JP2010059060A - Carnitine-containing preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stabilized carnitine-containing preparation with improved hygroscopicity so as to solve the problem that carnitine or a salt or derivative thereof produces trimethylamine upon deliquescence, deterioration by temperature or alkaline degradation and emits strong odor in small amounts. <P>SOLUTION: The carnitine-containing preparation with improved shelf stability as a preparation or food product is obtained by adding 5-6 wt.% porous starch to carnitine or a salt or derivative thereof so as to form a stabilized powder with reduced hygroscopicity. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a carnitine-containing preparation.

L-carnitine is a biological trace component made by the liver and kidney from two amino acids called lysine and methionine, and its production amount is known to decrease with age at the peak of 20s. L-carnitine plays an important role in the metabolism of nutritional components such as delivery of long-chain fatty acids to muscle cells, and was used as a pharmaceutical in Japan, but has been approved for use as a food since December 2002. Therefore, “so-called health foods” that focus on the physiological function of L-carnitine, which has an important role in fatty acid combustion in the body, are attracting attention as diet foods that are expected to have a body fat burning effect. The Ministry of Health, Labor and Welfare sets a standard amount of upper limit of intake per day to about 1000 mg. The physiological effectiveness of L-carnitine in humans is to improve renal function, improve thyroid function, alleviate carnitine deficiency with valproic acid, an anticonvulsant (antiepileptic drug), and effective against carnitine deficiency due to congenital metabolic disorders Many clinical uses of L-carnitine, such as sex, are often administered to compensate for deficiencies. L-carnitine has long been used as a drug and is also a biological component, so it is considered that no major safety problems arise.
Recently, for the purpose of appropriately taking L-carnitine, it has been used in foods and beverages or food and beverage compositions such as dietary supplements, diet products, and health foods. Many supplements containing carnitine have a daily intake of 500 to 600 mg as a guide. On the other hand, carnitine is a highly hygroscopic substance, so the content of other ingredients such as excipients is high to ensure stability. It is the actual situation that will be done.
Substances with high hygroscopicity such as carnitine, when moisture absorption occurs during production, causes problems such as change in flow characteristics, increase in stickiness, occurrence of aggregation, decrease in releasability, and handling becomes difficult. Chemical stability may decrease and the composition of raw materials and products may fluctuate. In addition, when moisture absorption occurs during storage, problems such as deterioration in appearance, chemical stability of the active ingredient contained, and changes in dissolution characteristics due to changes in crystal form may occur. There is a device to improve.

  Various methods for resolving hygroscopicity and deliquescence have been proposed for hygroscopic powder raw materials that are difficult to handle at the time of production and use, such as organic acid or inorganic acid salts, inorganic salts and chemicals used in pharmaceuticals, etc. ing. For example, a method for preventing deliquescence and caking by adding powdered fat and calcium carbonate to a powdered product (Patent Document 1), a method for preventing caking by adding sucrose fatty acid ester (Patent Document 2) , A method of adsorbing a deliquescent substance to an adsorbent substance to prevent deliquescence (Patent Document 3), a powder improved product obtained by coating a hygroscopic powder raw material with an enteric coating agent (Patent Document 4), and changing the crystal form A method of slowing deliquescence by this (Patent Document 5) and the like are disclosed.

Various ideas have been proposed to suppress and stabilize the hygroscopic property of L-carnitine having high hygroscopic property and extremely low stability.
Patent Document 6 proposes a moisture absorption suppressing method using L-carnitine L-tartrate instead of L-carnitine. L-carnitine L-tartrate is a white crystal containing 68% carnitine (Chemical Formula 1), and is considered to be more stable than L-carnitine.
However, it still has very high hygroscopicity and deliquescence, and absorbs and deliquesces in an environment with a humidity of 25% and a humidity of 63% or higher, and its moisture absorption rate is very high. Carnitine or a salt thereof or a derivative thereof generates trimethylamine by deliquescence, deterioration due to temperature, or decomposition under alkali, and generates a strong odor in a small amount. L-carnitine L-tartrate also produces a similar malodor due to moisture absorption.

When producing a preparation containing a high amount of powder hygroscopic active ingredient such as L-carnitine L-tartrate, the preparation obtained as described above may be discolored or denatured due to its high hygroscopicity. It is regarded as a problem. Such problems may be solved by increasing the amount of excipient. However, if the amount of excipient is increased, the amount consumed per day becomes very large. It is desirable to reduce the blending amount other than as much as possible.
Patent Document 7 (Japanese Patent Laid-Open No. 2007-244270) proposes to suppress the hygroscopicity of L-carnitine L-tartrate by adding sesamin to tablets and granules. However, specifically, in addition to sesamin, a large amount of excipient is necessary, which does not enable high compounding.
Patent Document 8 (Japanese Patent Application Laid-Open No. 2004-135515) discloses a moisture absorption suppressing effect by the calcium acetate addition method, but is effective at an addition amount of 10 to 95% by weight, and less effective at 10% by weight or less. Therefore, it is not suitable for high blending.
Patent Document 9 (Japanese Patent Application Laid-Open No. 2006-111550) proposes a method of coating a carnitine-containing preparation (tablet) with shellac and further covering with a yeast wrap to prevent moisture, but it is difficult to be convenient. It is.
Patent Document 10 (Republished No. 2006-28068) discloses that crude crystal L-carnitine is dissolved in a mixed solvent of lower alkyl alcohol and water and then recrystallized to reduce the hygroscopicity by increasing the particle size. L-carnitine has been disclosed.

JP 2001-224319 A JP 2004-121175 A Japanese Patent Laid-Open No. 2003-95980 JP 2004-35505 A JP 2000-342902 A Japanese Patent No. 2546068 JP 2007-244270 JP 2004-135515 A JP 2006-111550 A Republished 2006-28068

  The present invention provides carnitine that has high hygroscopicity, has deliquescence, and has stabilized carnitine or a salt thereof or a derivative thereof that easily becomes hygroscopic and liquid under high temperature and high humidity without blending a large amount of excipients. It is an object to provide a high-content preparation.

The main configuration of the present invention is as follows.
(1) A carnitine-containing preparation comprising carnitine or a salt thereof or a derivative thereof and porous starch.
(2) A carnitine-containing preparation comprising carnitine or a salt thereof or a derivative thereof and porous starch.
(3) The carnitine-containing preparation according to (1) or (2), wherein the porous starch is a porous dextrin.
(4) Carnitine content according to any one of (1) to (3), wherein the content ratio is carnitine or a salt thereof or a derivative thereof: porous starch = 80 to 95:20 to 5 Formulation.
(5) The carnitine-containing preparation according to any one of (1) to (4), wherein the preparation is in a powder form with improved hygroscopicity.
(6) The carnitine-containing preparation according to any one of (1) to (5), wherein the carnitine or a salt thereof or a derivative thereof is L-carnitine L-tartrate.

In the present invention, the stability of carnitine or a salt thereof or a derivative thereof is greatly improved by blending porous starch, and a high blending of 90% or more can be realized. A porous dextrin is preferred as the porous starch. As the carnitine salt, L-carnitine L-tartrate is preferred. Porous starch is only 5 to 6% by weight, and is characterized by a very simple and inexpensive method.
Since carnitine can be handled as a stabilized powder, storage stability as a raw material, improved handling of the manufacturing process, and storage stability as a preparation or food product are improved. Since the hygroscopicity is suppressed and stabilized, the mixing operation with other agents is easy and a uniform compounding agent can be obtained. The dosage form for oral intake that satisfies the recommended intake of carnitine can be reduced in size, and the intake becomes easier. It is particularly suitable for elderly people with weak swallowing power.

  The carnitine-containing preparation of the present invention comprises carnitine or a salt thereof or a derivative thereof and a porous starch, thereby providing a powder state in which hygroscopicity is suppressed and stabilized. By utilizing this stabilized powder state, it is possible to easily perform uniform mixing with other agents and process control of formulation, and provide a small and small-sized dosage form.

  Carnitine or a salt thereof or a derivative thereof includes carnitine [(CH3) 3N + CH2CH (OH) CH2COO-, γ-trimethylammonium-β-hydroxybutyric acid], its isomer, its salt, and carnitine, its isomer and its derivative Also included are derivatives of salts (for example, derivatives that are converted to carnitine in vivo). For example, carnitine, L-carnitine, carnitine chloride (DL-form, L-form), L-carnitine tartrate, L-carnitine L-tartrate, L-carnitine maleate, L-carnitine fumarate, L-carnitine Examples include sulfate, L-carnitine oxalate, L-carnitine magnesium salt, acyl-L-carnitine, acetyl-L-carnitine, propionyl-L-carnitine, carnitine orotate, and the like. These are not limited to the production method, and any of natural extracts, microbial fermentation products, and synthetic products may be used. Preferably, L-carnitine, a salt thereof, or a derivative thereof exists in nature. :

(In the formula, R is H or C1-C5 lower alkanoyl.)
It is represented by Note that the description of carnitine in the present specification also applies to a carnitine salt, carnitine or a salt derivative thereof.

Porous starch has shape characteristics in which numerous fine pores are formed on the surface of starch particles such as corn, potato, tapioca, and wheat.
In particular, porous dextrin is suitable. “Porous dextrin” has a shape characteristic in which innumerable micropores are formed on the surface of starch particles such as corn, potato, tapioca, and wheat by causing an enzyme to act.
Dextrin is a general term for degradation products obtained by degrading starch with acid or amylase, and includes amylodextrin, maltodextrin, erythrodextrin and the like. Porous dextrin can be obtained by placing a dextrin solution on a roller heated strongly and instantly evaporating the solvent. Examples of commercially available porous dextrin used in the present invention include Pine Flow and Pine Flow S (both manufactured by Matsutani Chemical Co., Ltd.).

A carnitine-containing preparation comprising a carnitine porous or a salt thereof or a derivative thereof and a porous starch has a content ratio of carnitine or a salt thereof or a derivative thereof: porous starch = 80 to 95:20 to 5 in a weight ratio. can do.
The present invention can be provided as a stable powder with improved hygroscopicity, and can be formulated by adding other agents as necessary. INDUSTRIAL APPLICABILITY The present invention can be used for conventionally used pharmaceutical or food / beverage products or food / beverage food compositions such as dietary supplements, diet products, and health foods.

It is suitable for the type that is taken orally as a miniaturized hard capsule. A stable hard capsule preparation can be produced while containing 92% of L-carnitine L-tartrate in a high proportion. For example, the product of the present invention can sufficiently take L-carnitine of 600 mg or more as a guide with No. 2 hard capsules × 3 capsules. No. 2 hard capsule can contain about 320 mg, so by filling a carnitine-containing preparation containing 92% by weight of L-carnitine L-tartrate containing 68% of L-carnitine, the equivalent amount of L-carnitine Can be made into one 200 mg / 2 hard capsule.
In addition, in the conventional product, it is necessary to mix many excipients in order to ensure moisture resistance, and the amount of L-carnitine L-tartrate is about 70% by weight at most and the capsule is large (No. 1) or Currently, the number of grains is large (4 grains or more). Carnitine such as L-carnitine L-tartrate is very hygroscopic and deliquescent, and easily becomes hygroscopic and liquid under high temperature and high humidity. It was necessary to impart a high level of functionality, and by adding a large amount of excipients, the size of tablets and capsules increased, or the number increased, which was a big negative in terms of ease of drinking. In the present invention, it is a small capsule and the number of ingested grains can be reduced.

In this specification, “hygroscopicity” refers to the property of capturing water vapor in the atmosphere when an object is exposed to the air. In particular, an aqueous solution that captures water vapor in the atmosphere, called deliquescence. This property is also included in the “hygroscopicity” in the present specification.
Hygroscopicity can be measured and / or evaluated using techniques known to those skilled in the art, for example, as described in the examples below. Specifically, the measured raw material is allowed to stand for a suitable time under certain conditions such as room temperature or high temperature and high humidity, and then visually observed for changes (confirmation of moisture on the raw material surface, confirmation of disappearance of solids, powder flow For example, confirmation of the degree of solidification and solidification, confirmation of discoloration, etc.) and measurement by measuring the weight increase (amount of absorbed water).
In this specification, “stabilization” does not only mean that deliquescence and / or caking due to moisture absorption is prevented, but no occurrence of discoloration or off-flavor (bad odor) is observed. It means that there is no problem in use as an external preparation.

L-carnitine L-tartrate (manufactured by LONZA) 92.0% by weight finely pulverized product, 2.0% by weight of Ryoto Sugar Ester S-370FU as a lubricant, 2 types as examples, 9 as comparative examples The seed excipients were weighed and sieved to 6.0% by weight, mixed for 10 minutes in a V-type mixer, and the mixed powder was filled into a transparent No. 2 NP hard capsule (manufactured by Capsugel).
Put 5 filled capsules in a polyethylene zipper bag and store them in an incubator kept at high temperature and high humidity (40 ° C, relative humidity 75%) to determine the number of days until product value is lost due to moisture absorption, deliquescence, and deterioration. Compared.
“Days until product value is lost” as described here is used as an oral or external preparation in terms of quality due to the occurrence of deliquescence and / or solidification due to moisture absorption, or the occurrence of discoloration and off-flavor (odor). It means that there is a problem.
The filled capsules were sealed in an aluminum bag and stored in an incubator at 60 ° C., and the appearance and odor after one week were compared.
Furthermore, regarding the pH, bulk, specific surface area, and starch degradation product of each excipient, the average molecular weight was measured.
As an example, the improvement of carnitine hygroscopicity was evaluated using a porous starch degradation product as a comparative example, and using a porous excipient or starch degradation product, starch, and an excipient frequently used in formulation.
Each test example and evaluation results are shown in Table 1.

(result)
Scallop powder and eggshell calcium provide high moisture resistance, but gas was generated by the reaction with L-carnitine L-tartrate, the capsule was removed, and the stability was greatly impaired.
In addition, although the carnitine used as the fat-and-oil coat and what carried out fluidized-bed granulation with the excipient | filler were examined, the moisture-proof effect was hardly seen. In addition, even when L-carnitine L-tartrate was used as a crystal without being pulverized, there was almost no difference in deliquescence and hygroscopicity compared to finely pulverized products.
Various studies were made on starch and starch degradation products, but the results differed greatly depending on physical properties such as pH and bulk. There were various types of products that showed little effect and high effect. However, as a result of investigation, porous dextrin (product name: Pine Flow, Pine Flow S) with a pH near acidity and a bulk of 0.3 g / mL or less was found. It has been found that the most stable and moisture-proof property can be imparted, and that L-carnitine L-tartrate can be highly formulated and the quality can be improved.
In addition, the conditions of 40 ° C. relative humidity 75% and polyethylene chuck bag, which are the test conditions, are very severe, and it is unlikely that such temperature and humidity conditions will occur throughout the year in Japan. In fact, cellulose, which is a common excipient, had a storage period of 3 days under the test conditions, but this number of days was from the hot and humid rainy season in Japan to the summer in the case of an aluminum chuck bag. This corresponds to the number of days for which the product value can be maintained for 3 to 4 months. However, depending on the conditions of use, such as forgetting to close the chuck, using it with wet hands, or damaging the aluminum packaging material, sticking, melting, or foul odor may occur within a few weeks to a month. Therefore, it is considered that higher quality such as imparting moisture resistance and improving stability can be secured by enabling storage for 6 days in a harsh environment such as this test condition.

Claims (6)

  A carnitine-containing preparation comprising carnitine or a salt thereof or a derivative thereof and porous starch.   A carnitine-containing preparation comprising carnitine or a salt thereof or a derivative thereof and porous starch.   The carnitine-containing preparation according to claim 1 or 2, wherein the porous starch is a porous dextrin.   The carnitine-containing preparation according to any one of claims 1 to 3, wherein the content ratio is carnitine or a salt thereof or a derivative thereof: porous starch = 80 to 95:20 to 5.   The carnitine-containing preparation according to any one of claims 1 to 4, which is in a powder form with improved hygroscopicity.   The carnitine-containing preparation according to any one of claims 1 to 5, wherein the carnitine or a salt thereof or a derivative thereof is L-carnitine L-tartrate.