KR20120011595A - Solubilizing Compositions of L-Tryptophan and Pharmaceutical preparation therefrom - Google Patents

Abstract

PURPOSE: A composition for solubilizing L-tryptophane and a formulation using the same are provided to improve solubility and to induce absorption enhancement. CONSTITUTION: A granule composition for improving L-tryptopahen solubilization contains 20-80 wt% of L-tryptophane having 70% or more with a particle size of 0.3-20μm and 90% or more with a particle size of 0.3-50μm; and 0.1-70 wt% sodium lauryl sulfate surfactant, glycerin fatty acid ester, or polysorbate.

Description

Solubilizing Compositions of L-Tryptophan and Pharmaceutical preparation therefrom

The present invention relates to a solubilizing composition which can be used as a food of L-tryptophan, which is a poorly soluble drug.

The origin of L-tryptophan shows that the protein's trypsin digest is purple by chlorine or bromine, but the presence of indole nuclei was estimated by Kuhne in 1875 and 1890. Neumeyster named it tryptophan as a positive indole colorant. Adamkiewitz, meanwhile, discovered that purple acetic acid and glacial sulfuric acid changed to protein in 1874. Hopkins and Cole used the Adamkiewitz reaction to trace the single tryptophan from casein's trypsin digest or yellow precipitate, which is easily precipitated by mercury sulfate under acid, and adopted the name Tryptophan, which was proposed by Neumeyster. In 1907, Ellinger and Flamand synthesized from indolealdehyde and manic acid to determine their structure. It is now called tryptophan.

L-Tryptophan has the structure of Formula 1 below, and is an essential amino acid that produces 5-Hydroxy-tryptophan (5-HTP), a substance for producing neurotransmitters serotonin and melatonin, proteins of many natural plants and organisms. It has been found in, and has been widely used as a raw material for pharmaceuticals and health foods as it shows excellent effects as an improvement in sleep effects for treating insomnia or as a treatment for various mental diseases.

<Formula 1>

The chemical formula of L-Tryptophan is C ₁₁ H ₁₂ N ₂ O _{2, which} is a pale yellow crystalline powder with a slight odor and a bit bitter taste, and insoluble in most organic solvents. The daily consumption of L-tryptophan varies from about 1 to 10 grams and is converted into serotonin by synaptic transmission in the brain by acting on the central nerveous system and plays an important role in biological processes such as mental and pain. In charge of. It is also important in vivo for polymerization of proteins and starting materials such as nicotinic acid amide. L-Tryptophan is an essential amino acid that must be obtained from food because it cannot be synthesized in the human body. Absorption of L-tryptophan is circulated in the blood with about 80% bound to plasma albumin, the remaining 20% circulating as free tryptophan, and under appropriate conditions, L-tryptophan is transported to the brain. Beyond the blood brain barrier (BBB), L-tryptophan is used for metabolism of serotonin, a neurotransmitter involved in mood and sleep regulation (Boman, 1988). Serotonin is then metabolized into melatonin (a sleep-related hormone found in the pineal gland, a small conical structure in the thalamus of the brain that regulates 24-hour rhythms in humans).

Sufficient intake of L-tryptophan steadily shortens the sleep potential, from “lightout” to sleep, and improves the overall quality of sleep by improving sleep structure (Boman, 1988). In addition, the influx of L-tryptophan into the brain in steady state can be attributed to other large neutral amino acids (LNAA): Leucine (Leu), Valine (Val), Isoleucine (Ile), Tyrosine (Tyr), Phenylalanine ( Phe) and methionine (Met) (Heine, 1995, Supra). These large neutral amino acids (LNAAs) use similar transport mechanisms to cross the blood-brain barrier, resulting in higher proportions of L-tryptophan in the blood and more. The transport of L-tryptophan into the central nervous system causes more serotonin to be made in the brain (Herderich and Gutsche, Supra).

L-tryptophan is manufactured through various chemical synthesis methods, and in addition to separation from natural proteins, enzyme methods and fermentation methods have been studied, but synthetic methods are generally used because of the low content of tryptophan in proteins. Chemical synthesis methods include synthesis from indophenol derivatives and synthesis of indole nuclei.

In addition, the solubility of L-tryptophan is known to dissolve 0.25 g (30 ° C.) and 0.4 g (100 ° C.) in 100 ml of water, but the solubility of the L-tryptophan is less than that. . And it is difficult to melt | dissolve with organic solvents, such as ethanol and acetone. In case of stability, it is weaker to acid than alkali, and separated by light rays, and when browned for a long time after dissolution, browning phenomenon tends to occur. The effect of D-tryptophan is the same as that of L-type, or about 3/4, and is more poorly soluble.

In order to be absorbed in the human body and exhibit high pharmacological activity, the rapid dissolution and absorption rate in the body should be high. However, due to the low solubility in water, L-tryptophan does not have high bioavailability. L-Tryptophan has a low solubility in water compared to the daily dose, and studies to increase the absorption rate after oral administration are needed.

Representative solubilization methods include, for example, methods using excipients and co-solvents, methods of making particles small through crushing, etc., methods of changing the crystalline form to amorphous through powder drying, etc. A method of making a salt of a base, a method of making a water-soluble polymer such as polyvinylpyrrolidone or hydroxypropylmethyl cellulose and a solid dispersion, and a method of preparing micelles.

However, these methods are not efficient because there is a stability problem due to toxicity due to the use of organic solvents, or the physical properties according to the characteristics of the drug, and takes a relatively large manufacturing cost and time. In particular, L-tryptophan is used more in food than in medicine, and most of the techniques are applicable to medicine or impossible to use in food.

Accordingly, the present inventors have discovered that solubilization is improved when micronizing L-tryptophan to a specific particle size and using a surfactant that can be used in food while studying a solubilization method of L-tryptophan that can be used in food. It was.

The present invention aims to provide a solubilizing composition of L-tryptophan, which is a poorly water-soluble substance that can be used in food, and a method thereof.

In order to achieve the above object, the present invention is prepared by preparing L-tryptophan having a specific particle size as an active ingredient, a composition by mixing a hydrophilic and an amphiphilic surfactant having a hydrophobic block that can be used in food And a solubilization method of L-tryptophan with improved dissolution rate.

Hereinafter, the solubilization method of L-tryptophan according to the present invention will be described in detail.

As a solubilization method of a poorly soluble substance, a method of making particles small through grinding or the like is often used. First, particle size was measured by classifying L-tryptophan by size using a grinder or mesh for each type, and the time of melting L-tryptophan classified by size was measured in purified water. As a result, in the following experimental example, it can be seen that the L-tryptophan does not have a large change in solubility according to the particle size, so that only L-tryptophan cannot be solubilized by only a method of making particles small through pulverization, which is known as a solubilization method of a poorly soluble substance.

However, the present invention surprisingly finds that the solubility of L-tryptophan is improved when several surfactants such as L-tryptophan and sodium lauryl sulfate having a specific particle size are used, and thus L-tryptophan is solubilized. The correlation between solubility change by mixing particle size and surfactant is revealed.

As shown in FIG. 3, undifferentiated L-tryptophan shows a wide particle size of 20 to 250 μm, and more than 90% has a size of 110 to 200 μm. In the present invention, when the L-tryptophan is micronized, the total particle size range is 0.3 to 60 μm, and the particles of 0.3 to 20 μm are about 70% or more and the particles of 0.3 to 50 μm are 90% or more. .

The present invention prepares L-tryptophan having an overall particle size range of 0.3-60 μm, 70-80% of particles having 0.3-20 μm, and 90-95% of particles having 0.3-50 μm as active ingredients, and The present invention relates to a solubilization method of L-tryptophan having improved solubility and dissolution rate by preparing a composition by mixing sodium lauryl sulfate, glycerin fatty acid esters or polysorbates, which are an amphiphilic surfactant having a hydrophilic and hydrophobic block, which can be used.

As the method of micronization of L-tryptophan, a sieve method or a grinding method may be used. The sieve is performed using a sieve which is generally used, and a size classification method such as air current classification instead of a sieve is performed. method) may be used. Grinding may be a conventional mill capable of micronizing particles such as a Z-mill, a hammer mill, a ball mill, a fluid energy mill, but is not limited thereto. no.

Amphiphilic surfactants having hydrophilic and hydrophobic blocks that can be used in the food according to the present invention may use sodium lauryl sulfate, glycerin fatty acid esters or polysorbates. Glycerin fatty acid esters are glycerin or polyglycerol esters and derivatives thereof, and specific examples thereof include glycerin, propylene glycol, propylene glycol fatty acid esters, glycerin acetic acid fatty acid esters, glycerin lactic acid fatty acid esters, glycerin citric acid fatty acid esters, glycerin zucchini fatty acid esters, Glycerin diacetyl tartrate fatty acid ester, glycerin acetic acid ester, polyglycerol condensed ricinoleic acid ester, glycerin lauric acid ester, glycerin myristic acid ester, glycerin palmitate ester, glycerin stearic acid ester, glycerin olein acid ester, glycerin behenic acid ester Esters, glycerin esca acid esters, glycerin mixed fatty acid esters, sorbitan fatty acid esters or sucrose fatty acid esters. In addition, polysorbates include polysorbate 20/60/65/80 and the like. Preferably sodium lauryl sulfate, glycerin myristic acid ester, polysorbate 80, more preferably sodium lauryl sulfate. Sodium lauryl sulfate is a copolymer of sodium alkyl sulfate and contains more than 85% of sodium lauryl sulfate. It is a skin permeant, dispersing, emulsifier, wetting agent, and disintegration for promoting absorption. It is an anionic surfactant that is widely used for. It is quite water soluble and has the highest HLB value among surfactants. Surfactants added for the purpose of solubilization may be used alone or in combination of two or more.

The micronized L-tryptophan solubilized granules according to the present invention have a total particle size in the range of 0.3 to 60 μm, 70 to 80% of particles having 0.3 to 20 μm, and 90 to 95% of particles having 0.3 to 50 μm of 1 weight of L-tryptophan. %, About 0.1 to 1% by weight of the surfactant is mixed homogeneously, it can be prepared using a suitable amount of purified water or a mixed solvent of purified water and ethanol, the water content of L- tryptophan of the granules produced is 1 to 1 Dry and sieve at 30-60 ° C., more preferably 50 ° C. until it reaches 10% and sieve. The binder may be added as needed before the drying process.

Alternatively, about 0.1 to 1% by weight of surfactant is dissolved in an appropriate amount of purified or purified water and an ethanol mixture, and then sprayed onto finely divided L-tryptophan to prepare granules, and then, as necessary, a binder is added and the water of the granulated L-tryptophan is added. Dry and sift at 30-60 ° C., more preferably 50 ° C. until the content is 1-10% of the total weight.

Conventional techniques in the process of preparing solubilized granules of undifferentiated L-tryptophan require excessive handling of the drying process by prolonging the high temperature drying process in order not to leave organic solvents harmful to the human body. In the method for producing the micronized solubilized granules of the invention, it is not necessary to use an excess of organic solvent because 50% ethanol can be used to produce safe, fully solubilized granules.

The content of the micronized L-tryptophan as an active ingredient in the micronized L-tryptophan solubilized granules is preferably 20 to 80% by weight, more preferably 40 to 80% by weight relative to the total weight of the solubilized granules so as to act pharmacologically and effectively.

In the micronized L-tryptophan solubilizing granules according to the present invention, the surfactant may contain 0.1 to 70% by weight, preferably 10 to 50% by weight relative to the total weight.

A binder may be further included in the preparation of micronized L-tryptophan solubilized granules, more preferably a binder that can be used for food addition. Specific examples thereof include purified water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl. Pyrrolidone, aribian rubber powder, tragacanth gum, and the like.

Excipients, disintegrants, moisturizers, adsorbents or glidants alone or in admixture of two or more of the micronized L-tryptophan solubilized granules according to the present invention, tablets, capsules, fine granules, granules It can be prepared in the form of granules, powders, pills, and the like. In addition, in order to prevent a decrease in content and browning phenomenon during long-term preservation can be prepared as a drinking solvent dissolved or mixed in a liquid, such as beverages, syrups immediately before taking.

Excipients that can be used in the present invention include those used in conventional food additive formulations, such as lactose, sucrose, sodium chloride, glucose, urea, starch, kaolin, (un) crystalline cellulose, silicic acid, cacao oil, hardened vegetable oil, talc, and the like. Include.

Disintegrants are used in conventional food additive formulations and include hydroxypropyl cellulose sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, (micro) crystalline cellulose and the like.

Moisturizing agents include glycerin, starch, etc., and adsorbents include starch, lactose, bentonite, colloidal silicic acid, and the like. Polyethylene glycol, hardened oil, and the like.

As needed, components, such as a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, and a sweetener, can be added.

In addition, tablets may be conventionally coated tablets, such as sugar coated tablets, gelatin coated tablets, enteric coated tablets, film coated tablets, coated tablets by water-permeable semipermeable membranes, double coated tablets, multilayer coated tablets, nucleated tablets, etc. It can be prepared by.

Capsules can be prepared by mixing with the various components exemplified above to fill hard gelatin capsules, soft capsules and the like.

The present invention can improve solubility by supplementing the disadvantages of the poorly soluble L-tryptophan by solubilizing using undifferentiated L-tryptophan and a surfactant, thereby providing convenience in taking oral administration and improving absorption through rapid dissolution. Can be.

In addition, according to the production method according to the present invention, it is possible to simplify the process without going through a complicated manufacturing process, such as solid dispersion, spray drying, micelles can be prepared L- tryptophan solubilizing composition with improved solubility.

1 is a graph showing the finely divided L-tryptophan particle size distribution having a total particle size range of 0.3 to 60 μm, 70% or more of the particle size, and 0.3 to 20 μm, and 90% or more to 0.3 to 50 μm.
Figure 2 is a graph showing the particle size distribution of the finely divided L- tryptophan having a total particle size range of 45 ~ 120㎛, 90% or more of the particle size of 50 ~ 110㎛.
3 is a graph showing the particle size distribution of undifferentiated L-tryptophan having a total particle size range of 20 to 250 μm and at least 90% of the particle size of 110 to 200 μm.
4 is an HPLC analysis peak of L-tryptophan.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the scope of the present invention is not limited by the following examples, and those skilled in the art to which the present invention pertains can make various modifications within the scope of the present invention.

&Lt; Example 1 > Preparation of L-Tryptophan with Particle Size Distribution According to the Present Invention

Grinding using Z-mill, and using mesh, L-tryptophan with a total particle size of 0.3 ~ 60㎛, 0.3 ~ 20㎛ particles, 70 ~ 80%, 0.3 ~ 50㎛ particles 90 ~ 95% Prepared. The particle size of L-tryptophan was measured using a particle size analyzer (CILAS, Scinco Co., LTD. Korea) and the results are shown in FIG. 1. In the measurement method, about 1 g at a time of one measurement was repeated dry using a pressure of 993 mb and a distributor 7.

Comparative Example 1 Preparation of L-Tryptophan (1) with Specific Particle Size Distribution

L-tryptophan was prepared by grinding using a Z-mill and using a mesh to have a total particle size in the range of 45 to 120 μm, and at least 90% of the particle size was in the range of 50 to 110 μm (hereinafter referred to as' L-tryptophan ( 1) '. The particle size of L-tryptophan was measured in the same manner as in Example 1 and is shown in FIG. 2.

< Comparative example  2> Preparation of L-Tryptophan (2) with Specific Particle Size Distribution

Using the mesh, L-tryptophan having a total particle size range of 20 to 250 μm and more than 90% of the particle size is in the range of 110 to 200 μm was manufactured (hereinafter referred to as 'L-tryptophan (2)'). The particle size of L-tryptophan was measured in the same manner as in Example 1 and is shown in FIG. 3.

Experimental Example 1 Dissolution Comparison Test According to Particle Size Distribution

The test is to determine whether the particle size affects the solubility of L-tryptophan.

Solubility test was performed for each 100 mg of L-tryptophan prepared in Example 1 and Comparative Examples 1 and 2. Eluent was used as purified water, and proceeded for 30 minutes at an eluent temperature of 37 ± 0.5 ℃, 50rpm according to the method of the Korean Chemical dissolution test method (paddle method), it is shown in Table 1 to obtain the content by HPLC method . Table 1 shows the amount of drug eluted by time based on the total content of L-tryptophan in%.

<Eluent>

Manufacturer: VARIAN

Model Name: VK7025 Vk8000

<HPLC Assay>

HPLC equipment: Agilent 1200

Analytical column: (150mm X 4.0 mm; hypersil？ C-18; 5㎛ particle size)

Mobile phase: buffer solution: acetonitrile = 94: 6 (filtered by 0.45㎛ membrane filter)

Buffer solution: After preparing 15mmol / L sodium acetate buffer solution, adjust pH to 5.5 with acetic acid

STD solution preparation: 250 mg of L-tryptophan standard is weighed and placed in a 50 mL flask, 40 mL of diluent is added and suspended, heated to 60-70 ° C, stirred / dissolved, cooled to room temperature, and diluted to 50 mL with diluent.

The solution is diluted 50-fold in the eluate, filtered through a 0.45 µm membrane filter to obtain a standard solution.

Diluent (pretreatment solution) method of preparation: water / acetonitrile / glacial acetic acid = 94/5/1 (v / v / v%)

Column temperature: 40 ℃

Flow rate: 1.0ml / min

Wavelength detection: 302nm

Injection volume: 20µl

As a solubilization method of the poorly soluble substance, a method of making particles smaller through grinding or the like may be used. However, as shown in Table 1, L-tryptophan was prepared in Examples 1 and 2, regardless of particle size. The dissolution rate of both L-tryptophan was low from the beginning, and did not completely dissolve even after 30 minutes, so it can be seen that the solubility of L-tryptophan was not improved only by making particles smaller.

< Example  2 to 10> Preparation of L-Tryptophan-Containing Granule Composition According to the Present Invention

Granules were prepared by using L-tryptophan having a particle size distribution prepared in Example 1, as shown in Table 2, dried at 50 ° C., and then sieved to 20 mesh to obtain Examples 2 to 10, respectively.

< Comparative example  3 to 5> Preparation of Granular Composition Containing L-Tryptophan (1)

Granules were prepared by using L-tryptophan having a particle size distribution prepared in Comparative Example 1 as shown in Table 3, dried at 50 ° C., and sized at 20 mesh to obtain Comparative Examples 3 to 5, respectively.

< Comparative example  6 to 9 Preparation of Granule Composition Containing L-Tryptophan (2)

Granules were prepared by using L-tryptophan having a particle size distribution prepared in Comparative Example 2 as shown in Table 4, dried at 50 ° C., and then sieved to 20 mesh to obtain Comparative Examples 6 to 9, respectively.

< Experimental Example  2> Granularity By distribution  Dissolution Comparison Test with Surfactant Content

This experiment is to investigate the dissolution rate of L-tryptophan by the mixed composition of L-tryptophan and surfactant having a difference in particle size distribution.

L-tryptophan having a particle size distribution according to the present invention, that is, the granulation composition of Examples 2 to 10, in which L-tryptophan and the surfactant prepared in Example 1 were mixed, and L-tryptophan (1) prepared in Comparative Example 1 A dissolution test was carried out with respect to the granule composition of Comparative Examples 3 to 5, which were mixed with the surfactant, and the granule composition of Comparative Examples 6 to 9, which were mixed with the L-tryptophan (2) prepared in Comparative Example 2. Dissolution test was conducted in the same manner as in Experiment 1, the test results are shown in Table 5.

In Table 5, L-tryptophan having a particle size distribution according to the present invention, that is, the total particle size range is 0.3 ~ 60㎛, 0.3 ~ 20㎛ particles of 70 ~ 80%, 0.3 ~ 50㎛ particles 90 ~ 95 The granule composition of L-tryptophan (%) and sodium lauryl sulfate, glycerin myristic acid ester or polysorbate 80, which is a surfactant, is very early in elution unlike the experimental results of Experimental Example 1 and is performed most of the time in 10 minutes. In the example, it can be seen that the average dissolution rate reaches 90% or more.

On the other hand, L-tryptophan (L-tryptophan (1)) having a total particle size range of 45 to 120 μm, and at least 90% of the particle size is in the range of 50 to 110 μm, and a total particle size range of 20 to 250 μm, Comparative Examples 3 to 9, which are granule compositions made of L-tryptophan (L-tryptophan (2)) having a range of 90% or more and 110 to 200 µm, have little change in dissolution rate as in Experimental Example 1 above. It can be seen that it is low from the beginning and does not completely dissolve after 30 minutes.

Therefore, the total particle size range in accordance with the present invention is 0.3 ~ 60 ㎛, 70% or more of the particle size is 0.3 ~ 20 ㎛, 90% or more has a range of 0.3 ~ 50 ㎛ Sodium lauryl sulfate as a surfactant and L- tryptophan, It can be seen that the composition in which glycerin myristic acid ester or polysorbate 80 is mixed can improve the dissolution rate of L-tryptophan, a poorly soluble drug.

< Example  11 to 13> Preparation of L-Tryptophan-Containing Tablets According to the Present Invention

The L-tryptophan granules according to the present invention prepared in Examples 2, 5 and 8 were homogeneously mixed with lactose, hydroxypropylmethylcellulose, and carboxymethylcellulose calcium, and then magnesium stearate was added and post-mixed granules were used. It was established at 20mesh. The granulated granules were tableted to a hardness of 5.0 ± 1.0 kp (kilopascal) with a tableting machine to prepare tablets, and the results were shown in Examples 11 to 13. Table 6 shows the composition of Examples 11 to 13.

< Comparative example  10 to 12 Preparation of L-Tryptophan (1) Granule-Containing Tablets

L-Tryptophan (1) granules prepared in Comparative Examples 3 to 5 were prepared in the same manner as in Examples 11 to 13, and Comparative Examples 10 to 12 were prepared. Table 7 shows the composition of Comparative Examples 10 to 12.

< Comparative example  13 to 16 Preparation of L-Tryptophan (2) Granule-Containing Tablets

L-Tryptophan 2 granules prepared in Comparative Examples 6 to 9 were prepared in the same manner as in Examples 11 to 13, and Comparative Examples 13 to 16 were prepared. Table 8 shows the composition of Comparative Examples 13 to 16.

< Experimental Example  3> Formulation dissolution comparison test: Evaluation of dissolution rate effect by excipients of L-tryptophan 1

This experiment is to evaluate the dissolution rate by excipients by formulating poorly soluble drugs into tablets.

Examples 11 to 13 according to the present invention, Comparative Examples 10 to 12 according to L- tryptophan (1) and Comparative Examples 13 to 16 according to L- tryptophan (2) was carried out with a dissolution test to the table 9 is shown. Purified water was used as the eluate, and proceeded for 60 minutes at an eluent temperature of 37 ± 0.5 ° C. and 50 rpm according to the 2nd method (paddle method) of the Korean Pharmacopoeia Elution Test. The content was determined by HPLC method. Table 9 shows the amount of drug eluted by time based on the total amount of L-tryptophan included in the formulation in%.

In Table 9, L-tryptophan having a particle size distribution according to the present invention, that is, the total particle size range is 0.3 ~ 60㎛, particles of 0.3 ~ 20㎛ 70 ~ 80%, particles of 0.3 ~ 50㎛ 90 ~ 95 Tablets made by mixing excipients in granules mixed with% L-tryptophan and surfactant sodium lauryl sulfate, glycerin myristic acid ester or polysorbate 80 reached an average dissolution rate of 90% or more after 1 hour. can confirm.

On the other hand, L-tryptophan (L-tryptophan (1)) having a total particle size range of 45 to 120 μm, and at least 90% of the particle size is in the range of 50 to 110 μm, and a total particle size range of 20 to 250 μm, Comparative Examples 10 to 16, which are granule compositions made of L-tryptophan (L-tryptophan (2)) having a range of 90% or more and 110 to 200 µm, have little change in dissolution rate as in Experimental Example 1 above. It was confirmed that the initial rate was low and the elution rate was low even after 1 hour.

Therefore, L-tryptophan, a poorly soluble drug, does not have any effect on improving the dissolution rate by the general excipients used in the formulation, but the total particle size range of 0.3 to 60 ㎛ according to the present invention, more than 70% of the particle size is 0.3-20 L-tryptophan, a poorly soluble drug, even when formulating a composition in which 90% or more of L-tryptophan having a range of 0.3-50 μm is mixed with a surfactant of sodium lauryl sulfate, glycerin myristin ester or polysorbate 80. It can be seen that the dissolution rate of can be significantly improved.

< Example  14 to 16 Preparation of L-Tryptophan-Containing Capsules According to the Present Invention

After homogeneously mixing the L-tryptophan granules according to the present invention prepared in Examples 2, 5 and 8 together with lactose and hydroxypropylmethylcellulose, magnesium stearate was added and the post-mixed granules were formed into 20mesh capsules. It charged to it and it was set as Examples 14-16, respectively. Filled capsule compositions are shown in Table 10.

< Comparative example  17 to 19> Preparation of L-Tryptophan (1) Granule-containing Capsules

The capsules of L-tryptophan (1) granules prepared in Comparative Examples 3 to 5 were prepared in the same manner as in Examples 14 to 16, and Comparative Examples 17 to 19 were used. Table 11 shows the compositions of Comparative Examples 17 to 19.

< Comparative example  20 to 23 Preparation of L-Tryptophan (2) Granule-containing Capsules

L-Tryptophan (2) granules prepared in Comparative Examples 6 to 9 were prepared in the same manner as in Examples 14 to 16, respectively, and Comparative Examples 20 to 23 were used. Table 12 shows the composition of Comparative Examples 20 to 23.

< Experimental Example  4> Formulation dissolution comparison test: evaluation of the effect of dissolution rate of L-tryptophan by excipients 2

This experiment is to evaluate the dissolution rate by excipients by formulating a poorly soluble drug with a capsule.

Examples 14 to 16 according to the present invention, Comparative Examples 17 to 19 according to the L- tryptophan (1) and Comparative Examples 20 to 23 according to the L- tryptophan (2) was carried out using a capsule prepared in the dissolution test It is shown in 13. The eluate was purified water, and proceeded for 30 minutes using a sinker at an eluent temperature of 37 ± 0.5 ° C and 50 rpm according to the KEPCO Elution Test Method 2 (paddle method), and the content was determined by HPLC method. . Table 13 shows the amount of drug eluted by time based on the total content of L-tryptophan in the formulation.

In Table 13, L-tryptophan having a particle size distribution according to the present invention, that is, the total particle size range of 0.3 ~ 60㎛, 70% or more of the particle size is 0.3 ~ 20㎛, 90% or more of the range of 0.3 ~ 50㎛ The capsules prepared by mixing excipients in granules mixed with L-tryptophan and sodium lauryl sulfate, glycerin myristin acid ester or polysorbate 80, which are surfactants, reached an average dissolution rate of 95% or more after 30 minutes. You can check it.

On the other hand, L-tryptophan (L-tryptophan (1)) having a total particle size range of 45 to 120 μm, and at least 90% of the particle size is in the range of 50 to 110 μm, and a total particle size range of 20 to 250 μm, Comparative Examples 10 to 16, which are granule compositions made of L-tryptophan (L-tryptophan (2)) having a range of 90% or more and 110 to 200 µm, have little change in dissolution rate as in Experimental Example 1 above. It is low from the beginning, and the dissolution rate is low even after 30 minutes.

Therefore, L-tryptophan, a poorly soluble drug, does not have any effect on improving the dissolution rate by the general excipients used in the formulation, but the total particle size range of 0.3 to 60 ㎛ according to the present invention, more than 70% of the particle size is 0.3-20 L-tryptophan, a poorly soluble drug, even when formulating a composition in which 90% or more of L-tryptophan having a range of 0.3-50 μm is mixed with a surfactant of sodium lauryl sulfate, glycerin myristin ester or polysorbate 80. It can be seen that the dissolution rate of can be significantly improved.

Claims (13)

Iii) 20 to 80% by weight of L-tryptophan having a total particle size in the range of 0.3 to 60 µm, 70% or more of the particle size to 0.3 to 20 µm, and 90% or more to 0.3 to 50 µm, and ii A granule composition for improving solubility of L-tryptophan, characterized by containing 0.1 to 70% by weight of a surfactant selected from sodium lauryl sulfate, glycerin fatty acid esters and polysorbates.
The L-tryptophan according to claim 1, wherein the L-tryptophan has a total particle size range of 0.3 to 60 µm, 70 to 80% of particles having 0.3 to 20 µm, and 90 to 95% of particles having 0.3 to 50 µm. Granule composition.
The glycerin fatty acid ester according to claim 1, wherein the glycerin fatty acid ester is glycerin, propylene glycol, propylene glycol fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, glycerin pumpkin acid fatty acid ester, glycerin diacetyl tartrate fatty acid ester, glycerin acetate Ester, Polyglycerol Condensed Licinoleic Acid Ester, Glycerine Lauric Acid Ester, Glycerin Myristic Acid Ester, Glycerine Palmitine Ester, Glycerine Stearic Acid Ester, Glycerine Oleic Acid Ester, Glycerine Behenic Acid Ester, Glycerine Escarate Ester, Glycerine Mixture Granular composition, characterized in that selected from fatty acid esters, sorbitan fatty acid esters or sucrose fatty acid esters.
The granular composition according to claim 3, wherein the glycerin fatty acid ester is glycerin myristic acid ester.
The granule composition of claim 1, wherein the polysorbates are selected from polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80.
The granule composition of claim 5, wherein the polysorbates are polysorbate 80.
The total particle size ranges from 0.3 to 60 µm, 70% or more of the particle size is 0.3 to 20 µm, and 90% or more is L-tryptophan as an active ingredient, and sodium lauryl sulfate, glycerin fatty acid ester, and Tablets made from granules containing a surfactant selected from polysorbates.
The total particle size ranges from 0.3 to 60 µm, 70% or more of the particle size is 0.3 to 20 µm, and 90% or more is L-tryptophan as an active ingredient, and sodium lauryl sulfate, glycerin fatty acid ester, and A capsule made from granules containing a surfactant selected from polysorbates.
I) L-tryptophan having a total particle size in the range of 0.3 to 60 µm, 70% or more of the particle size, 0.3 to 20 µm, and 90% or more to 0.3 to 50 µm, and ii) sodium lauryl sulfate, glycerin fatty acid ester, and A method for solubilizing L-tryptophan, characterized by containing a surfactant selected from polysorbates.
10. The glycerin fatty acid ester according to claim 9, wherein the glycerin fatty acid ester is glycerin, propylene glycol, propylene glycol fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, glycerin pumpkin acid fatty acid ester, glycerin diacetyl tartrate fatty acid ester, glycerin acetate Ester, Polyglycerol Condensed Licinoleic Acid Ester, Glycerine Lauric Acid Ester, Glycerin Myristic Acid Ester, Glycerine Palmitine Ester, Glycerine Stearic Acid Ester, Glycerine Oleic Acid Ester, Glycerine Behenic Acid Ester, Glycerine Escarate Ester, Glycerine Mixture Solubilization method, characterized in that selected from fatty acid esters, sorbitan fatty acid esters or sucrose fatty acid esters.
The solubilization method according to claim 10, wherein the glycerin fatty acid esters are glycerin myristic acid esters.
The solubilization method according to claim 9, wherein the polysorbates are selected from polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80.
The solubilization method according to claim 12, wherein the polysorbates are polysorbate 80.

Images