanisole

Inert excipients: xanthan gum, ruddy press, celluloses, talc, ethyl cellulose, hiropromelose, magnesium stearate

< Example  2> Pesoterodine Fumarate and Sugar alcohol  Or preparation of tablets of inert excipients

45 Aliquots of the sugar alcohol or excipient sieved in the same conditions as the syrup of phe- thero-furan-fumarate (5 mg) are mixed together and placed in a glass vial. Store the glass vials for 60 ° C and 80% relative humidity. The sugar alcohols or excipients corresponding to each example are shown in Table 2 below. The mixture shown in Table 2 below was tableted using a hydraulic tablet press and a circular punch die under the conditions of 1 ton pressure.

2-1 2-2 2-3 2-4 2-5 Comparative Example 1 Fesoterodine fumarate 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg Xylitol 45 mg - - - - - Erythritol - 45 mg 45 mg 5 mg 5 mg - Butylhydroxyanisole - - 1 mg - 1 mg -

< Example  3> Pesoterodine Fumarate , Erythritol  And Rudy Press  Preparation of tablets containing

(Primary mixing)

4 mg of pethoterodin fumarate salt and 45 mg of erythritol were mixed for 1 minute, and the granules were poured in distilled water. The granules were dried at 60 DEG C for 3 hours, and sieved through a 30-well tumbler to obtain a total of 40 mg of the primary mixture.

(Secondary mixing)

40 mg of the above primary mixture and 120 mg of Rudy Press were mixed, sieved through a No. 30 sieve, and mixed for 15 minutes. 70 mg of Metholose 90SH, 70 mg of Metolose 60SH-4000 and 10 mg of Campitol were added and mixed for 5 minutes. Finally, 8.5 mg of talc , which had been sieved through a No. 60 sieve, was mixed for 3 minutes to obtain a second mixture.

* Metholose 90SH and Metholose 60SH-4000 are types of hydroxypropylmethylcellulose and are one kind of excipient.

(Tablet)

The secondary mixture was compressed through a hydraulic tablet press to a pressure of 1 ton. Tablets tableted through the above procedure are referred to as Example 3.

< Example  4> Pesoterodine Fumarate , Xylitol  And Rudy Press  Preparation of tablets containing

(Primary mixing)

Chyeonaen sieve sieve No. 45 fesoterodine 4 mg of fumaric acid salt and 36 mg of xylitol were mixed for 1 minute, and the granules were put in distilled water, and then sieved through an 18th tumbler. The granules were dried at 60 DEG C for 3 hours, and sieved through a 30-well tumbler to obtain a total of 40 mg of the primary mixture.

(Secondary mixing)

40 mg of the above primary mixture and 120 mg of Rudy Press were mixed, sieved through a No. 30 sieve, and mixed for 15 minutes. 70 mg of Metholose 90SH, 70 mg of Metolose 60SH-4000 and 10 mg of Campitol were added and mixed for 5 minutes. Finally, 8.5 mg of talc , which had been sieved through a No. 60 sieve, was mixed for 3 minutes to obtain a second mixture.

* Metholose 90SH and Metholose 60SH-4000 are types of hydroxypropylmethylcellulose and are one kind of excipient.

(Tablet)

The secondary mixture was compressed through a hydraulic tablet press to a pressure of 1 ton. Tablets tableted through the above procedure are referred to as Example 4.

< Example  5> Pesoterodine Fumarate , Erythritol  And Cellulose  Preparation of tablets containing

(Primary mixing)

4 mg of pethoterodin fumarate salt and 45 mg of erythritol were mixed for 1 minute, and the granules were poured in distilled water. The granules were dried at 60 DEG C for 3 hours, and sieved through a 30-well tumbler to obtain a total of 40 mg of the primary mixture.

(Secondary mixing)

The mixture of the primary cell and the mixture 40mg Lactose 121.5mg was mixed 15 minutes after hitting the material body No. 30. Metholose 90SH OSU to 70mg and metol 60SH - 4000 70mg and campitol 10mg were added and mixed for 5 minutes. Finally, 8.5 mg of talc , which had been sieved through a No. 60 sieve, was mixed for 3 minutes to obtain a second mixture.

* Metholose 90SH and Metholose 60SH-4000 are types of hydroxypropylmethylcellulose and are one kind of excipient.

(Tablet)

The secondary mixture was compressed through a hydraulic tablet press to a pressure of 1 ton. Tablets tableted through the above procedure are referred to as Example 5.

< Example  6> Pesoterodine Fumarate , Xylitol  And Cellulose  Preparation of tablets containing

(Primary mixing)

Chyeonaen sieve sieve No. 45 fesoterodine 4 mg of fumaric acid salt and 36 mg of xylitol were mixed for 1 minute, and the granules were put in distilled water, and then sieved through an 18th tumbler. The granules were dried at 60 DEG C for 3 hours, and sieved through a 30-well tumbler to obtain a total of 40 mg of the primary mixture.

(Secondary mixing)

The mixture of the primary cell and the mixture 40mg Lactose 121.5mg was mixed 15 minutes after hitting the material body No. 30. Metholose 90SH OSU to 70mg and metol 60SH - 4000 70mg, and was put to mix for 5 minutes Kam toll-free 10mg. Finally, 8.5 mg of talc , which had been sieved through a No. 60 sieve, was mixed for 3 minutes to obtain a second mixture.

* Metholose 90SH and Metholose 60SH-4000 are types of hydroxypropylmethylcellulose and are one kind of excipient.

(Tablet)

The secondary mixture was compressed through a hydraulic tablet press to a pressure of 1 ton. Tablets tableted through the above procedure are referred to as Example 6.

< Comparative Example  1> Pesoterodine Fumarate  refine

The pesoterodine fumarate salt tablet was prepared as Comparative Example 1.

< Comparative Example  2> Tobias  Sujung Jeong (Manufacturer: Pfizer)

4 mg of the Tobias sustained-release formulation was prepared as Comparative Example 2.

< Experimental Example  1> Example  Evaluation of the stability of the mixture prepared in 1-1 to 1-14

The mixture prepared in Examples 1-1 to 1-14 and the pesoterodine fumaric acid salt (not tableted) were respectively stored in glass vials and stored at 60 ° C and 80% relative humidity for 1, 3, 5, and 10 days The residual (undifferentiated) content of the pesoterodine fumarate salt after the decomposition was measured, and the results are shown in Table 3 below.

After 1 day 3 days later After 5 days After 10 days Fesoterodine fumarate 97.2 87.9 52.5 12.1 Example 1-1
(Xylitol) 99.7 93.4 83.3 63.1 Examples 1-2
(Erythritol) 98.7 73.0 54.5 26.9 Example 1-3
(Inositol) 93.3 88.4 51.4 21.7 Examples 1-4
(Ethylcellulose) 101.3 69.1 49.1 19.4 Examples 1-5
(Dibutylhydroxytoluene) 99 78.6 78.6 20 Examples 1-6
(Butylhydroxyanisole) 99.6 105.5 94.1 96.2 Examples 1-7
(Hi Prom Melos) 96.1 64.5 39.0 13.2 Examples 1-8
(Xanthan gum) 92.7 86.2 53.4 26.1 Examples 1-9
(Rudy Press) 95.5 82.8 55.5 27.1 Example 1-10
(Cell Lactose) 94.2 83.1 46.8 22.9 Example 1-11
(Talc) 94.7 79.0 51.4 25.5 Examples 1-12
(Campitol) 95.4 68.6 48.6 19.2 Examples 1-13
(Fresh roll) 98.6 68.6 46.9 20.1 Examples 1-14
(Magnesium stearate) 100 68.6 44.8 19.8

As shown in Table 3, the stability of the pesoterodine fumarate salt for 10 days from Examples 1-1 to 1-14 was confirmed. As a result, the 9: 1 ratio of butylhydroxyanisole to pesoterodine fumarate was most stable , Butylhydroxyanisole, the butylhydroxyanisole was excluded from the usable examples, since it exceeded the range of daily doses that can be administered to humans. Xylitol and erythritol were found to be effective in improving stability as 'stabilizers' to prevent degradation of pesoterodine fumarate.

< Experimental Example  2> Example  Evaluation of the stability of the tablets prepared in 2-1 to 2-5

Tablets prepared in Examples 2-1 to 2-5 and Comparative Example 1 (pterotrophin fumarate salt tablets) were stored for 1, 3, 5, and 10 days at a temperature of 60 ° C and a relative humidity of 80% The residual (undifferentiated) content of the fumarate salt was measured and the results are shown in Fig.

Fig. 1 shows the results obtained when the tablets prepared in Examples 2-1 to 2-5 and Comparative Example 1 (tablets of pterothelin fumarate) were stored at 60 DEG C and 80% relative humidity for 1, 3, 5 and 10 days, (Non-decomposed) content of the terodine fumarate salt without decomposition.

As shown in FIG. 1, when the mixture of erythritol and pesoterodine fumarate was mixed at a ratio of 9: 1, the residual amount of the undifferentiated pterotrophin fumarate salt was the highest. This is because the pesoterodine fumarate salt is not decomposed well after the compression and compression than in the case of the tablet prior to tableting in Experimental Example 1. In the case of pesoterodine fumarate mixed with erythritol, the compressed mixture greatly contributes to stability And it was found.

< Experimental Example  3> Evaluation of dissolution

The dissolution test was carried out using Comparative Example 2, Example 3 and Example 5. Using 900 mL of pH 6.8 buffer as the eluant, the mixture was subjected to 37 ° C and 75 rpm according to Method 2 of the Korean Pharmacopoeia dissolution assay. The elution time was up to 20 hours, and 5 mL of the eluate was taken at each time interval. The filtrate was filtered through a membrane filter with 0.45 μm pores and used as the sample solution. The results of this experiment are shown in Fig.

(HPLC analysis conditions)

- mobile phase: a solution of acetonitrile, water and trifluoroacetic acid in a ratio of 550: 450: 1, respectively, was used.

- Column: CN column (Spherisorb CN column or similar column) 250 x 4.0 mm

- Column temperature: 35 ° C

- Detector: UV 220nm

- Flow rate: 0.8 mL / min

- Injection amount: 50μm

2 is a graph showing the results of evaluations of the amounts of pesoterodin fumarate salts of Examples 3 and 5 and Comparative Example 2. Fig.

As shown in Fig. 2, it was confirmed that the dissolution amount similar to that of the pesoterodine fumarate salt similar to that of Comparative Example 2, which is commercially available in both Example 3 and Example 5 in which the type of excipient is different, is confirmed.

Claims (10)

Claims 1. A pharmaceutical composition comprising fesoterodine fumaric acid represented by the following formula (1) or a pharmaceutically acceptable salt thereof;
Erythritol as stabilizer; And
As an inert excipient, Ludipress or Cellactose,
8 to 10 parts by weight of a stabilizer relative to 1 part by weight of the pesoterodine fumaric acid or a pharmaceutically acceptable salt thereof,
And 2-4 parts by weight of an inert excipient relative to 1 part by weight of the total amount of the pesoterodine fumaric acid or a pharmaceutically acceptable salt thereof and the stabilizer.
[Chemical Formula 1]

delete delete delete delete delete delete An oral dosage form comprising the multiparticulate of claim 1.
9. The method of claim 8,
Wherein said oral administration form further comprises at least one selected from the group consisting of pharmaceutically acceptable carriers and additives.
9. The method of claim 8,
Wherein said oral dosage form is a granule, sustained release tablet, compressed tablet, or multiple compression tablet.

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