JP4691434B2 - Stabilized cabergoline solid formulation - Google Patents

Description

The present invention seeks to provide a stable oral solid preparation that does not lose its content due to degradation even during storage.

Cabergoline is an ergot alkaloid derivative that stimulates central nervous system dopamine receptors and is therefore used to treat Parkinson's disease. It acts on the dopamine receptors in the anterior pituitary gland and exhibits antiprolactin action on the endocrine system. Therefore, it is used to suppress milk secretion.

In general, ergot alkaloid derivatives are gradually colored by light, are unstable to heat and humidity, and are easily affected by pharmaceutical additives. Since the ergot alkaloid derivative is a substance having a strong physiological activity, it is often a micro-form preparation, and for the accurate administration, a decrease in the content of the active ingredient due to the above-mentioned unstable factors must be avoided.

For example, Cabasar tablets (Pfizer Co., Ltd./Kissei Pharmaceutical Co., Ltd.) are uncoated tablets consisting only of cabergoline, anhydrous lactose and L-leucine, and have a formulation that suppresses the influence of additives as much as possible. In the international publication WO2002 / 49608, the cabergoline is particularly unstable to humidity, so granulation in a non-aqueous system and an organic acid selected from citric acid, tartaric acid, maleic acid, glycine, lysine, methanesulfonic acid and leucine It is disclosed that a stable cabergoline oral preparation can be obtained by addition. However, in view of the instability of cabergoline, a better formulation was needed.

The present invention is intended to provide an oral solid preparation excellent in storage stability.

Conventionally, mannitol is a known substance as an excipient, and talc is a known substance as a lubricant. However, it is not known at all that a cabergoline solid preparation with improved storage stability against humidity can be obtained when these are used. It was. In other words, in addition to the discovery that a solid preparation containing cabergoline and mannitol is stable against humidity,
Furthermore, the present invention was completed by finding that a solid preparation containing talc as an excipient rather than as a lubricant exhibits even better stability against humidity.

The cabergoline of the present invention includes pharmaceutically acceptable salts thereof. Mannitol, talc and L-leucine are not particularly limited as long as they are used for oral solid preparations. Although the theory of mannitol is not limited, it is considered that cabergoline is incorporated into the pore structure and the physical stability is increased. Therefore, mannitol having an appropriate pore size can be selected in consideration of the balance between the pore size and the particle size of cabergoline. For example, a combination of mannitol having a median diameter of about 100 μm is suitable for cabergoline ground to 20 μm or less.

The amount of each component may be adjusted as appropriate according to the purpose. For example, mannitol is 50 to 97% by weight, preferably 85 to 95% by weight, based on the formulation weight. Talc is preferably 0.05 to 10% by weight, particularly 1 to 5% by weight in the preparation when mixed with the granulating component. Moreover, it can also use together with L-leucine as a lubricant.

The preparation of the present invention can be produced by a conventional method, and talc is added to a mixed powder obtained by adding appropriate additives such as excipients to the main drug and, if necessary, powdered binders and disintegrants. Alternatively, tableting may be performed directly after mixing with a granulator, or tableting may be performed after mixing talc with granules for tableting obtained by an appropriate granulation method. If a tablet is demonstrated as an example, it can carry out by tableting the granule for tableting obtained with the appropriate granulation method. For example, in the case of the dry granulation method, cabergoline, mannitol and talc are pulverized and then compressed to produce a molded body. The obtained solidified product is pulverized with a pulverizer so as to have a desired particle size, and sized with a granulator. A lubricant is added to the obtained granules for tableting, and after mixing gently, tablets are obtained by tableting.

A solid preparation in which mannitol is blended with cabergoline and talc is blended not as a lubricant but as an excipient provides a tablet having excellent stability against humidity.

Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples, and Test Examples.
Example 1
Cabergoline 0.25mg in a tablet
Mannitol 74.58mg
Talc 1.67mg
L-leucine 3.5mg
80mg total

The main drug, a part of mannitol, and talc are mixed and placed in a granulator and sized. This sized product and the remaining mannitol are placed in a Boule mixer and mixed for 15 minutes. After mixing, L-leucine is added and mixed, and the mixture is directly tableted with a rotary tableting machine (diameter 5.5 mm, tableting pressure 4.0 to 4.2 kN) to obtain 80 mg tablets per tablet. .

Comparative Example 1
Cabergoline 0.25mg in a tablet
Mannitol 76.25mg
L-leucine 3.5mg
80mg total

Same as Example 1, except that the talc is not added in Example 1.

Comparative Example 2
Cabergoline 0.25mg in a tablet
Anhydrous lactose 76.25mg
L-leucine 3.5mg
80mg total

Same as Example 1 except that talc was not added and mannitol was changed to anhydrous lactose in Example 1.

Stability test The obtained preparation was made into a PTP package, stored at 40 ° C. and 75% RH for 2 weeks, and a degradation product of cabergoline contained in the tablet 1-[(6aR, 9R, 10aR) -7-allyl-4, The amount of 6,6a, 7,8,9,10,10a-octahydroindolo [4,3-fg] quinoline-9-carboxylic acid (hereinafter referred to as IMP-1) was measured by high performance liquid chromatography. .

As shown in Table 1, in the preparation (Example 1) of the present invention containing mannitol and talc, the production of the degradation product IMP-1 is suppressed. In the preparation containing no talc (Comparative Example 1), about twice as much IMP-1 was produced as compared with the preparation of the present invention, the effect of talc on humidity can be confirmed. In the preparation (Comparative Example 2) in which mannitol is changed to anhydrous lactose and talc is not blended, IMP-1 is produced about 6 times as compared with the preparation of the present invention. It was confirmed that excellent stability was exhibited.

Claims (2)

A stable oral solid preparation comprising cabergoline mixed with mannitol and talc, mixed with L-leucine as a lubricant, and directly compressed .   The stable oral solid preparation according to claim 1, wherein the amount of talc is 0.05 to 10% by weight based on 1 part by weight of the preparation.