KR20070034798A - Acetyl-L-carnitine powder or granules with improved hygroscopicity - Google Patents

Abstract

The present invention relates to acetyl-L-carnitine powder and granules with improved hygroscopicity. The present invention prepares acetyl-L-carnitine powder or granules having improved hygroscopicity by mixing fatty acid esters, waxes, enteric coating materials or materials selected from surfactants with acetyl-L-carnitine.

Acetyl-L-carnitine, powders, granules, hygroscopicity, fatty acid esters, waxes, enteric coatings, surfactants

Description

Acetyl-L-carnitine composition of pulveres or granula improved Thygroscopic property}

The present invention relates to acetyl-L-carnitine powder and granules with improved hygroscopicity.

Acetyl-L-carnitine is a physiological substance present in various organs, including the brain, and is synthesized by acetylation of carnitine in the mitochondria, and easily crosses the blood brain barrier, leading to cranial nerve cells. Not only to supply nutrients to promote the production of acetylcholine, a neurotransmitter to facilitate neurotransmission, and to improve the function of nerve cells. In addition, it has an active acetyl group, which activates nerve growth factor receptors to enhance the nutrition of nerve cells, and is known to improve dementia symptoms caused by damage to the central nervous system such as degenerative diseases and cerebrovascular diseases. .

However, acetyl-L-carnitine has a high hygroscopicity, which increases the water content in the process of manufacturing and shipping the product, making it easy to change to a non-standard product. Therefore, preservation of the product requires great care and granulation with various excipients. Alternatively, even when tableted, browning may occur depending on the type of excipient used, or the fluidity of the granules at the time of storage and the solubility in tablets are reduced.

In addition, when the acetyl-L-carnitine formulation is prepared in a tablet formulation, dementia patients with impaired performance and behavioral disorders may be difficult to swallow or may be dangerous due to swallowed tablets, which may make it difficult to take the medication. In addition, granules and powders may be reluctant to be taken for the reason of remaining in the oral cavity, making it difficult to swallow and breathing when taken.

The present invention completes the present invention by preparing a powdery or granular preparation which can improve storage stability by blocking strong hygroscopicity of acetyl-L-carnitine while studying hygroscopic improvement with respect to acetyl-L-carnitine powder and granules. It became.

It is an object of the present invention to provide a formulation in which stability is established by improving hygroscopicity of a water-sensitive acetyl-L-carnitine-containing formulation.

In order to achieve the above object, the present invention provides an acetyl-L-carnitine powdery or granular preparation prepared by mixing acetyl-L-carnitine with a substance selected from fatty acid esters, waxes, enteric coating materials or surfactants. .

Acetyl-L-carnitine has a high hygroscopic physical property even if it is made of powder or granules to be easily taken by patients with dementia, which is a problem in the storage stability of the formulation.

Therefore, in the present invention, the acetyl-L-carnitine preparation prepared as a powder or granule should be a preparation capable of blocking hygroscopicity.

Surprisingly, the present invention is prepared by mixing acetyl-L-carnitine with a material selected from fatty acid esters, waxes, enteric coating materials or surfactants to block the strong hygroscopicity of acetyl-L-carnitine to improve the storage stability. It can manufacture. In addition, it does not contain moisture at the time of manufacture, thereby preventing the hygroscopicity in the manufacturing process.

In the present invention, a substance selected from fatty acid esters, waxes, enteric coating materials or surfactants is dissolved in ethanol and the solution is sprayed and mixed with acetyl-L-carnitine, followed by acetyl-L-carnitine powder. Or to prepare granules.

The feature of the present invention is to prepare a formulation that enhances storage stability by blocking the strong hygroscopicity of acetyl-L-carnitine.

The present invention uses the active ingredient acetyl-L-carnitine in the form of a pharmaceutically acceptable salt thereof. As a salt applicable to this invention, salt, such as hydrochloric acid, citric acid, fumaric acid, adipic acid, tartaric acid, phosphoric acid, or maleic acid, is mentioned, Preferably a hydrochloride salt is used.

The fatty acid esters used in the present invention are stearic acid, palmitic acid, stearyl stearate, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, cetyl alcohol, polyoxy One or more selected from the group consisting of ethylene stearate, sorbitan monostearate and sorbitan monopalmitate can be used.

Waxes used in the present invention is cetyl consisting of biswax, carnauba wax, castor wax, paraffin wax, sorbitan monostearate and cetyl laurate, cetyl myristate, cetyl palmitate, cetyl stearate alone or as a mixture One or two or more selected from stearates may be used.

The enteric coatings used in the present invention are hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellac, methacrylic acid-methylmethacrylate copolymer and methacrylic acid One or more selected from the group consisting of -ethyl acrylate copolymer can be used.

Surfactants used in the present invention include polyoxyethylene, sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene polyoxypropylene block copolymers, reaction products of natural or hydrogenated vegetable oils with ethylene glycol, Dioctyl sulfosuccinate, phospholipids, propylene glycol mono or di fatty acid esters, trans-esterification reaction products of natural vegetable oil triglycerides with polyalkylene polyols, mono-, di- or mono / diglycerides, propylene glycol mono or One or more selected from the group consisting of mixtures of di fatty acid esters with mono-, di- or mono / diglycerides and derivatives thereof can be used.

The present invention is also prepared by mixing acetyl-L-carnitine with a pharmaceutically acceptable excipient and spraying and drying an ethanol solution of a fatty acid ester, wax, enteric coating or surfactant. The acetyl-L-carnitine containing formulations can be prepared by forming film powders or granules.

Excipients that can be used include sodium chloride, precipitated calcium carbonate, hard silicic anhydride, silicic anhydride, sodium bicarbonate, calcium citrate, die-alanine, glycine, glucose, di-mannitol, alginic acid, sodium alginate, hydroxypropylmethylcellulose, methylcellulose One or more of pharmaceutically acceptable excipients such as sodium cellulose, sodium carboxymethyl cellulose, and the like can be selected and used, and the selection of the type and amount of these additives can be easily determined by one of ordinary skill in the art.

In addition, the present invention has the composition as described above and may further include at least one or more conventional additives such as sweeteners, flavoring agents, pigments, lubricants, etc. The selection of the type and content of these additives is common knowledge in the art It can be easily determined by the person having

As a sweetening agent, one or more of sucrose, sorbitol, aspartame, acesulfame potassium, sucralose, and saccharin may be selected and used. As a flavoring agent, an apple flavor, an artificial vanilla flavor, etc. may be used, but other pharmaceutically acceptable flavoring agents may be used. Also available.

The present invention can be prepared in powder or granule formulations by the following general methods.

⑴ A substance selected from fatty acid esters, waxes, enteric coating materials or surfactants is dissolved in ethanol to prepare an ethanol solution.

⑵ Separately, additives comprising acetyl-L-carnitine or its salts and sweeteners are mixed in powder form.

Spray and dry the ethanol solution of 에 to the mixture of 제 to granulate and establish.

⑷ The powder or granules obtained were classified into powders and granules using No. 14 (1410 μm), No. 35 (500 μm), No. 45 (354 μm) and No. 50 (297 μm). Mix.

(5) Pack the mixture of (4).

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

<Example 1>

250 g of stearic acid are dissolved in 1000 ml of ethanol. 590 g of acetyl hydrochloride-L-carnitine, 50 g of sodium chloride, 200 g of erythritol, 20 g of hard silicic anhydride, 250 g of die-alanine, 200 g of glycine and 5 g of sucralose were mixed. The mixture was placed in a fluidized bed granulator and the stearic acid mixture was coated with a spray pressure of 2.5 kg / cm 2 with 500 ml of stearic acid ethanol solution and then granulated with a spray pressure of 1 kg / cm 2. The granules were heat-treated and dried at 80 ° C. for 20 minutes to establish a passage through No. 45 (354 μm), and a powder formulation was prepared by mixing an appropriate amount of 5 g of acesulfame potassium with an apple flavor and a required root flavor.

<Example 2>

In Example 1, the passage that passed the No. 14 sieve (1410 μm) among the granules that failed to pass the No. 45 (354 μm) sieve was established, and a granule formulation was prepared by mixing 5 g of acesulfame potassium with an appropriate amount of apple and required root fragrances. It was.

<Example 3>

200 g of carnauba wax is dissolved in 1000 ml of ethanol. 590 g of acetyl hydrochloride-L-carnitine, 50 g of sodium chloride, 200 g of erythritol, 20 g of hard silicic anhydride, 250 g of die-alanine, 200 g of glycine and 5 g of sucralose were mixed. The mixture was placed in a fluidized bed granulator and coated with a spray pressure of 2.5 kg / cm 2 with 500 ml of Carnauba wax ethanol solution and then granulated with a spray pressure of 1 kg / cm 2. The granules were heat-treated and dried at 80 ° C. for 20 minutes to establish a passage through No. 45 (354 μm), and a powder formulation was prepared by mixing an appropriate amount of 5 g of acesulfame potassium with an apple flavor and a required root flavor.

<Example 4>

400 g of hydroxypropyl methylcellulose phthalate is dissolved in 10 L of ethanol methylene chloride mixed solution. 590 g of acetyl hydrochloride-L-carnitine, 50 g of sodium chloride, 200 g of erythritol, 20 g of hard silicic anhydride, 250 g of die-alanine, 200 g of glycine and 5 g of sucralose were mixed. The mixture was placed in a fluid bed granulator and the lactose mixture was coated with a spray pressure of 2.5 kg / cm 2 with 500 ml of lactose ethanol solution and then granulated with a spray pressure of 1 kg / cm 2. The granules were heat-treated and dried at 80 ° C. for 20 minutes to establish a passage through No. 45 (354 μm), and a powder formulation was prepared by mixing an appropriate amount of 5 g of acesulfame potassium with an apple flavor and a required root flavor.

Example 5

250 g of sorbitan fatty acid ester are dissolved in 1000 ml of ethanol. 590 g of acetyl hydrochloride-L-carnitine, 50 g of sodium chloride, 200 g of erythritol, 20 g of hard silicic anhydride, 250 g of die-alanine, 200 g of glycine and 5 g of sucralose were mixed. The mixture was placed in a fluidized bed granulator and the mixture was coated with a spray pressure of 2.5 kg / cm 2 with 500 ml of sorbitan fatty acid ester ethanol solution and then granulated with a spray pressure of 1 kg / cm 2. The granules were heat-treated and dried at 80 ° C. for 20 minutes to establish a passage through No. 45 (354 μm), and a powder formulation was prepared by mixing an appropriate amount of 5 g of acesulfame potassium with an apple flavor and a required root flavor.

Test Example 1 Hygroscopicity Test

Examples 1 to 5 were stored for 24 hours at 25 ° C. and 60% relative humidity, and then, 1, 2 and 4 weeks later, according to the Karl Fischer Moisture Test. In other words, granules were taken, ground in a mortar and pestle, and then about 100 mg were taken and measured using a Karl Fischer moisture meter (model name Metrohm 751 GPD Titrino) to measure the water content in the formulation. The results are shown in Table 1.

At the start 1 week 2 weeks 4 Weeks Example 1 Constellation No change No change No change No change content 99.8% 99.4% 99.3% 99.2% Water content 1.8% 2.0% 2.2% 2.8% Example 2 Constellation No change No change No change No change content 100.1% 99.9% 99.6% 99.4% Water content 1.5% 2.1% 2.3% 2.4% Example 3 Constellation No change No change No change No change content 100.2% 99.8% 99.4% 99.1% Water content 2.3% 2.5% 2.9% 3.0% Example 4 Constellation No change No change No change No change content 100.1% 99.8% 99.6% 99.4% Water content 1.4% 2.0% 2.1% 2.4% Example 5 Constellation No change No change No change No change content 99.9% 99.7% 99.4% 99.3% Water content 1.3% 1.8% 2.1% 2.4%

As can be seen in Table 1, it can be seen that Examples 1 to 5 can significantly improve the storage stability of the acetyl-L-carnitine formulation with strong hygroscopicity by blocking the moisture in the air sufficiently.

The present invention prepares acetyl-L-carnitine powder and granules, including fatty acid esters, waxes, enteric coating materials or materials selected from surfactants, thereby blocking the strong hygroscopicity of acetyl-L-carnitine, which is sensitive to moisture, and thus storage stability. This enhanced formulation is provided.

Claims (5)

An acetyl-L-carnitine powder or granules prepared with acetyl-L-carnitine and fatty acid esters, waxes, enteric coatings or at least one substance selected from surfactants and having improved hygroscopicity. The method of claim 1, wherein the fatty acid esters are stearic acid, palmitic acid, stearyl stearate, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, cetyl alcohol, poly An acetyl-L-carnitine powder or granules selected from the group consisting of oxyethylene stearate, sorbitan monostearate and sorbitan monopalmitate. The wax according to claim 1, wherein the wax is composed of biswax, carnauba wax, castor wax, paraffin wax, sorbitan monostearate and cetyl laurate, cetyl myristate, cetyl palmitate, cetyl stearate alone or a mixture thereof. Acetyl-L-carnitine powder or granules selected from one or two or more from cetyl stearate. The method of claim 1 wherein the enteric coating material is hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellac, methacrylic acid-methylmethacrylate copolymer and methacrylate. An acetyl-L-carnitine powder or granules selected from the group consisting of acid-ethylacrylate copolymers. The method of claim 1, wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer, reaction product of natural or hydrogenated vegetable oil with ethylene glycol, Dioctyl sulfosuccinate, phospholipids, propylene glycol mono or di fatty acid esters, trans-esterification reaction products of natural vegetable oil triglycerides with polyalkylene polyols, mono-, di- or mono / diglycerides, propylene glycol mono or An acetyl-L-carnitine powder or granules selected from the group consisting of mixtures of di fatty acid esters with mono-, di- or mono / diglycerides and derivatives thereof.