JP2009091292A - Tablet of temocapril hydrochloride with excellent preservation stability - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet of temocapril hydrochloride stable at a high temperature and high humidity comprising combination of temocapril hydrochloride which is a principal ingredient, with other adjuvants such as a vehicle, a binder, a disintegrant, a lubricant, etc. <P>SOLUTION: The tablet of temocapril hydrochloride consisting of the temocapril hydrochloride as the principal ingredient, a stearic acid and/or L-leucine as a lubricant, lactose or D-mannitol as a preferable vehicle, hydroxypropyl cellulose as a binder, and a low substituted hydroxypropyl cellulose as a disintegrant, is stable at a high temperature and high humidity. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a temocapril hydrochloride tablet having excellent storage stability even under high temperature and high humidity.

Some angiotensin converting enzyme (ACE) inhibitors used as therapeutic agents for hypertension and the like are known to be unstable depending on humidity and temperature (Leo Gu, et al. Pharmaceutical Research). 7 (4) 379 (1990)).
In particular, the compound (2S, 6R)-[[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] amino] tetrahydro-5-oxo-2- (2-thienyl) used as an ACE inhibitor 1,4-thiazepine-4 (5H) -acetic acid / hydrochloride (generic name: temocapril hydrochloride) has a property that decomposition is likely to proceed under high temperature and high humidity.
This temocapril hydrochloride is usually provided in the form of tablets. When manufacturing tablets, direct compression or rolling granulation using excipients, binders, disintegrants, lubricants, etc. as active ingredients. Prepared by law.
However, if the active ingredient is an unstable compound, the chemical interaction with the auxiliaries accelerates the decomposition of the active ingredient, and the auxiliaries interact with each other, resulting in adverse effects on the active ingredient. It is also known that this tendency is further promoted at high humidity and high temperature.

In the case of producing a tablet, an auxiliary agent usually used as an excipient includes celluloses. However, these celluloses are highly hygroscopic and have a fairly high equilibrium moisture value in a normal environment such as an environment such as 25 ° C. and 60% RH. For this reason, if an amount of cellulose that can maintain the moldability of the preparation is prescribed, the water content in the preparation inevitably increases, and furthermore, depending on the storage environment of the preparation, the influence of temperature is further added. A preparation containing a compound unstable to humidity as a main agent has a drawback that the decomposition of the main agent is accelerated.
Therefore, as a method of stabilizing the ACE inhibitor in the preparation, a method of suppressing the decomposition of the active ingredient by blending an alkaline metal salt (Patent Documents 1 and 2) A method of blending a lipophilic component (Patent Documents 3 and 4) ) And a method of blending silicate (Patent Document 5) and the like have been proposed.

JP-A-63-225322 Japanese translation of PCT publication No. 2002-516881 JP 2000-264843 A Japanese Patent Laid-Open No. 2001-131068 However, all of these reports relate to ACE inhibitors having a chemical structure different from that of temocapril, such as enalapril maleate and quinapril hydrochloride.

In general, when preparing tablets, auxiliary agents such as excipients, binders, disintegrants, lubricants, etc. are used in addition to the active ingredient, and in some cases, pigments, antioxidants, stabilizers, etc. are added. .
Therefore, first, a blending change test was conducted in which temocapril hydrochloride and various additives were mixed and sieved, and the resulting powder was stored under high temperature and high humidity conditions of 60 ° C. and 60% RH. Contrary to 2 and 5, alkaline metal salts and silicates were found to tend to cause an increase in the amount of temocapril hydrochloride hydrolyzate and discoloration.
Therefore, when tablets were prepared using other commonly used auxiliaries, and their stability to temperature and humidity and disintegration were examined, croscarmellose sodium, carmellose calcium and carboxymethyl starch sodium were disintegrants. It has also been found that auxiliaries containing metals such as the lubricants magnesium stearate and calcium stearate also destabilize temocapril hydrochloride.
However, when stearic acid and / or L-leucine was used as a lubricant, it was found that neither a decrease in the content of the main agent nor an increase in degradation products was observed even under high temperature and high humidity conditions. Furthermore, when lactose or mannitol is used as an excipient, hydroxypropylcellulose (HPC) is used as a binder, and low-substituted hydroxypropylcellulose is used as a disintegrant, the disintegration of the tablet is further improved, and the disintegration time is greatly increased. Improved.

  As described above, the present inventors have conducted intensive studies on a prescription for providing an unstable main drug of the present invention that is easily decomposed by humidity and temperature as a stable tablet, and as a result, selects a specific lubricant. In addition, we obtained the knowledge that more stable tablets can be obtained by selecting certain kinds of excipients, binders, disintegrants, etc., and further research based on these findings As a result, the present invention was completed.

That is, the present invention
(1)
Excellent storage stability, characterized by using stearic acid and / L-leucine as a lubricant in tablets containing temocapril hydrochloride as the active ingredient and excipients, disintegrants, binders and lubricants Temocapril hydrochloride tablets,
(2)
The tablet according to (1), wherein the amount of stearic acid and / or L-leucine used is 0.5 to 10% by weight based on the preparation,
(3)
The excipient according to (1), wherein the excipient is lactose hydrate or D-mannitol,
(4)
The tablet according to (1), wherein the disintegrant is low-substituted hydroxypropylcellulose;
(5)
The tablet according to (1), wherein the binder is hydroxypropylcellulose;
(6)
A method for stabilizing temocapril hydrochloride-containing tablets, wherein stearic acid and / or L-leucine is used as a lubricant for tablets containing temocapril hydrochloride as the active ingredient,
It is about.

The present invention is described in detail below.
The main ingredient of the tablet of the present invention is temocapril hydrochloride effective as an ACE inhibitor, which is a compound that is unstable under high temperature and high humidity. In the present invention, the term “high temperature” includes from a temperature slightly higher than room temperature to a higher temperature including room temperature. Further, high humidity refers to a case where the relative humidity exceeds 80% at room temperature, for example.

  The (1S) -1-ethoxycarbonyl ester moiety of temocapril hydrochloride described in JP-B-05-59909 is relatively easily hydrolyzed under high temperature and high humidity to change into a carboxyl form having low oral absorption. . The present invention relates to a preparation that suppresses such decomposition of temocapril hydrochloride and enhances storage stability, and a method for stabilizing the same.

Next, the stabilizer component used in the present invention will be described.

  In the present invention, stearic acid and / or L-leucine is used as a lubricant, and the blending amount thereof is 0.5 to 10% by weight, preferably 1 to 6% by weight in the preparation.

In the tablet of the present invention, when a specific excipient, a disintegrant and a binder aid are used in addition to the lubricant, the tablet can be made more stable and more disintegratable.
The excipient is an additive for increasing the volume, and generally includes sugars (lactose, mannitol), starches (corn starch, partially pregelatinized starch), celluloses (crystalline cellulose) and the like. In the present invention, lactose or mannitol is preferred. The blending amount is 25 to 90% by weight, preferably 70 to 90% by weight, based on the preparation.

  A disintegrant is a component for promoting rapid disintegration of a solid preparation after taking a tablet, and low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, etc. are generally used. In the present invention, low-substituted hydroxypropylcellulose is used. The blending amount is suitably 5 to 15% by weight in the tablet.

  The binder is an additive for strengthening the bond between particles and improving fluidity and uniformity, and generally includes hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol and the like. Hydroxypropylcellulose is preferably used. The blending amount is 1 to 15% by weight, preferably 3 to 6% by weight in the tablet.

If necessary, a stabilizer can be further blended. In the present invention, a compound not containing a metal salt, for example, benzoic acid, is preferred because it does not change the appearance (colorability). The blending amount is 0.1 to 1% by weight in the tablet, preferably 0.5 to 5% by weight.
Each of the above auxiliaries is not particularly problematic when used alone, but when combined, it may react with each other and cause unexpected results.
In any case, the main drug temocapril hydrochloride is an unstable compound, and some decomposition and discoloration during storage cannot be avoided.
In addition, even if a sufficient amount of the main ingredient remains, since the product value of the tablet with a significant change in the appearance due to discoloration of the main ingredient decreases, the lubricant that directly affects the change in appearance color from that point. The choice is important.
If necessary, pigments, fragrances, antioxidants, and the like can be further blended with these auxiliaries.

  The compounding amount of temocapril hydrochloride, which is the main drug, can be contained in an amount of 0.5 to 4 mg per unit of preparation. The dosage of the excipient, disintegrant, binder and lubricant contained in the tablet of the present invention is 5 to 90% by weight of the excipient, preferably 70 to 90% by weight, and 5 to 15% by weight of the disintegrant. The binder is 3 to 6% by weight and the lubricant is 1 to 6% by weight.

An example of the method for producing a stable tablet of the present invention will be described.
Lactose hydrate or D-mannitol, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and stearic acid or L-leucine are added to temocapril hydrochloride, for example, a tumbler mixer, a V-type mixer or a high-speed stirring mixer Mix using a mixer. The obtained mixed powder is tableted by a tableting machine such as a single tableting machine to obtain tablets. In order to make the individual components of the mixed powder uniform, the mixing order may be changed, or some components may be once granulated using an appropriate granulator and then mixed with other components. it can.

In the case of industrial production, the same method as described above is used, but an appropriate mixer such as a V-type mixer or a high-speed stirring mixer having a different capacity depending on the target production scale is used.
The final tablet can be manufactured through the tableting process.

  Tablets containing temocapril hydrochloride as the active ingredient of the present invention and stearic acid and / or L-leucine as a lubricant have a low decomposition rate of the active ingredient even under high temperature and high humidity. Furthermore, when lactose mannitol is used as an excipient, hydroxypropylcellulose is used as a binder, and low-substituted hydroxypropylcellulose is used as a disintegrant, the disintegration of the tablet is further improved and the disintegration time is greatly improved.

  The present invention will be specifically described below with reference to test examples, examples and comparative examples.

[Test Example 1]
Stability test of main agent against various auxiliaries First, in order to see the stability of various auxiliaries to temocapril hydrochloride, add the temocapril hydrochloride and the auxiliaries listed in Table 1 in an agate mortar and mix well. Sieve with a No. sieve. This was repeated twice to prepare a sample.
Each sample was stored in an environment of 60 ° C. and 60 RH for 2 weeks, and the residual ratio of the main drug in the samples in the first week and the second week was measured by HPLC, and the color change was measured visually and by a color difference meter. It described in Table 1.

この試験の結果から次の事実が判明した。
（１）賦形剤は錠剤の成分中大部分を占めるものであるが、デンプンより、乳糖水和物、Ｄ−マンニトールの方が主薬の安定性、外観において優れていた。
（２）結合剤はヒドロキシプロピルセルロースがよく、他は主薬の安定性、外観変化にやや劣る結果となった。
（３）崩壊剤、低置換度ヒドロキシプロピルセルロースが特に優れていた。
（４）安定化剤としては、金属含有化合物が主薬の安定性、外観ともに劣る結果となり、金属を含まない安息香酸がよい結果を示した。
（５）滑沢剤は、錠剤の外観に直接影響を与える成分であるので色状の変化に注目した。安定化剤と同様にステアリン酸等の金属塩はいずれもかなり変色の度合いが大きかった。可塑剤として汎用されるポリエチレングリコールは固結してしまった。
これに対しステアリン酸およびＬ−ロイシンは主薬の安定性に優れ、着色変化も少なく、良好な結果を与えた。
２）錠剤の安定性
上記１）配合変化試験の結果を踏まえ、乳糖マンニトール、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、および滑沢剤としてステアリン酸および／又はＬ−ロイシンを使用し、下記の製造方法により錠剤を調製した。得られた錠剤について、加温加湿条件（６０℃、６０％ＲＨ）下の安定性試験を行った。

The following facts were found from the results of this test.
(1) Although the excipient occupies most of the components of the tablet, lactose hydrate and D-mannitol were superior in starch stability and appearance to starch.
(2) The binder was hydroxypropylcellulose, and the others were slightly inferior to the stability of the active ingredient and the appearance change.
(3) Disintegrants and low-substituted hydroxypropylcellulose were particularly excellent.
(4) As a stabilizer, the metal-containing compound was inferior in both stability and appearance of the main agent, and benzoic acid containing no metal showed good results.
(5) Since the lubricant is a component that directly affects the appearance of the tablet, attention was paid to the color change. Similar to the stabilizer, all of the metal salts such as stearic acid had a considerable degree of discoloration. Polyethylene glycol, which is widely used as a plasticizer, has consolidated.
On the other hand, stearic acid and L-leucine were excellent in the stability of the main agent, had little color change, and gave good results.
2) Stability of tablets Based on the results of the above 1) compounding change test, lactose mannitol, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and stearic acid and / or L-leucine as a lubricant were used. Tablets were prepared by the manufacturing method. The obtained tablets were subjected to a stability test under heating and humidification conditions (60 ° C., 60% RH).

[Test formulation] 3 g of temocapril hydrochloride, a suitable amount of lactose hydrate or D-mannitol, and 30 g of low-substituted hydroxypropylcellulose were mixed in a high speed mixer for 3 minutes. Next, an aqueous hydroxypropylcellulose solution (solid content: 10.5 g) was added and granulated by a wet kneading method using a high speed mixer. The obtained granulated product was dried and sized at 60 ° C., added with stearic acid and / or L-leucine, mixed for 7 minutes with a V-type mixer to obtain 300 g of powder before tableting. This powder was tableted with a single tableting machine (compression pressure of about 800 kg) to produce a tablet with a thickness of about 2.30 mm, a diameter of about 6.5 mm, and a weight of about 100 mg.
Instead of stearic acid or L-leucine, tablets were prepared in the same manner using Mg stearate, hydrogenated oil, or sucrose fatty acid ester as a comparative example.
The adjusted tablet composition is listed in Table 2.

[Test method] After storing each tablet in an environment of 60 ° C and 60% RH for 2 weeks, the content of the active ingredient and the amount of hydrolyzate in the tablet are measured by the HPLC method, and the color difference of the tablet and the disintegration time in water are measured. evaluated.
The test results are shown in Table 3.

[Test Results] Comparative tablets containing Mg stearate showed significant discoloration, and the main drug content in the tablets was greatly reduced to about 60%, and the amount of hydrolyzate was increased to 25% of the main drug. In addition, tablets containing hydrogenated oil and sucrose fatty acid ester are able to suppress tablet disintegration time and degradation of the active ingredient, but the tablet disintegration time is significantly delayed from 2-3 minutes immediately after production to 10 minutes or 30 minutes. It was.
On the other hand, it was found that the tablet to which stearic acid and / or L-leucine was added was an excellent preparation in which a decrease in the main drug content and an increase in the amount of hydrolyzate were suppressed, and there was no tablet disintegration delay.

  Since the temocapril hydrochloride tablet of the present invention is stable even at high temperatures and high humidity, it can be stored at normal temperature and humidity in hospitals and pharmacies. In addition, when a patient takes a prescribed medicine home, the main drug will not be decomposed within one month even if it is stored in a room temperature room. Can do.

Claims (6)

  Storage stability characterized by the use of stearic acid and / or L-leucine as a lubricant in a tablet comprising temocapril hydrochloride as the main ingredient and excipients, disintegrants, binders and lubricants Excellent temocapril hydrochloride tablets.   The tablet of Claim 1 whose usage-amount of a stearic acid and / or L-leucine is 0.5-20 weight% with respect to a formulation.   The tablet according to claim 1, wherein the excipient is lactose hydrate or D-mannitol.   The tablet according to claim 1, wherein the disintegrant is a low-substituted hydroxypropylcellulose.   The tablet according to claim 1, wherein the binder is hydroxypropylcellulose.   A method for stabilizing a temocapril hydrochloride-containing tablet, wherein stearic acid and / or L-leucine is used as a lubricant in a tablet containing temocapril hydrochloride as a main drug.