WO2013147451A1 - Pharmaceutical composition containing branched chain amino acid, and production method therefor - Google Patents

Pharmaceutical composition containing branched chain amino acid, and production method therefor Download PDF

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Publication number
WO2013147451A1
WO2013147451A1 PCT/KR2013/002304 KR2013002304W WO2013147451A1 WO 2013147451 A1 WO2013147451 A1 WO 2013147451A1 KR 2013002304 W KR2013002304 W KR 2013002304W WO 2013147451 A1 WO2013147451 A1 WO 2013147451A1
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liquid suspension
branched chain
chain amino
suspension composition
amino acids
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PCT/KR2013/002304
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French (fr)
Korean (ko)
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이단비
정용혁
김현수
연규정
박진규
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주식회사 서울제약
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Publication of WO2013147451A1 publication Critical patent/WO2013147451A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to a pharmaceutical liquid suspension composition containing a branched chain amino acid as an active ingredient and concealing the high content of the active ingredient, and a method for producing the same.
  • the present invention relates to a pharmaceutical liquid suspension composition containing three branched chain amino acids, specifically, isoleucine, leucine, and valine, as an active ingredient, and concealing the gluten of the active ingredient, and a method for preparing the same.
  • the present invention contains three branched chain amino acids with controlled particle size distribution, specifically, isoleucine, leucine, and valine as active ingredients, and includes a specific thickener or a combination of specific thickeners.
  • the present invention relates to a liquid suspension composition having a dispersing ability and a preparation method thereof.
  • the present invention relates to a method for preparing a liquid suspension composition, characterized in that the three branched chain amino acids are introduced under specific temperature conditions in a specific order in mass production for commercial use of the liquid suspension composition.
  • liquid suspension compositions are used to improve the nutritional status of patients or healthy people, are widely used in the medical field, etc., and are usually taken in a dissolved or suspended state in a solvent such as water.
  • a solvent such as water.
  • the pharmaceutical liquid suspension composition containing three branched chain amino acids has a bitter taste, which is a burden on the patient or the like taking it.
  • suspending agents comprising three branched chain amino acids of isoleucine, leucine and valine have been proposed.
  • Japanese Laid-Open Patent Publication No. 2002-114674 discloses a pharmaceutical suspension containing a branched chain amino acid and at least one organic acid as an acidulant.
  • simply adding an organic acid does not have enough masking effect of bitterness, and therefore it is difficult to put it to commercial use.
  • Patent Publication No. 10-2005-0095833 (published Oct. 4, 2005) states that in order to obtain an oral composition having a bitter taste in fact, the branched chain amino acid mixture should be taken immediately after the preparation of the solution or suspension. Since it is necessary to prepare a solution or suspension directly at the time of taking, it is not only cumbersome when taking, but the amount of water, the mixing time, and the mixing method vary depending on the user, so it is difficult to expect the same and effective drug efficacy.
  • Patent No. 10-0927254 registered on November 10, 2009
  • three kinds of branched chain amino acids are mixed with aloe vera, gum and acidulant to reduce unpleasant taste and feeling such as bitterness peculiar to branched chain amino acids and at the same time, branched chain amino acids. It is described to improve the convenience of taking by formulating the into a liquid suspension composition.
  • commercially available suspensions are prepared in fixed doses or weights and are sold in pouches, usually in units of 5 mL to 20 mL (specific gravity 0.8 to 1.2 g / mL).
  • the doses of branched chain amino acids are 474 mg of isoleucine, leucine 952 mg, and valine 572 mg per 20 mL.
  • this method does not complete the composition of a liquid suspension composition suitable for therapeutic treatment due to the large amount of one-time use of three branched chain amino acids constituting the suspension. This is also a result of not completely eliminating bitter taste, foreign matter in the oral cavity derived from powder, and troubles in the mass production process for commercial sale.
  • compositions containing three branched chain amino acids consisting of isoleucine, leucine and valine as active ingredients are known as effective therapeutic drugs for liver disease.
  • These branched chain amino acids have the effect of correcting the imbalance of plasma amino acids in patients with cirrhosis, thereby improving the nitrogen balance.
  • it improves the perception and cognitive symptoms of cirrhosis, fatigue, etc. of patients with cirrhosis, increases plasma protein and albumin, improves protein nutrition status, inhibits muscle protein degradation and hepatic secretory protein reduction, and prevents platelet count reduction. It shows an effect.
  • granules are generally used by pulverizing the active ingredient in order to satisfy the requirements of securing content uniformity and improving solubility.
  • a solid preparation containing particles of the three branched chain amino acids In order to cope by reducing only the particle size of the raw material amino acid particles, the specific volume thereof increases, resulting in a large volume per dose, making it difficult to swallow due to a large volume in the mouth at the time of taking it. The same problem arises.
  • granules thus prepared generally have a specific volume of 2.0 mL / s. g or more, since the single dose of branched chain amino acid is about 4 to 5 g, when the granule formulation is prepared by pulverizing to 50 ⁇ m or less, its volume becomes about 8 to 10 mL and becomes large in the mouth, making it very difficult to swallow. .
  • pouch packaging is commercially available in volumes of 5 mL to 20 mL (specific gravity 0.8 to 1.2 g / mL), but
  • the three chain amino acids isoleucine, leucine and valine
  • a fluid liquid formulation that can be easily eaten when taken is not made in a sufficient concentration, and should be taken with water when taken.
  • the side effects of bloating can be brought about, and when the branched chain amino acid preparation is administered to liver disease patients in need of water control such as ascites, difficulty in controlling water can cause a patient's symptoms to worsen.
  • the three branched chain amino acids consisting of isoleucine, leucine and valine, have a strong bitter taste and a characteristic amino acid odor, and once they have adequate fluidity but should not be large in dosage volume, it is difficult to formulate them. It has become a problem in commercial use.
  • the present invention relates to a liquid suspension composition
  • a liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine, and valine, and a method for preparing the same.
  • a branched chain amino acid is mixed with a thickener, a pH adjusting agent, and a sweetener to provide a branched chain amino acid.
  • the purpose is to provide a liquid suspension composition to reduce the unpleasant taste and feeling, such as bitter taste.
  • Another problem is to formulate three branched chain amino acids (isoleucine, leucine and valine) into liquid suspension compositions by solving problems in the mass production process for commercial sale.
  • the branching A liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, a thickening agent, a pH adjusting agent and a pharmaceutically acceptable additive
  • the branching A liquid suspension composition characterized in that the particle size of the chain amino acids is from 35 mesh to 100 mesh.
  • the thickener is provided with a liquid suspension composition, characterized in that selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose sodium carboxymethyl cellulose, and polyvinylpyrrolidone.
  • the pH adjusting agent is provided with a liquid suspension composition, characterized in that selected from the group consisting of citric acid and anhydrous sodium hydrogen phosphate.
  • liquid suspension composition characterized in that the pH range of 5 to 7.
  • hydroxypropyl cellulose is 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition
  • microcrystalline cellulose-carboxymethyl cellulose sodium is 1.0 to 3.4% (w / w) by weight of the liquid suspension composition.
  • a liquid suspension composition containing 2.0% to 4.0% (w / w) of polyvinylpyrrolidone by weight of the liquid suspension composition is provided.
  • liquid suspension composition dissolving or suspending a thickener selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose carboxymethyl cellulose sodium and polyvinylpyrrolidone in purified water at room temperature or mild temperature ; Adding and dispersing one amino acid selected from isoleucine, leucine and valine to the suspension solution; Adding the remaining two amino acids to the suspension solution at 50 ° C.
  • a thickener selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose carboxymethyl cellulose sodium and polyvinylpyrrolidone in purified water at room temperature or mild temperature ; Adding and dispersing one amino acid selected from isoleucine, leucine and valine to the suspension solution; Adding the remaining two amino acids to the suspension solution at 50 ° C.
  • an orally administrable liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, comprising dissolving by adding a preservative, a sweetener, and a pH adjusting agent to the suspension solution. .
  • the pharmaceutical liquid suspension composition of the present invention may contain 4 g to 5 g of three branched chain amino acids in a volume of about 20 mL, thereby providing a liquid suspension composition with a convenient flavor and minimized taste to the patient for therapeutic purposes. .
  • there is no process, such as coating the main ingredient is generally used for high concealment can be easily manufactured by a low cost simplified manufacturing method.
  • FIG. 1 is a view showing a manufacturing process diagram of the manufacturing method of the present invention.
  • 2 and 3 is a view comparing the aggregation phenomenon according to the manufacturing process.
  • composition of the present invention is a liquid suspension containing one or more additives commonly used in the manufacture of pharmaceuticals, for example, acidulant, sweetener, flavoring agent, binder, antifoaming agent, dispersing agent, suspending agent, stabilizer, excipient, preservative, etc. It may be included in an amount suitable for preparing the composition.
  • additives commonly used in the manufacture of pharmaceuticals, for example, acidulant, sweetener, flavoring agent, binder, antifoaming agent, dispersing agent, suspending agent, stabilizer, excipient, preservative, etc. It may be included in an amount suitable for preparing the composition.
  • Branched chain amino acids contained in the pharmaceutical liquid suspension composition of the present invention include isoleucine, leucine, and valine, which are commonly used in medicines and foods.
  • branched chain amino acids composed of three kinds of amino acids, isoleucine, leucine and valine are known to play an important role as an energy source during exercise and to increase protein, and include various branched chain amino acids. Has been developed and released.
  • the amino acid can be any of L-form, D-form, and DL-form, but preferably L-form, DL-form, and more preferably L-form.
  • an amino acid can use not only a free body but a salt form, and in this invention, an amino acid is a concept containing both a free body and a salt.
  • salts include acid addition salts and salts with bases, and it is preferable to select salts that are acceptable as pharmaceuticals of amino acids.
  • permitted as a medicine in addition to an amino acid For example, inorganic acids, such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid; And organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and monomethyl sulfuric acid.
  • permitted as a medicament of an amino acid For example, Inorganic bases, such as hydroxide or carbonate of metal, such as sodium, potassium, calcium, or ammonia; And organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine and triethanolamine.
  • the pharmaceutical liquid suspension composition of the present invention contains three branched chain amino acids of isoleucine, leucine and valine together, preferably in the range of 19% to 21% (w / w) based on the weight of the pharmaceutical liquid suspension composition.
  • the pharmaceutical composition of the present invention may contain a thickener.
  • Cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose phthalate Starch such as corn starch, wheat starch, etc .: Synthesis of polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymer Polymers: Natural polymers such as agar, xanthan gum, gum arabic and gelatin, microcrystalline cellulose, cellulose polymers, microcrystalline cellulose and sodium carboxymethyl cellulose.
  • the quality of the suspension liquid is not constant depending on the combination of the thickeners, and in particular, polyvinylprolidone, microcrystalline cellulose, carboxymethylcellulose sodium and hydroxide as thickeners. It has been found that the suspension state is excellent when used in combination with oxypropyl cellulose.
  • the content of the thickener may be within the range in which the usual liquid suspension composition can be prepared.
  • hydroxypropyl cellulose is 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, and microcrystalline cellulose and carboxymethyl cellulose sodium are used.
  • polyvinylpyrrolidone is preferably included 2.0 to 4.0% (w / w) of the weight of the liquid suspension composition.
  • the pharmaceutical composition of the present invention may contain a pH adjusting agent.
  • a pH adjusting agent such as citric acid and anhydrous sodium hydrogen phosphate may be appropriately used to range from pH3.0 to pH9.0, preferably pH4.0 to pH8.0, more preferably pH5.0 to pH7. It can be produced in the 0 range.
  • Three branched chain amino acids of the present invention show a tendency to be stable near pH 5.0 to 7.0, and also minimize the bitter or unpleasant taste in the same range.
  • any one that can be used for the manufacture of a pharmaceutical product is acceptable, but ascorbic acid, citric acid (citric acid) and malic acid are preferable from the viewpoint of improving the flavor and reducing the bitter taste.
  • acidulant any one that can be used for the manufacture of a pharmaceutical product is acceptable, but ascorbic acid, citric acid (citric acid) and malic acid are preferable from the viewpoint of improving the flavor and reducing the bitter taste.
  • There is no particular limitation on the amount of acid added and it may be used alone in the amino acid mixture and may be added together with other additives.
  • Flavors that can be used include odor enhancers such as apple or strawberry flavors.
  • the pharmaceutical composition of the present invention may contain a sweetening agent.
  • sweeteners sugar, glucose, maltose, oligosaccharide, galactose, syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, hydrogenated syrup, mannitol, trehalose, aspartame, acesulfame salt, sucralose, saccharin salt, neotime, tao
  • It may be one or more high sweetening sweeteners selected from the group consisting of martin, tomatin mixtures, cyclate salts, taumartin, Nahan fruit extract, licorice extract, stevioside, enzyme treatment stevioside, neohesperidine and monelin.
  • the antifoaming agent may be appropriately selected from among those generally known as medical antifoaming agents such as myristic acid, palmitic acid, simethicone, silicone antifoaming agent, and the amount of use may vary depending on the composition of the active ingredient.
  • medical antifoaming agents such as myristic acid, palmitic acid, simethicone, silicone antifoaming agent, and the amount of use may vary depending on the composition of the active ingredient.
  • the liquid suspension composition of the present invention may include a preservative commonly used in liquid formulations for safety.
  • Preservatives that can be used include sorbic acid and salts thereof, benzoic acid and salts thereof, and paraoxybenzoic acid and salts thereof.
  • the pharmaceutical composition of the present invention may also comprise perfume. Since the pharmaceutical composition of the present invention is a product to be taken through the oral cavity, it is necessary to add an appropriate flavor.
  • the flavor may be natural flavors, artificial flavors or mixtures thereof. Natural flavors may be extracts from the leaves, flowers, fruits and the like of plants, oils of plants and the like. Plant oils include spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage ( sage) oil, almond oil and the like.
  • artificial flavors of fruits such as lemons, oranges, grapes, limes, strawberries and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, citrus may be used.
  • the pharmaceutical composition of the present invention may include a pigment suitable for the product.
  • the pigment may be appropriately adjusted in amount as necessary, and in general, 0.1 to 1.0% by weight (w / w) may be added to the weight of the pharmaceutical liquid suspension composition.
  • the pigment may be a natural or synthetic pigment.
  • the pharmaceutical composition of the present invention may also further comprise a cooling agent.
  • the refreshing agent may be, but is not limited to, for example, l-menthol, WS3, WS23, or Questais-L.
  • the refreshing agent can be appropriately adjusted in accordance with the content, if necessary, in general, may be added up to 10% by weight (w / w) relative to the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention may further include a bad breath remover to reduce oral odor.
  • the bad breath remover may be a metal salt.
  • the metal salt may be, for example, one or more components selected from the group consisting of metal salts of chlorite, copper gluconate, zinc chloride, zinc citrate and zinc gluconate. Another example is nium chloride, red ginseng extract, green tea extract, seaweed extract, herbal extract, grapefruit extract, apple extract, time oil, thymol, antibiotic, geraniol, carbachol, citral, hinokithiol, One or more components selected from the group consisting of eucalyptol, catechol, methylsalicylate and hydrogen peroxide. Such one or more bad breath remover components may be used together or independently with the one or more metal salts.
  • the viscosity was measured using a No. 62 spindle containing about 40 mL of the pharmaceutical liquid suspension in a centrifuge tube of about 3 cm in diameter and 50 mL.
  • BROOKFIELD model name: DV-2 + Pro, USA, measurement method: cup and bob, measurement temperature: room temperature
  • the particle size of the three branched chain amino acids was used as commercially available raw materials without separate classification, and the mixed three branched chain amino acids had a wide distribution of coarse particles of 18 mesh or more and fine particles of 100 mesh or less.
  • a liquid suspension composition was prepared in the same manner as in Comparative Example 1 with the exception of the three branched chain amino acids, but the particle size distribution of the three branched chain amino acids as the main component was shown in Table 1 and Table 2.
  • Commercial corporation, Korea to prepare a liquid suspension composition for each particle size.
  • Comparative Example 1 three main ingredients were used commercially as raw materials without separate classification, and Comparative Examples 2 to 8 were prepared by classifying only L-isoleucine, and Comparative Examples 9 to 12, L-leucine. It was prepared by classifying only, in the case of Comparative Examples 13 to 17 was prepared by classifying only L-valine.
  • Each 20 g of pharmaceutical liquid suspension was prepared.
  • the prepared solution was evaluated in accordance with the evaluation criteria described above in terms of suspension state, viscosity, bitter taste and foreign matter.
  • a liquid suspension composition was prepared in the same process as in Comparative Example 1 (prescription is shown in Table 3), and the particle sizes of the three branched chain amino acids were classified using a standard sieve network (TESTING SIEVE, Cheonggye Sangpo, Korea) and 35mesh.
  • a liquid suspension composition was prepared from three branched chain amino acids remaining at 100 mesh. It is also one selected from the group of hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose and microcrystalline carboxymethyl cellulose sodium as shown in Table 3 to prepare a branched chain amino acid suspension. Or more than one thickener was used. Unexpectedly, the quality of the suspension was not constant according to the combination of the thickeners, and as a result, the suspension was found to be excellent when used in combination with PVPK30, AvicelRC591, HPC-L as the thickener.
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 Example 9
  • Example 10 Example 11
  • Example 12 Example 13
  • Example 14 Example 15
  • Example 16 Example 17
  • a liquid suspension composition was prepared in the same process as in Comparative Example 1 (prescription is described in Tables 4 and 5), and the particle size of the three branched chain amino acids was classified using a standard sieve network (TESTING SIEVE, Cheonggye Sangpo, Korea).
  • the liquid suspension composition was prepared from three branched chain amino acids remaining in 100 mesh through 35 mesh. It was prepared as described in Tables 4 and 5 below to find the appropriate component ratios with PVPK30, AvicelRC591 and HPC-L selected in Table 3, and the suspensions were evaluated.
  • PVPK30 as a thickener was 2.0 to 4.0% (w / w) based on the weight of the pharmaceutical liquid suspension composition
  • AvicelRC591 was 1.0 to 3.4% by weight of the pharmaceutical liquid suspension composition ( w / w)
  • HPC-L was found to be excellent in suspension state when used in combination with 0.2 to 2.0% (w / w) relative to the weight of the pharmaceutical liquid suspension composition.
  • production scale For commercial use, mass production at the factory is essential and the production scale may be in accordance with separate scale provisions relating to the manufacturer or distributor's situation or permit.
  • Example 35 Although the results of Comparative Examples 20 to 23 and the known fact of agglomeration at high temperature heating of hydroxypropyl cellulose were not unexpected at all, when manufactured by the manufacturing process described in Example 35 below, the problem was not only solved. It has been found that commercially available products can be obtained.
  • Figure 1 the manufacturing process of Example 35 is shown in Figure 1, the aggregation phenomenon of hydroxypropyl cellulose is shown in Figure 2 (a), the preparation of Example 35 of the pharmaceutical liquid suspension composition The process is shown in FIG. 3.
  • Comparative Examples 20 to 23 and 35 The preparation methods of Comparative Examples 20 to 23 and 35 are shown below.
  • the particle size of three branched chain amino acids used here used the raw material classified into 35 mesh-100 mesh.
  • the scope of the present invention is not limited to the ranges of the comparative examples and examples, and similar effects can be obtained by mixing relatively small amounts of particles larger than 35 mesh or particles smaller than 100 mesh.
  • the particle size range of the amino acid is most preferably used having a particle size of the above 35 mesh to 100 mesh.
  • the temperature is increased by setting the temperature to 90 ⁇ 5 °C. Agglomeration phenomenon starts to occur when the temperature of the preparation liquid in the preparation tank is around 45 ⁇ 50 °C.
  • the addition of three branched chain amino acids (14.280 kg L-isoleucine, 28.560 kg and 17.160 kg) does not disintegrate the mass and can no longer proceed.
  • the temperature is increased by setting the temperature to 90 ⁇ 5 °C.
  • the temperature is increased by setting the temperature to 90 ⁇ 5 °C.
  • Two kinds of branched chain amino acids are added and stirred in the vicinity of the temperature of the preparation liquid in the preparation tank of 50 to 70 ° C. Agglomeration phenomenon starts to occur when the temperature of the preparation liquid in the preparation tank is around 70 ⁇ 90 °C.
  • One branched chain amino acid (L-isoleucine) is added to the preparation tank and stirred.
  • the temperature is increased by setting the temperature to 90 ⁇ 5 °C. Agglomeration does not occur even when the temperature of the preparation liquid inside the preparation tank rises to 90 ° C.
  • a pharmaceutical liquid suspension composition of the same properties can be obtained even when the order of the three branched chain amino acids to be added to the above-described production steps 2 and 3 is changed.
  • the present invention contains three branched chain amino acid isoleucine, leucine, and valine as effective ingredients in which the particle size distribution is adjusted as described in the above embodiments, and a specific thickener or a combination of specific thickeners, specific A sweetening agent and a pharmaceutical liquid suspension composition are provided in a volume suitable for the patient's intake while concealing bitter taste and foreign body by adjusting a specific range of pH.
  • the present invention also provides a preferred process for the preparation of a pharmaceutical liquid suspension composition commercially available under sterile conditions by solving the agglomeration of thickeners arising from mass production for commercial use.
  • an excellent pharmaceutical liquid suspension composition having improved taste and volume which is easy to administer to the patient, can be easily prepared. It can be produced on an industrial scale.

Abstract

The present invention relates to: a pharmaceutical liquid suspension composition which contains a branched chain amino acid and various drugs as active ingredients and in which the bitter taste of the active ingredients is concealed; and a production method. More specifically, the present invention relates to: a pharmaceutical liquid suspension composition which contains three types of branched chain amino acid, isoleucine, leucine and valine, as active ingredients and in which the bitter taste of the active ingredients is concealed; and a production method for same. Even more specifically, the present invention relates to: a pharmaceutical liquid suspension composition which contains three types of branched chain amino acid, isoleucine, leucine and valine, of adjusted particle size distribution as active ingredients and which contains a specific thickener or specific thickener combination, a sweetener, an aromatic constituent and a pH adjuster; and a production method therefor.

Description

분지쇄아미노산을 함유하는 약제학적 조성물 및 그 제조방법Pharmaceutical compositions containing branched chain amino acids and methods for preparing the same
본 발명은, 분지쇄아미노산을 유효성분으로 함유하고, 유효성분의 고미가 은폐된 약제학적 액상현탁조성물 및 제조방법에 관한 것이다. The present invention relates to a pharmaceutical liquid suspension composition containing a branched chain amino acid as an active ingredient and concealing the high content of the active ingredient, and a method for producing the same.
구체적으로는, 본 발명은 분지쇄 아미노산 3종, 구체적으로는, 이소류신, 류신 및 발린을 유효성분으로 함유하고, 유효성분의 고미가 은폐된 약제학적 액상현탁조성물 및 이의 제조방법에 관한 것이다.Specifically, the present invention relates to a pharmaceutical liquid suspension composition containing three branched chain amino acids, specifically, isoleucine, leucine, and valine, as an active ingredient, and concealing the gluten of the active ingredient, and a method for preparing the same.
더욱 구체적으로는, 본 발명은 입도분포를 조절한 분지쇄아미노산 3종, 구체적으로는, 이소류신, 류신 및 발린을 유효성분으로 함유하고, 특정의 점증제 또는 특정의 점증제의 조합을 포함하는 우수한 분산능을 갖는 액상현탁조성물 및 이의 제조방법에 관한 것이다.More specifically, the present invention contains three branched chain amino acids with controlled particle size distribution, specifically, isoleucine, leucine, and valine as active ingredients, and includes a specific thickener or a combination of specific thickeners. The present invention relates to a liquid suspension composition having a dispersing ability and a preparation method thereof.
나아가, 본 발명은 상기 액상현탁조성물의 상업적 이용을 위한 대량생산에서 분지쇄아미노산 3종을 특정 순서에 따라 특정한 온도조건에서 투입하는 것을 특징으로 하는 액상현탁조성물의 제조방법에 관한 것이다.Furthermore, the present invention relates to a method for preparing a liquid suspension composition, characterized in that the three branched chain amino acids are introduced under specific temperature conditions in a specific order in mass production for commercial use of the liquid suspension composition.
약제학적으로 허용되는 액상현탁조성물은 환자 또는 건강한 사람의 영양 상태를 개선하기 위해서 사용되는 것이고, 의료 분야 등에서 널리 이용되고 있으며, 통상 물 등의 용제에 용해 또는 현탁된 상태로 복용된다. 그러나, 분지쇄아미노산 3종을 함유하는 약제학적 액상현탁조성물은 쓴 맛이 있고, 그 때문에 이것을 복용하는 환자 등에게 부담이 되고 있다.Pharmaceutically acceptable liquid suspension compositions are used to improve the nutritional status of patients or healthy people, are widely used in the medical field, etc., and are usually taken in a dissolved or suspended state in a solvent such as water. However, the pharmaceutical liquid suspension composition containing three branched chain amino acids has a bitter taste, which is a burden on the patient or the like taking it.
한편, 이소류신, 류신 및 발린의 3종의 분지쇄아미노산을 포함하는 현탁제가 제안되었다. On the other hand, suspending agents comprising three branched chain amino acids of isoleucine, leucine and valine have been proposed.
일본 공개특허공보 제2002-114674호 (2002년 4월 16일 공개)는 분지쇄아미노산 및 산미제로서 적어도 1종의 유기산을 포함하는 의약용 현탁액을 개시하고 있다. 그러나, 단지 유기산을 첨가하는 것만으로는 쓴맛의 마스킹 효과가 충분치 않고, 따라서 상업적으로 실용화하기는 어렵다.Japanese Laid-Open Patent Publication No. 2002-114674 (published April 16, 2002) discloses a pharmaceutical suspension containing a branched chain amino acid and at least one organic acid as an acidulant. However, simply adding an organic acid does not have enough masking effect of bitterness, and therefore it is difficult to put it to commercial use.
공개특허 10-2005-0095833 (2005년 10월 04일 공개)에서는 실제로 쓴맛이 억제된 경구용 조성물을 얻기 위해서는 분지쇄아미노산 혼합물을 용액 또는 현탁액으로 제조한 직후에 복용해야 한다고 기술하고 있으므로, 사용자가 복용시에 직접 용액 또는 현탁액을 제조해야 하므로 복용시 번거로울 뿐만 아니라 사용자에 따라 물의 양, 섞는 시간, 섞는 방법 등이 다르므로 동일하고 효과적인 약효를 기대하기 힘들다. Since Patent Publication No. 10-2005-0095833 (published Oct. 4, 2005) states that in order to obtain an oral composition having a bitter taste in fact, the branched chain amino acid mixture should be taken immediately after the preparation of the solution or suspension. Since it is necessary to prepare a solution or suspension directly at the time of taking, it is not only cumbersome when taking, but the amount of water, the mixing time, and the mixing method vary depending on the user, so it is difficult to expect the same and effective drug efficacy.
등록특허 10-0927254 (2009년 11월 10일 등록)에서는 3종의 분지쇄아미노산에 알로에베라, 검류 및 산미제를 혼합함으로써 분지쇄아미노산 특유의 쓴맛 등 불쾌한 맛과 느낌을 경감시키는 동시에 분지쇄아미노산을 액상현탁조성물로 제형화함으로써 복용상 편리성을 개선하였다고 기술하고 있다. 그러나 상업적으로 이용할 경우 현탁제는 일정한 용량 또는 중량으로 제조하여 파우치로 판매되며, 보통 5mL~20mL (액상의 비중 0.8~1.2 g/mL) 단위이다. 그러나, 이 특허 문헌에서는 분지쇄아미노산의 용량이 20mL 당 이소류신 474mg, 류신 952mg, 발린 572mg으로, 치료용 제제인 리박트 과립 (LIVACT GRANULE)의 1회 복용량 이소류신 952mg,, 류신 1,904mg, 발린 1,144mg에 비해 사용량이 현저히 적다. 이는 이 문헌의 제시하는 방법 즉, 분지쇄아미노산 3종을 50~150 메쉬로 사용할 경우에는 의약용의 분지쇄아미노산 액상현탁조성물을 제조하기가 어렵다는 것을 보여주는 사례라고 볼 수 있다. 또한 알로에베라의 쓴맛으로 아미노산의 쓴맛을 마스킹한 제제이기 때문에 불쾌한 맛을 근본적으로 감추는 것이 아니라는 기술적인 한계가 있다. In Patent No. 10-0927254 (registered on November 10, 2009), three kinds of branched chain amino acids are mixed with aloe vera, gum and acidulant to reduce unpleasant taste and feeling such as bitterness peculiar to branched chain amino acids and at the same time, branched chain amino acids. It is described to improve the convenience of taking by formulating the into a liquid suspension composition. However, commercially available suspensions are prepared in fixed doses or weights and are sold in pouches, usually in units of 5 mL to 20 mL (specific gravity 0.8 to 1.2 g / mL). However, in this patent document, the doses of branched chain amino acids are 474 mg of isoleucine, leucine 952 mg, and valine 572 mg per 20 mL. Compared to the use is significantly less. This can be seen as an example showing that it is difficult to prepare a branched chain amino acid liquid suspension composition for medical use when the method proposed in this document, that is, three branched chain amino acids 50 to 150 mesh. In addition, there is a technical limitation that does not fundamentally mask the unpleasant taste because it is a preparation that masks the bitter taste of amino acids with the bitter taste of Aloe vera.
현재 분지쇄아미노산 3종을 포함하는 액상현탁 제제로서 시판중인 제품은 없는 실정이다. Currently, there are no commercially available liquid suspension preparations containing three branched chain amino acids.
이는 현탁액을 구성하는 분지쇄아미노산 3종의 1회 복용량이 많기 때문에 통상적인 방법으로는 치료용으로 적합한 액상현탁조성물의 구성을 완성하지 못하는 것으로 사료된다. 이는 또한 쓴맛은폐 뿐만 아니라, 분말에서 유래되는 구강내의 이물감, 상업적 판매를 위한 대량생산공정상의 트러블 등을 완전히 해결하지 못한 결과라고 사료된다.It is considered that this method does not complete the composition of a liquid suspension composition suitable for therapeutic treatment due to the large amount of one-time use of three branched chain amino acids constituting the suspension. This is also a result of not completely eliminating bitter taste, foreign matter in the oral cavity derived from powder, and troubles in the mass production process for commercial sale.
이소류신, 류신 및 발린으로 이루어지는 3종의 분지쇄아미노산을 유효성분으로 함유하는 의약용 제제는 간 질환에 효과적인 치료약으로 알려져 있다. 이들 분지쇄아미노산은 간경변 환자의 혈장 아미노산의 불균형을 시정하여 질소평형을 개선시키는 효과가 있다. 또한, 간경변 환자의 복수, 피로감 등의 자각 및 타각 증상을 개선시키고, 혈장 단백질 및 알부민의 증가, 단백 영양 상태를 개선하며, 근단백 분해 및 간분비성 단백 저하를 억제하며 혈소판수의 감소를 방지하는 효과를 나타낸다. Pharmaceutical preparations containing three branched chain amino acids consisting of isoleucine, leucine and valine as active ingredients are known as effective therapeutic drugs for liver disease. These branched chain amino acids have the effect of correcting the imbalance of plasma amino acids in patients with cirrhosis, thereby improving the nitrogen balance. In addition, it improves the perception and cognitive symptoms of cirrhosis, fatigue, etc. of patients with cirrhosis, increases plasma protein and albumin, improves protein nutrition status, inhibits muscle protein degradation and hepatic secretory protein reduction, and prevents platelet count reduction. It shows an effect.
현재 이들 3종의 분지쇄아미노산은 고형 제제인 과립제로 제형화되어 리박트 과립 (LIVACT GRANULE)으로 시판되고 있다. 그러나, 시판 중인 과립제의 경우, 복용시 아미노산 특유의 쓴맛으로 인해 불쾌감이 있고, 입 안에 과립제가 달라붙어 불편하다. These three branched chain amino acids are currently formulated as granules as solid preparations and marketed as LIVACT GRANULE. However, in the case of commercially available granules, there is an unpleasant feeling due to the bitterness peculiar to amino acids when taken, and it is uncomfortable because the granules adhere to the mouth.
또한, 과립제는 일반적으로 함량 균일성의 확보 및 용해성 향상 등의 요구를 만족시키기 위해 유효성분을 잘게 분쇄하여 사용하는 경우가 많은데, 특히, 당해 3종의 분지쇄아미노산의 입자를 함유하는 고형 제제의 경우, 원료 아미노산 입자의 입도만을 감소시켜 대처하고자 하면, 이의 비용적 (specific volume)이 커져 결과적으로 1회 복용량당 용적이 커져 복용시에 입안에서 부피가 커져 삼키기가 어렵다는 난점이 있고, 액상의 현탁제로 제형화 할 경우도 동일한 문제점이 발생하게 된다.In addition, granules are generally used by pulverizing the active ingredient in order to satisfy the requirements of securing content uniformity and improving solubility. In particular, in the case of a solid preparation containing particles of the three branched chain amino acids, In order to cope by reducing only the particle size of the raw material amino acid particles, the specific volume thereof increases, resulting in a large volume per dose, making it difficult to swallow due to a large volume in the mouth at the time of taking it. The same problem arises.
예를 들면, 함량 균일성의 확보 및 용해성 향상 등의 요구를 만족시키기 위해서 유효성분을 50㎛ 이하로 분쇄하여 사용하는 경우, 이와 같이 제조된 과립은 통상적으로 이의 비용적 (specific volume)이 2.0mL/g 또는 그 이상이 되며, 분지쇄아미노산의 1회 용량이 4 내지 5g 정도이므로 50㎛ 이하로 분쇄하여 과립 제제를 제조하면, 이의 용적은 8 내지 10mL 정도가 되어 입안에서 부피가 커져 매우 삼키기 어렵게 된다. For example, when the active ingredient is pulverized to 50 μm or less in order to satisfy the requirements such as ensuring content uniformity and improving solubility, granules thus prepared generally have a specific volume of 2.0 mL / s. g or more, since the single dose of branched chain amino acid is about 4 to 5 g, when the granule formulation is prepared by pulverizing to 50 μm or less, its volume becomes about 8 to 10 mL and becomes large in the mouth, making it very difficult to swallow. .
현탁제로 제형화 할 경우는 복용 및 휴대의 간편성을 위해 병 또는 파우치로 포장할 경우가 많은데, 파우치 포장을 예로 들면, 통상 5mL~20mL (비중 0.8~1.2 g/mL)의 용적으로 시판되지만, 분지쇄아미노산 3종 (이소류신, 류신 및 발린) 이 미분화되면 복용 시 용이하게 먹을 수 있는 유동성 있는 액상제제가 충분한 농도로 만들어지지 않고, 복용 시 물과 함께 복용해야 하며, 이때 물을 과도하게 섭취하면 복부 팽만의 부작용을 가져올 수 있고, 분지쇄아미노산 제제가 복수 등 수분조절이 필요한 간 질환자에게 투여되는 경우 수분조절의 어려움은 환자의 증상이 오히려 악화되는 원인이 될 수 있다. 분지쇄아미노산을 포함하는 의약용 제제가 주로 장기복용을 요하는 간경변 환자에게 투여됨을 고려할 때, 이러한 복용상의 어려움은 환자들이 중도에 복용을 중단하는 원인이 될 수도 있다. 따라서, 기 판매중인 현재의 과립제가 가지고 있는 복용상 문제점에 대한 개선이 절실한 실정이다. When formulated as a suspension, they are often packaged in bottles or pouches for ease of taking and carrying. For example, pouch packaging is commercially available in volumes of 5 mL to 20 mL (specific gravity 0.8 to 1.2 g / mL), but When the three chain amino acids (isoleucine, leucine and valine) are undifferentiated, a fluid liquid formulation that can be easily eaten when taken is not made in a sufficient concentration, and should be taken with water when taken. The side effects of bloating can be brought about, and when the branched chain amino acid preparation is administered to liver disease patients in need of water control such as ascites, difficulty in controlling water can cause a patient's symptoms to worsen. Given that medicinal preparations, including branched chain amino acids, are administered to patients with cirrhosis who require predominantly long-term use, this difficulty in dosing may cause patients to discontinue taking their medications. Therefore, there is an urgent need to improve the dosage problems of current granules on the market.
결론적으로 이소류신, 류신 및 발린으로 이루어지는 3종의 분지쇄아미노산은 강한 쓴맛과 특유의 아미노산 냄새가 있다는 점과 1회 적절한 유동성을 가지면서도 복용용적이 크지 않아야 한다는 점이 제제화하는데 어려움이 있어 이를 해결하는 것이 상업적 이용에 있어서 과제가 되고 있다. In conclusion, the three branched chain amino acids, consisting of isoleucine, leucine and valine, have a strong bitter taste and a characteristic amino acid odor, and once they have adequate fluidity but should not be large in dosage volume, it is difficult to formulate them. It has become a problem in commercial use.
본 발명은 이소류신, 류신 및 발린의 3종의 분지쇄아미노산을 포함하는 액상현탁조성물 및 이의 제조방법에 관한 것으로, 3종의 분지쇄아미노산에 점증제, pH조절제 및 감미제를 혼합하여 분지쇄아미노산 특유의 쓴맛 등 불쾌한 맛과 느낌을 경감시키는 액상현탁조성물을 제공함에 그 목적이 있다. The present invention relates to a liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine, and valine, and a method for preparing the same. A branched chain amino acid is mixed with a thickener, a pH adjusting agent, and a sweetener to provide a branched chain amino acid. The purpose is to provide a liquid suspension composition to reduce the unpleasant taste and feeling, such as bitter taste.
또한 상업적 판매를 위한 대량생산공정상의 트러블을 해결하여 분지쇄아미노산 3종 (이소류신, 류신 및 발린) 을 액상현탁조성물로 제형화하는 것을 또 하나의 과제로 한다. Another problem is to formulate three branched chain amino acids (isoleucine, leucine and valine) into liquid suspension compositions by solving problems in the mass production process for commercial sale.
위 과제의 해결수단으로서, 본 발명에서는, 이소류신, 류신 및 발린의 3종의 분지쇄 아미노산, 점증제, pH 조절제 및 약제학적으로 허용가능한 첨가제를 포함하는 경구투여 가능한 액상현탁조성물에 있어서, 상기 분지쇄 아미노산의 입도가 35메쉬 내지 100메쉬인 것을 특징으로 하는 액상현탁조성물이 제공된다.In order to solve the above problems, in the present invention, in the orally administrable liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, a thickening agent, a pH adjusting agent and a pharmaceutically acceptable additive, the branching A liquid suspension composition is provided, characterized in that the particle size of the chain amino acids is from 35 mesh to 100 mesh.
또한, 상기 액상현탁조성물에 있어서, 상기 점증제는 히드록시프로필셀룰로오스, 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 및 폴리비닐피롤리돈으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 액상현탁조성물이 제공된다.Further, in the liquid suspension composition, the thickener is provided with a liquid suspension composition, characterized in that selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose sodium carboxymethyl cellulose, and polyvinylpyrrolidone.
또한, 상기 액상현탁조성물에 있어서, 상기 pH 조절제는 시트르산 및 무수인산수소나트륨으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 액상현탁조성물이 제공된다.In the liquid suspension composition, the pH adjusting agent is provided with a liquid suspension composition, characterized in that selected from the group consisting of citric acid and anhydrous sodium hydrogen phosphate.
또한, 상기 액상현탁조성물에 있어서, pH범위가 5 내지 7인 것을 특징으로 하는 액상현탁조성물이 제공된다.In addition, in the liquid suspension composition, there is provided a liquid suspension composition, characterized in that the pH range of 5 to 7.
또한, 상기 액상현탁조성물에 있어서, 히드록시프로필셀룰로오스를 액상현탁조성물 중량대비 0.2 내지 2.0% (w/w), 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨을 액상현탁조성물 중량대비 1.0 내지 3.4% (w/w), 폴리비닐피롤리돈을 액상현탁조성물 중량대비 2.0 내지 4.0% (w/w) 를 함유하는 액상현탁조성물이 제공된다. In the liquid suspension composition, hydroxypropyl cellulose is 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, and microcrystalline cellulose-carboxymethyl cellulose sodium is 1.0 to 3.4% (w / w) by weight of the liquid suspension composition. ), A liquid suspension composition containing 2.0% to 4.0% (w / w) of polyvinylpyrrolidone by weight of the liquid suspension composition is provided.
마지막으로, 상기 액상현탁조성물을 제조하는 방법으로서, 실온 또는 미온의 정제수에 히드록시프로필셀룰로오스, 미결정셀룰로오스카르복시메칠셀룰로오스나트륨 및 폴리비닐피롤리돈으로 이루어지는 군으로부터 선택되는 점증제를 용해 또는 현탁시키는 단계; 상기 현탁용액에 이소류신, 류신 및 발린으로부터 선택되는 1종의 아미노산을 첨가하고 분산시키는 단계; 상기 현탁용액에 나머지 아미노산 2종을 50℃이하에서 첨가하고, 70 내지 90℃로 승온 및 분산시키는 단계; 상기 현탁용액에 보존제, 감미제, pH조절제를 첨가하여 용해시키는 단계를 포함하는 것을 특징으로 하는 이소류신, 류신 및 발린의 3종의 분지쇄아미노산을 포함하는 경구투여 가능한 액상현탁조성물의 제조방법이 제공된다.Finally, as a method for preparing the liquid suspension composition, dissolving or suspending a thickener selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose carboxymethyl cellulose sodium and polyvinylpyrrolidone in purified water at room temperature or mild temperature ; Adding and dispersing one amino acid selected from isoleucine, leucine and valine to the suspension solution; Adding the remaining two amino acids to the suspension solution at 50 ° C. or lower, and heating and dispersing at 70 to 90 ° C .; Provided is a method for preparing an orally administrable liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, comprising dissolving by adding a preservative, a sweetener, and a pH adjusting agent to the suspension solution. .
본 발명의 약제학적 액상현탁조성물은 약 20mL 정도의 용적에 분지쇄아미노산 3종을 4g~5g 포함할 수 있으므로 치료목적으로 환자에게 복용이 편리한 용략과 고미가 최소화된 맛의 액상현탁조성물을 제공한다. 또한 일반적으로 고미은폐에 이용되는 주성분 코팅 등의 공정이 없어 저비용 단순화된 제법으로 쉽게 제조할 수 있다. The pharmaceutical liquid suspension composition of the present invention may contain 4 g to 5 g of three branched chain amino acids in a volume of about 20 mL, thereby providing a liquid suspension composition with a convenient flavor and minimized taste to the patient for therapeutic purposes. . In addition, there is no process, such as coating the main ingredient is generally used for high concealment can be easily manufactured by a low cost simplified manufacturing method.
도 1은 본 발명의 제조방법의 제조공정도를 나타낸 도이다.1 is a view showing a manufacturing process diagram of the manufacturing method of the present invention.
도 2 및 3은 제조공정에 따른 뭉침현상을 비교한 도이다.2 and 3 is a view comparing the aggregation phenomenon according to the manufacturing process.
본 발명의 조성물은 의약품 제조에 통상적으로 사용되는 첨가제, 예를 들면, 산미제, 감미제, 풍미제, 결합제, 소포제, 분산제, 현탁화제, 안정화제, 부형제, 보존제 등을 1종 이상 함유하는 액상 현탁조성물 제조에 적합한 양으로 포함할 수 있다.The composition of the present invention is a liquid suspension containing one or more additives commonly used in the manufacture of pharmaceuticals, for example, acidulant, sweetener, flavoring agent, binder, antifoaming agent, dispersing agent, suspending agent, stabilizer, excipient, preservative, etc. It may be included in an amount suitable for preparing the composition.
분지쇄아미노산Branched chain amino acid
본 발명의 약제학적 액상현탁조성물에 함유되어 있는 분지쇄아미노산은 통상적으로 의약품이나 식품 등에 사용되는 이소류신, 류신 및 발린을 들 수 있다. 종래부터, 이소류신, 류신 및 발린의 3종의 아미노산으로 이루어지는 분지쇄아미노산은 단백질을 증가시키는 작용이나, 운동 시의 에너지원으로 중요한 역할을 하는 것이 알려져, 여러 가지 분지쇄아미노산을 함유하는 의약품, 식품 등이 개발되어 출시되었다. Branched chain amino acids contained in the pharmaceutical liquid suspension composition of the present invention include isoleucine, leucine, and valine, which are commonly used in medicines and foods. Conventionally, branched chain amino acids composed of three kinds of amino acids, isoleucine, leucine and valine, are known to play an important role as an energy source during exercise and to increase protein, and include various branched chain amino acids. Has been developed and released.
하지만, 일반적으로, 분지쇄아미노산을 함유하는 의약품, 식품 등은 분지쇄아미노산으로부터 유래하는 특유의 쓴 맛·냄새가 있고, 또한, 1회의 복용량이 다른 의약품, 식품 등과 비교하여 다량이기 때문에, 그 복용감은 그다지 양호하다고는 하기 어려운 것이다.However, in general, medicines and foods containing a branched chain amino acid have a unique bitter taste and smell derived from the branched chain amino acid, and since the dosage is a large amount compared to other medicines and foods, Persimmon is not so good.
한편, 아미노산은 L-체, D-체, DL-체 중 어느 것이라도 사용 가능하지만, 바람직하게는, L-체, DL-체이며, 더욱 바람직하게는, L-체이다. 또한, 아미노산은, 유리체 뿐만 아니라, 염의 형태라도 사용할 수 있고, 본 발명에 있어서, 아미노산은 유리체, 염의 양자를 포함하는 개념이다. 염의 예로서는, 산 부가염이나 염기와의 염 등을 들 수 있고, 아미노산의 의약으로서 허용될 수 있는 염을 선택하는 것이 바람직하다.On the other hand, the amino acid can be any of L-form, D-form, and DL-form, but preferably L-form, DL-form, and more preferably L-form. In addition, an amino acid can use not only a free body but a salt form, and in this invention, an amino acid is a concept containing both a free body and a salt. Examples of salts include acid addition salts and salts with bases, and it is preferable to select salts that are acceptable as pharmaceuticals of amino acids.
아미노산에 부가하여 의약으로서 허용될 수 있는 염을 형성하는 산으로서는, 예를 들면, 염화수소, 브롬화수소, 황산, 인산 등의 무기산; 아세트산, 락트산, 시트르산, 타르타르산, 말레산, 푸말산, 모노메틸황산 등의 유기산을 들 수 있다. 아미노산의 의약으로서 허용될 수 있는 염을 형성하는 염기의 예로서는, 예를 들면, 나트륨, 칼륨, 칼슘 등의 금속의 수산화물 또는 탄산화물, 또는 암모니아 등의 무기염기; 에틸렌디아민, 프로필렌디아민, 에탄올아민, 모노알킬에탄올아민, 디알킬에탄올아민, 디에탄올아민, 트리에탄올아민 등의 유기 염기를 들 수 있다.As an acid which forms a salt which can be accept | permitted as a medicine in addition to an amino acid, For example, inorganic acids, such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid; And organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and monomethyl sulfuric acid. As an example of the base which forms the salt which can be accept | permitted as a medicament of an amino acid, For example, Inorganic bases, such as hydroxide or carbonate of metal, such as sodium, potassium, calcium, or ammonia; And organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine and triethanolamine.
본 발명의 약제학적 액상현탁조성물은 이소류신, 류신 및 발린의 분지쇄아미노산 3종을 함께 함유하며, 약제학적 액상현탁조성물 중량대비 바람직하게는 19%~21% (w/w) 범위로 함유된다.The pharmaceutical liquid suspension composition of the present invention contains three branched chain amino acids of isoleucine, leucine and valine together, preferably in the range of 19% to 21% (w / w) based on the weight of the pharmaceutical liquid suspension composition.
점증제Thickener
본 발명의 약제학적조성물은 점증제를 함유할 수 있다. 메틸셀룰로오스, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스, 하이드록시프로필메틸셀룰로오스프탈레이트 등의 셀룰로오스 유도체: 옥수수 전분, 밀 전분 등의 전분류: 폴리비닐피롤리돈, 폴리비닐알코올, 아크릴산 중합체 등의 합성 고분자류: 한천, 잔탄검, 아라비아 고무, 젤라틴 등의 천연고분자류, 미결정셀룰로오스, 셀룰로오스중합체, 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 등을 들 수 있다. 한편, 본 발명자의 연구에 의하면, 예기치 않게도, 점증제의 조합에 따라서 현택액의 품질이 일정하지 않음을 알았고, 특히, 점증제로서 폴리비닐프롤리돈, 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 및 히드록시프로필셀룰로오스를 조합하여 사용할 때 현탁상태가 우수함을 발견하였다. 또한, 점증제의 함유량은 통상의 액상현탁조성물 제조가 가능한 범위 내면 좋은데, 바람직하게는, 히드록시프로필셀룰로오스를 액상현탁조성물 중량대비 0.2 내지 2.0% (w/w), 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨을 액상현탁조성물 중량대비 1.0 내지 3.4% (w/w), 폴리비닐피롤리돈을 액상현탁조성물 중량대비 2.0 내지 4.0% (w/w)포함하는 것이 좋다.The pharmaceutical composition of the present invention may contain a thickener. Cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose phthalate Starch such as corn starch, wheat starch, etc .: Synthesis of polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymer Polymers: Natural polymers such as agar, xanthan gum, gum arabic and gelatin, microcrystalline cellulose, cellulose polymers, microcrystalline cellulose and sodium carboxymethyl cellulose. On the other hand, studies by the inventors have unexpectedly found that the quality of the suspension liquid is not constant depending on the combination of the thickeners, and in particular, polyvinylprolidone, microcrystalline cellulose, carboxymethylcellulose sodium and hydroxide as thickeners. It has been found that the suspension state is excellent when used in combination with oxypropyl cellulose. In addition, the content of the thickener may be within the range in which the usual liquid suspension composition can be prepared. Preferably, hydroxypropyl cellulose is 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, and microcrystalline cellulose and carboxymethyl cellulose sodium are used. To 1.0 to 3.4% (w / w) of the weight of the liquid suspension composition, polyvinylpyrrolidone is preferably included 2.0 to 4.0% (w / w) of the weight of the liquid suspension composition.
pH조절제pH regulator
본 발명의 약제학적조성물은 pH조절제를 함유할 수 있다. 대한약전 제9개정에는 pH를 조절할 수 있는 인산수소이나트륨시트르산완충액의 제조법이 개시되어 있다. 이에 한정되는 것은 아니지만, 시트르산과 무수인산수소나트륨과 같은 pH조절제를 적절히 사용하여 pH3.0 내지 pH9.0 범위, 바람직하게는 pH4.0 내지 pH8.0, 더욱 바람직하게는 pH5.0 내지 pH7.0 범위로 제조할 수 있다. The pharmaceutical composition of the present invention may contain a pH adjusting agent. In the ninth revision of the Korean Pharmacopoeia, there is disclosed a method for preparing disodium hydrogen phosphate citrate buffer which can adjust pH. Although not limited thereto, pH adjusting agents such as citric acid and anhydrous sodium hydrogen phosphate may be appropriately used to range from pH3.0 to pH9.0, preferably pH4.0 to pH8.0, more preferably pH5.0 to pH7. It can be produced in the 0 range.
본 발명의 분지쇄아미노산 3종은 pH5.0~7.0 부근에서 안정한 경향을 보이고, 또한 같은 범위에서 쓴맛 내지는 불쾌한 맛이 최소화된다. Three branched chain amino acids of the present invention show a tendency to be stable near pH 5.0 to 7.0, and also minimize the bitter or unpleasant taste in the same range.
산미제Acid
사용할 수 있는 산미제로서는 의약품 제조에 사용가능한 것이면 어떠한 것이라도 양호하지만, 풍미를 개선하고 쓴맛을 감소시킨다는 관점에서 아스코르브산, 시트르산 (구연산) 및 말산이 바람직하다. 산의 첨가량에는 특별한 제한은 없고, 단독으로 아미노산 혼합물에 사용될 수 있으며 다른 첨가제와 함께 첨가될 수도 있다. 사용가능한 풍미제로는 사과향 또는 딸기향 등의 냄새 개선제를 들 수 있다.As the acidulant that can be used, any one that can be used for the manufacture of a pharmaceutical product is acceptable, but ascorbic acid, citric acid (citric acid) and malic acid are preferable from the viewpoint of improving the flavor and reducing the bitter taste. There is no particular limitation on the amount of acid added, and it may be used alone in the amino acid mixture and may be added together with other additives. Flavors that can be used include odor enhancers such as apple or strawberry flavors.
감미제Sweetener
본 발명의 약제학적조성물은 감미제를 함유할 수 있다. 감미제로서는 설탕, 포도당, 말토스, 올리고당, 갈락토스, 물엿, 솔비톨, 말티톨, 전화당, 자일리톨, 에리스리톨, 수첨물엿, 만니톨, 트레할로스, 아스파탐, 아세설팜염, 슈크랄로스, 사카린염, 네오타임, 타오마틴, 토마틴혼합물, 사이클라메이트염, 타우마틴, 나한과 추출물, 감초 추출물, 스테비오사이드, 효소처리스테비오사이드, 네오헤스페리딘 및 모넬린로 이루어진 군에서 선택되는 하나 이상의 고감미 감미료일 수 있다. The pharmaceutical composition of the present invention may contain a sweetening agent. As sweeteners, sugar, glucose, maltose, oligosaccharide, galactose, syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, hydrogenated syrup, mannitol, trehalose, aspartame, acesulfame salt, sucralose, saccharin salt, neotime, tao It may be one or more high sweetening sweeteners selected from the group consisting of martin, tomatin mixtures, cyclate salts, taumartin, Nahan fruit extract, licorice extract, stevioside, enzyme treatment stevioside, neohesperidine and monelin.
소포제Antifoam
소포제로서는 미리스트산, 팔미트산, 시메티콘, 실리콘 소포제 등 의약용 소포제로서 일반적으로 공지된 것 중 에서 적절히 선택할 수 있으며, 사용량은 유효성분의 조성에 따라 달라질 수 있다. The antifoaming agent may be appropriately selected from among those generally known as medical antifoaming agents such as myristic acid, palmitic acid, simethicone, silicone antifoaming agent, and the amount of use may vary depending on the composition of the active ingredient.
보존제Preservative
본 발명의 액상현탁조성물은 안전성을 위해 액상 제제에 통상적으로 사용되는 보존제를 포함할 수 있다. 사용할 수 있는 보존제로는 소르빈산 및 이의 염, 안식향산 및 이의 염, 및 파라옥시안식향산 및 이의 염 등을 들 수 있다.The liquid suspension composition of the present invention may include a preservative commonly used in liquid formulations for safety. Preservatives that can be used include sorbic acid and salts thereof, benzoic acid and salts thereof, and paraoxybenzoic acid and salts thereof.
향료Spices
본 발명의 약제학적조성물은 또한 향료를 포함할 수 있다. 본 발명의 약제학적조성물은 구강을 통해 복용하는 제품이므로 적절한 향을 가할 필요가 있다. 상기 향료는 천연 향료, 인공향료 또는 이들의 혼합물일 수 있다. 천연 향료는 식물의 잎, 꽃, 열매 등으로부터의 추출물, 식물의 오일 등일 수 있다. 식물의 오일은 스피어민트오일, 계피오일, 페퍼민트 오일, 레몬 오일, 정향 (clove) 오일, 베이 (bay) 오일, 백리향 (thyme) 오일, 삼나무잎 (cedar leaf) 오일, 육두구 (nutmeg) 오일, 세이지 (sage) 오일 및 아몬드 (almond) 오일 등을 포함한다. 또한 인공 향료로는 레몬, 오렌지, 포도, 라임, 딸기 등의 과일의 인공합성 과일향 및 바닐라, 초코렛, 커피, 코코아, 솔잎, 인삼, 홍삼, 시트러스와 같은 인공 합성향이 사용될 수 있다. The pharmaceutical composition of the present invention may also comprise perfume. Since the pharmaceutical composition of the present invention is a product to be taken through the oral cavity, it is necessary to add an appropriate flavor. The flavor may be natural flavors, artificial flavors or mixtures thereof. Natural flavors may be extracts from the leaves, flowers, fruits and the like of plants, oils of plants and the like. Plant oils include spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage ( sage) oil, almond oil and the like. In addition, artificial flavors of fruits, such as lemons, oranges, grapes, limes, strawberries and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, citrus may be used.
색소Pigment
본 발명의 약제학적조성물은 제품에 알맞은 색소를 포함할 수 있다. 색소는 필요에 따라 그 함량을 적절히 조절할 수 있으며, 일반적으로 약제학적 액상현탁조성물 중량 대비, 0.1 ~ 1.0 중량% (w/w) 첨가될 수 있다. 상기 색소는 천연 또는 합성 색소일 수 있다.The pharmaceutical composition of the present invention may include a pigment suitable for the product. The pigment may be appropriately adjusted in amount as necessary, and in general, 0.1 to 1.0% by weight (w / w) may be added to the weight of the pharmaceutical liquid suspension composition. The pigment may be a natural or synthetic pigment.
청량제Coolant
본 발명의 약제학적조성물은 또한 청량제를 추가로 포함할 수 있다. 청량제는 제한되는 것은 아니나, 예를 들어, l-멘톨, WS3, WS23 또는 퀘스타이스-엘 일 수 있다. 청량제는 필요에 따라 그 함량을 적절히 조절할 수 있으며, 일반적으로 약제학적조성물 전체중량 대비, 10 중량% (w/w) 이하로 첨가될 수 있다. The pharmaceutical composition of the present invention may also further comprise a cooling agent. The refreshing agent may be, but is not limited to, for example, l-menthol, WS3, WS23, or Questais-L. The refreshing agent can be appropriately adjusted in accordance with the content, if necessary, in general, may be added up to 10% by weight (w / w) relative to the total weight of the pharmaceutical composition.
구취제거제Deodorant
본 발명의 약제학적조성물은 구강악취를 경감시키는 구취제거제가 추가로 포함될 수 있다. 상기 구취 제거제는 금속염일 수 있다. 상기 금속염은 예를 들어, 클로라이트의 금속염, 카퍼 글루코네이트, 징크 클로라이드, 징크 시트레이트 및 징크 글루코네이트로 이루어진 군으로부터 선택되는 하나 이상의 성분일 수 있다. 또 다른 하나의 예로는 늄 클로라이드, 홍삼 추출물, 녹차 추출물, 해조 추출물, 한방추출물, 그레이프후르트 추출물, 사과 추출물, 타임오일, 티몰, 항생제, 게라니올, 카르바크롤, 시트랄, 히노키티올, 유칼립톨, 카테콜, 메틸살리실레이트 및 과산화수소로 이루어진 군으로부터 선택되는 하나 이상의 성분일 수 있다. 이러한 하나 이상의 구취 제거제 성분은 상기 하나 이상의 금속염과 함께 또는 독립적으로 사용될 수 있다. The pharmaceutical composition of the present invention may further include a bad breath remover to reduce oral odor. The bad breath remover may be a metal salt. The metal salt may be, for example, one or more components selected from the group consisting of metal salts of chlorite, copper gluconate, zinc chloride, zinc citrate and zinc gluconate. Another example is nium chloride, red ginseng extract, green tea extract, seaweed extract, herbal extract, grapefruit extract, apple extract, time oil, thymol, antibiotic, geraniol, carbachol, citral, hinokithiol, One or more components selected from the group consisting of eucalyptol, catechol, methylsalicylate and hydrogen peroxide. Such one or more bad breath remover components may be used together or independently with the one or more metal salts.
이하, 본 발명의 조성물을 제조하는 방법을 하기의 비교예 및 실시예를 통해 상세히 설명하지만, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the method of preparing the composition of the present invention will be described in detail through the following Comparative Examples and Examples, but the scope of the present invention is not limited thereto.
점도측정:Viscosity Measurement:
내경 약 3cm, 50mL의 원심분리 튜브에 약제학적 액상현탁액 약 40mL을 담아 62번 스핀들을 이용하여 점도를 측정하였다. (BROOKFIELD, 모델명: DV-2+ Pro, USA, 측정법: cup and bob, 측정온도: 실온)The viscosity was measured using a No. 62 spindle containing about 40 mL of the pharmaceutical liquid suspension in a centrifuge tube of about 3 cm in diameter and 50 mL. (BROOKFIELD, model name: DV-2 + Pro, USA, measurement method: cup and bob, measurement temperature: room temperature)
입도분급:Granularity classification:
분지쇄아미노산 3종의 입도분급에는 표준체 (TESTING SIEVE, 청계상공社, 대한민국)와 Sieve shaker (동서과학社, 모델명: CG-211-8, 대한민국)를 사용하여 5분간 흔들어 (shaking) 분급한 뒤, 각각의 표준체망 및 받침대 (pan)에 잔류하는 분말를 수거하여 사용하였다. 대량생산에서는 별도의 설비를 사용하여 수동분급을 진행하였다. For the particle size classification of three branched chain amino acids, shake for 5 minutes using a standard (TESTING SIEVE, Cheonggye Sangyo, Korea) and Sieve shaker (East-West Science, model name: CG-211-8, Korea). The powder remaining in each of the standard sieve network and the pan was collected and used. In mass production, manual classification was performed using a separate facility.
쓴 맛 평가 점수:Bitter Taste Score:
하기 사항에 관하여 25세~40세 남녀 10명의 평균값을 계산하였다. With respect to the following matters, the average value of ten men and women aged 25 to 40 years was calculated.
1: 쓴맛이 전혀 없음 2: 쓴맛이 거의 없음 1: no bitter taste 2: little bitter taste
3: 쓴맛이 보통임 4: 쓴맛이 있어 약간 불쾌함3: moderate bitterness 4: slightly unpleasant due to bitter taste
5: 쓴맛이 강하여 매우 불쾌함 5: very bitter, very unpleasant
이물감 평가 점수:Foreign body evaluation score:
하기 사항에 관하여 25세~40세 남녀 10명의 평균값을 계산하였다. With respect to the following matters, the average value of ten men and women aged 25 to 40 years was calculated.
1: 이물감이 전혀 없음 2: 이물감이 거의 없음 1: no foreign material at all 2: almost no foreign material
3: 이물감이 보통임 4: 이물감이 있어 약간 불쾌함3: Foreign object is normal 4: There is foreign object and it is slightly unpleasant
5: 이물감이 강하여 매우 불쾌함5: very unpleasant due to strong foreign body
온도의 정의 (대한약전 제 9개정 통칙 인용)Definition of temperature (quoted from the ninth amendment to the KP)
1. 20℃는 표준온도 2. 15~25℃는 상온 1. Standard temperature at 20 ℃ 2. Normal temperature at 15 ~ 25 ℃
3. 1~30℃는 실온 4. 30~40℃는 미온3. 1 ~ 30 ℃ is room temperature 4. 30 ~ 40 ℃ is lukewarm
분지쇄아미노산 함유 약제학적조성물의 제조Preparation of Branched Chain Amino Acid-Containing Pharmaceutical Compositions
비교예1:Comparative Example 1:
정제수10g 및 D-소르비톨4.8g 의 혼합물에 히드록시프로필셀룰로오스200mg, 폴리비닐피롤리돈200mg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 (Microcrystalline and carboxymethylcellulose Sodium)200mg 을 고르게 분산시킨 뒤, 분지쇄아미노산 3종 (L-이소류신952mg, L-류신1,904mg, L-발린1,144mg) 을 넣고 교반현탁시킨 뒤, 가온하여 70~90℃로 1시간 유지시키면서, 파라옥시벤조산메틸1.6mg, 파라옥시베조산프로필0.4mg을 투입하고, 이어서 시트르산120mg 및 무수인산수소나트륨 400mg을 넣어서 pH를 조절한 뒤, 냉각시켜 정제수로 표선하여 20g의 분지쇄아미노산 현탁액을 수득하였다. In a mixture of 10 g of purified water and 4.8 g of D-sorbitol, 200 mg of hydroxypropyl cellulose, 200 mg of polyvinylpyrrolidone and 200 mg of microcrystalline and carboxymethylcellulose sodium were uniformly dispersed, followed by three branched chain amino acids ( L-isoleucine 952mg, L-leucine 1,904mg, L-valine 1,144mg) was added and the mixture was suspended and stirred, and maintained at 70-90 ° C. for 1 hour, 1.6 mg of methyl paraoxybenzoate and 0.4 mg of paraoxybezoic acid profile. The pH was adjusted by adding 120 mg of citric acid and 400 mg of anhydrous sodium hydrogen phosphate, followed by cooling to obtain purified 20 g of branched chain amino acid suspension.
이때의 분지쇄아미노산 3종의 입도는 별도의 분급없이 상업적으로 판매되고 있는 원료를 그대로 사용하였으며, 혼합한 3종의 분지쇄아미노산은 18mesh 이상의 굵은 입자와 100mesh 이하의 미세한 입자가 넓게 분포하였다. At this time, the particle size of the three branched chain amino acids was used as commercially available raw materials without separate classification, and the mixed three branched chain amino acids had a wide distribution of coarse particles of 18 mesh or more and fine particles of 100 mesh or less.
상기의 공정을 통하여 제조된 현탁액은 상분리가 발생하고, 아미노산 특유의 불쾌한 쓴맛 및 오취가 있다. Suspensions prepared through the above processes occur in phase separation and have an unpleasant bitterness and foul smell peculiar to amino acids.
비교예 및 실시예Comparative Example and Example
비교예2 내지 19Comparative Examples 2 to 19 , , 실시예1 내지 3Examples 1 to 3
분지쇄아미노산 3종 이외의 성분을 비교예1과 동일한 처방과 순서로 액상현탁조성물을 제조하되, 주성분인 분지쇄아미노산 3종의 입도분포를 표1 및 표 2와 같이 표준체망 (TESTING SIEVE, 청계상공사, 한국)을 사용하여 분급하여 각 입도별로 액상현탁조성물을 제조하였다. 비교예1의 경우 주성분 3종을 별도의 분급없이 상업적으로 판매되고 있는 원료를 그대로 사용하였으며, 비교예2 내지 8의 경우 L-이소류신만 분급하여 제조하였고, 비교예9 내지 12의 경우 L-류신만 분급하여 제조하였고, 비교예13 내지 17의 경우 L-발린만 분급하여 제조하였다.A liquid suspension composition was prepared in the same manner as in Comparative Example 1 with the exception of the three branched chain amino acids, but the particle size distribution of the three branched chain amino acids as the main component was shown in Table 1 and Table 2. Commercial corporation, Korea) to prepare a liquid suspension composition for each particle size. In Comparative Example 1, three main ingredients were used commercially as raw materials without separate classification, and Comparative Examples 2 to 8 were prepared by classifying only L-isoleucine, and Comparative Examples 9 to 12, L-leucine. It was prepared by classifying only, in the case of Comparative Examples 13 to 17 was prepared by classifying only L-valine.
비교예18, 비교예19, 실시예1 내지 3의 경우 분지쇄아미노산 3종을 각각 분급하여 L-이소류신 : L-류신 : L-발린 = 1 : 2 : 1.2 의 비율 (소수점 둘째자리 반올림) 로 각각 20g의 약제학적 액상현탁액을 제조하였다. 제조한 액에 대하여 현탁상태, 점도, 쓴 맛 및 이물감을 상기한 평가기준에 맞춰 평가하였다.In Comparative Example 18, Comparative Example 19, and Examples 1 to 3, three branched chain amino acids were classified, respectively, in a ratio of L-isoleucine: L-leucine: L-valine = 1: 2: 1.2 (rounded to two decimal places). Each 20 g of pharmaceutical liquid suspension was prepared. The prepared solution was evaluated in accordance with the evaluation criteria described above in terms of suspension state, viscosity, bitter taste and foreign matter.
놀랍게도, 표1 및 2에서 알 수 있는 바와 같이, 분지쇄 아미노산 3종은 35mesh 내지 100mesh의 입도를 이용하면 (실시예1 내지 실시예3), 기존의 분지쇄아미노산 3종을 이용한 현탁액제 공지기술로는 기대 할 수 없었던 제제 즉, 우수한 현탁상태를 가지고, 또한 동시에 분지쇄아미노산 자체의 쓴맛도 개선되면서 이물감도 개선되어 복용하기에 적절한 의약용 내용 현탁액제를 만들 수 있는 것을 발견하였다. 이때의 점도는 120cp 내지 400cp 임을 확인할 수 있었다. Surprisingly, as can be seen in Tables 1 and 2, three branched chain amino acids using a particle size of 35 mesh to 100 mesh (Examples 1 to 3), known suspension formulation using three conventional branched chain amino acids It was found that Roh could make a pharmaceutical suspension suitable for use, which had an excellent suspension, that is, it also improved the bitter taste of the branched chain amino acid itself and improved the foreign body. The viscosity at this time was confirmed to be 120cp to 400cp.
표 1
구성성분 비교예1 비교예2 비교예3 비교예4 비교예5 비교예6 비교예7 비교예8 비교예9 비교예10 비교예11
엘-이소류신 238.0 1000 1000 1000 1000 1000 1000 1000 - - -
엘-류신 476.0 - - - - - - - 1000 1000 1000
엘-발린 286.0 - - - - - - - - - -
입도(mesh) 분급없음 18-20 20-25 25-35 35-40 40-60 60-100 100통과 35-40 40-60 60-100
고형분 총량 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
현탁상태 상분리 경시적상분리 경시적상분리 경시적상분리 양호 양호 양호 양호 양호 양호 양호
점도 미측정 394.6 314.1 267.7 203.5 212.6 222.7 356.9 269.8 153.5 112.5
쓴 맛 평가점수(1~5점) 5.0 2.4 2.4 2.7 2.8 3.0 3.3 4.1 2.2 2.3 2.2
이물감 평가점수(1~5점) 5.0 5.0 5.0 4.6 4.1 2.2 2.0 1.4 2.1 2.2 1.7
Table 1
Ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
L-isoleucine 238.0 1000 1000 1000 1000 1000 1000 1000 - - -
L-leucine 476.0 - - - - - - - 1000 1000 1000
L-valine 286.0 - - - - - - - - - -
Particle size No classification 18-20 20-25 25-35 35-40 40-60 60-100 100 passes 35-40 40-60 60-100
Total solids 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
Suspension Phase separation Over time phase separation Over time phase separation Over time phase separation Good Good Good Good Good Good Good
Viscosity Unmeasured 394.6 314.1 267.7 203.5 212.6 222.7 356.9 269.8 153.5 112.5
Bitter Taste Score (1-5 points) 5.0 2.4 2.4 2.7 2.8 3.0 3.3 4.1 2.2 2.3 2.2
Foreign body evaluation score (1-5 points) 5.0 5.0 5.0 4.6 4.1 2.2 2.0 1.4 2.1 2.2 1.7
(단위 : mg/5g)(Unit: mg / 5g)
표 2
구성성분 비교예12 비교예13 비교예14 비교예15 비교예16 비교예17 비교예18 실시예1 실시예2 실시예3 비교예19
엘-이소류신 - - - - - - 238.0 238.0 238.0 238.0 238.0
엘-류신 1000 - - - - - 476.0 476.0 476.0 476.0 476.0
엘-발린 - 1000 1000 1000 1000 1000 286.0 286.0 286.0 286.0 286.0
입도(mesh) 100통과 25-35 35-40 40-60 60-100 100통과 18-35 35-40 40-60 60-100 100통과
고형분 총량 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
현탁상태 양호 양호 양호 양호 케이킹 케이킹 상분리 양호 양호 양호 경시적상분리
점도 126.3 138.8 150.6 259.9 2318.0 5397.0 109.4 123.5 232.8 349.9 720.2
쓴 맛 평가점수(1~5점) 2.4 1.4 1.5 1.4 1.3 1.6 1.5 1.7 1.6 1.9 1.8
이물감 평가점수(1~5점) 1.0 2.2 2.0 1.6 1.5 1.2 4.2 2.3 2.1 1.7 1.5
TABLE 2
Ingredient Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Example 1 Example 2 Example 3 Comparative Example 19
L-isoleucine - - - - - - 238.0 238.0 238.0 238.0 238.0
L-leucine 1000 - - - - - 476.0 476.0 476.0 476.0 476.0
L-valine - 1000 1000 1000 1000 1000 286.0 286.0 286.0 286.0 286.0
Particle size 100 passes 25-35 35-40 40-60 60-100 100 passes 18-35 35-40 40-60 60-100 100 passes
Total solids 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
Suspension Good Good Good Good Caking Caking Phase separation Good Good Good Over time phase separation
Viscosity 126.3 138.8 150.6 259.9 2318.0 5397.0 109.4 123.5 232.8 349.9 720.2
Bitter Taste Score (1-5 points) 2.4 1.4 1.5 1.4 1.3 1.6 1.5 1.7 1.6 1.9 1.8
Foreign body evaluation score (1-5 points) 1.0 2.2 2.0 1.6 1.5 1.2 4.2 2.3 2.1 1.7 1.5
(단위 :mg/5g)(Unit: mg / 5g)
실시예4 내지 17Examples 4 to 17
비교예1과 동일한 공정 (처방은 표 3에 기재) 으로 액상현탁조성물을 제조하되, 이때의 분지쇄아미노산 3종의 입도를 표준체망 (TESTING SIEVE, 청계상공사, 한국)을 사용하여 분급하여 35mesh 통과 100mesh에 잔류한 분지쇄아미노산 3종으로 액상현탁조성물을 제조하였다. 또한 분지쇄 아미노산 현탁액을 제조하기 위하여 표3에 기재된 바와 같이 히드록시프로필셀룰로오스, 폴리비닐피롤리돈, 히드록시프로필메틸셀룰로오스 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨(Microcrystalline and carboxymethylcellulose Sodium) 군에서 선택되는 하나 또는 둘이상의 점증제를 사용하였다. 예기치 않게도, 점증제의 조합에 따라 현탁액의 품질이 일정하지 않았고, 결과적으로는 점증제로서 PVPK30, AvicelRC591, HPC-L 조합하여 사용할 때 현탁상태가 우수함을 알 수 있었다. A liquid suspension composition was prepared in the same process as in Comparative Example 1 (prescription is shown in Table 3), and the particle sizes of the three branched chain amino acids were classified using a standard sieve network (TESTING SIEVE, Cheonggye Sangpo, Korea) and 35mesh. A liquid suspension composition was prepared from three branched chain amino acids remaining at 100 mesh. It is also one selected from the group of hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose and microcrystalline carboxymethyl cellulose sodium as shown in Table 3 to prepare a branched chain amino acid suspension. Or more than one thickener was used. Unexpectedly, the quality of the suspension was not constant according to the combination of the thickeners, and as a result, the suspension was found to be excellent when used in combination with PVPK30, AvicelRC591, HPC-L as the thickener.
표 3
구성성분 실시예4 실시예5 실시예6 실시예7 실시예8 실시예9 실시예10 실시예11 실시예12 실시예13 실시예14 실시예15 실시예16 실시예17
주성분(3종 총량) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-소르비톨액 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 300 - - - 150 150 150 - - - 100 100 100 -
Avicel RC 591 - 300 - - 150 - - 150 150 - 100 100 - 100
HPC-L - - 300 - - 150 - 150 - 150 100 - 100 100
HPMC 2910 - - - 300 - - 150 - 150 150 - 100 100 100
아스파탐 5 5 5 5 5 5 5 5 5 5 5 5 5 5
시트르산 30 30 30 30 30 30 30 30 30 30 30 30 30 30
무수인산수소나트륨 100 100 100 100 100 100 100 100 100 100 100 100 100 100
정제수 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365
총량 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
현탁상태 상분리 상분리 상분리 상분리 경시적상분리 상분리 상분리 상분리 상분리 상분리 양호 상분리 상분리 상분리
TABLE 3
Ingredient Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17
Main ingredient (three kinds of total quantities) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-sorbitol solution 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 300 - - - 150 150 150 - - - 100 100 100 -
Avicel RC 591 - 300 - - 150 - - 150 150 - 100 100 - 100
HPC-L - - 300 - - 150 - 150 - 150 100 - 100 100
HPMC 2910 - - - 300 - - 150 - 150 150 - 100 100 100
Aspartame 5 5 5 5 5 5 5 5 5 5 5 5 5 5
Citric acid 30 30 30 30 30 30 30 30 30 30 30 30 30 30
Sodium Hydrogen Phosphate Anhydrous 100 100 100 100 100 100 100 100 100 100 100 100 100 100
Purified water 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365
Total amount 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
Suspension Phase separation Phase separation Phase separation Phase separation Over time phase separation Phase separation Phase separation Phase separation Phase separation Phase separation Good Phase separation Phase separation Phase separation
(단위 : mg/5g)(Unit: mg / 5g)
실시예 18 내지 34Examples 18-34
비교예1과 동일한 공정 (처방은 표 4 및 5에 기재) 으로 액상현탁조성물을 제조하였고, 이때의 분지쇄아미노산 3종의 입도를 표준체망 (TESTING SIEVE, 청계상공사, 한국)을 사용하여 분급하여 35mesh 통과 100mesh에 잔류한 분지쇄아미노산 3종으로 액상현탁조성물을 제조하였다. 표3에서 선정된 PVPK30, AvicelRC591 및 HPC-L 을 가지고 적절한 구성성분 비를 찾기 위하여 하기 표4 및 5에 기재된 바와 같이 제조하고, 현탁상태를 평가하였다.A liquid suspension composition was prepared in the same process as in Comparative Example 1 (prescription is described in Tables 4 and 5), and the particle size of the three branched chain amino acids was classified using a standard sieve network (TESTING SIEVE, Cheonggye Sangpo, Korea). The liquid suspension composition was prepared from three branched chain amino acids remaining in 100 mesh through 35 mesh. It was prepared as described in Tables 4 and 5 below to find the appropriate component ratios with PVPK30, AvicelRC591 and HPC-L selected in Table 3, and the suspensions were evaluated.
시험 결과를 면밀히 관찰한 결과인 표 4및 5로부터, 점증제로서 PVPK30을 약제학적 액상현탁조성물 중량대비 2.0 내지 4.0%(w/w), AvicelRC591을 약제학적 액상현탁조성물 중량대비 1.0 내지 3.4%(w/w), HPC-L을 약제학적 액상현탁조성물 중량대비 0.2 내지 2.0%(w/w) 조합하여 사용할 때에 그 현탁상태가 우수함을 발견할 수 있었다. From Tables 4 and 5, which are closely observed test results, PVPK30 as a thickener was 2.0 to 4.0% (w / w) based on the weight of the pharmaceutical liquid suspension composition, and AvicelRC591 was 1.0 to 3.4% by weight of the pharmaceutical liquid suspension composition ( w / w), HPC-L was found to be excellent in suspension state when used in combination with 0.2 to 2.0% (w / w) relative to the weight of the pharmaceutical liquid suspension composition.
표 4
구성성분 실시예8 실시예14 실시예18 실시예19 실시예20 실시예21 실시예22 실시예23 실시예24
주성분(3종 총량) 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-소르비톨액 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 150 100 100 100 100 100 150 150 150
Avicel RC 591 150 100 140 170 60 30 140 130 100
HPC-L - 100 60 30 140 170 10 20 50
HPMC 2910 - - - - - - - - -
아스파탐 5 5 5 5 5 5 5 5 5
시트르산 30 30 30 30 30 30 30 30 30
무수인산수소나트륨 100 100 100 100 100 100 100 100 100
정제수 2365 2365 2365 2365 2365 2365 2365 2365 2365
총량 5000 5000 5000 5000 5000 5000 5000 5000 5000
현탁상태 경시적상분리 양호 양호 양호 상분리 상분리 상분리 양호 양호
Table 4
Ingredient Example 8 Example 14 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24
Main ingredient (three kinds of total quantities) 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-sorbitol solution 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 150 100 100 100 100 100 150 150 150
Avicel RC 591 150 100 140 170 60 30 140 130 100
HPC-L - 100 60 30 140 170 10 20 50
HPMC 2910 - - - - - - - - -
Aspartame 5 5 5 5 5 5 5 5 5
Citric acid 30 30 30 30 30 30 30 30 30
Sodium Hydrogen Phosphate Anhydrous 100 100 100 100 100 100 100 100 100
Purified water 2365 2365 2365 2365 2365 2365 2365 2365 2365
Total amount 5000 5000 5000 5000 5000 5000 5000 5000 5000
Suspension Over time phase separation Good Good Good Phase separation Phase separation Phase separation Good Good
(단위 : mg/5g)(Unit: mg / 5g)
표 5
구성성분 실시예25 실시예26 실시예27 실시예28 실시예29 실시예30 실시예31 실시예32 실시예33 실시예34
주성분(3종 총량) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-소르비톨액 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 150 150 200 200 200 200 200 50 50 50
Avicel RC 591 80 50 90 80 70 50 20 125 100 150
HPC-L 70 100 10 20 30 50 80 125 150 100
HPMC 2910 - - - - - - - - - -
아스파탐 5 5 5 5 5 5 5 5 5 5
시트르산 30 30 30 30 30 30 30 30 30 30
무수인산수소나트륨 100 100 100 100 100 100 100 100 100 100
정제수 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365
총량 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
현탁상태 양호 상분리 양호 양호 양호 양호 상분리 상분리 상분리 상분리
Table 5
Ingredient Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Example 32 Example 33 Example 34
Main ingredient (three kinds of total quantities) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
D-sorbitol solution 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200
PVPK30 150 150 200 200 200 200 200 50 50 50
Avicel RC 591 80 50 90 80 70 50 20 125 100 150
HPC-L 70 100 10 20 30 50 80 125 150 100
HPMC 2910 - - - - - - - - - -
Aspartame 5 5 5 5 5 5 5 5 5 5
Citric acid 30 30 30 30 30 30 30 30 30 30
Sodium Hydrogen Phosphate Anhydrous 100 100 100 100 100 100 100 100 100 100
Purified water 2365 2365 2365 2365 2365 2365 2365 2365 2365 2365
Total amount 5000 5000 5000 5000 5000 5000 5000 5000 5000 5000
Suspension Good Phase separation Good Good Good Good Phase separation Phase separation Phase separation Phase separation
(단위 :mg/5g)(Unit: mg / 5g)
비교예 20~비교예23, 실시예35Comparative Example 20- Comparative Example 23, Example 35
상업적 이용을 위해서는 공장에서의 대량생산이 필수적이며 생산 scale은, 제조처, 판매처의 상황 또는 허가와 관련한 별도의 scale 규정에 따를 수 있다. For commercial use, mass production at the factory is essential and the production scale may be in accordance with separate scale provisions relating to the manufacturer or distributor's situation or permit.
일반적으로 실험실규모에서 상업적 판매를 위한 대량생산으로 scale up이 되면서 소규모 실험실규모에서 발생되지 않은 또는 예상하지 못한 공정트러블이 발생하기도 한다. In general, scale-up from laboratory scale to mass production for commercial sale may result in unexpected or unexpected process troubles at small laboratory scale.
본 발명의 최종 마무리단계인 대량생산을 위한 scale up 과정에서는, 실온 또는 미온에서 용해되었던 히드록시프로필셀룰로오스가, 약제학적액상현탁조성물의 멸균을 위해 온도를 승온 시킬 때, 물질 자체의 특이적 성질에 의해 다시 뭉치는 현상이 발생하였다. (그림 2의 (a))In the scale-up process for mass production, which is the final finishing step of the present invention, when hydroxypropyl cellulose dissolved at room temperature or lukewarm temperature is elevated for sterilization of a pharmaceutical liquid suspension composition, The aggregates again occurred. ((A) of Figure 2)
뭉침현상이 발생한 약제학적 액상현탁액을 그대로 제품화할 경우, 1)액상현탁조성물의 고른 점도를 유지하기가 어렵고, 2)성상 불량, 3)복용시 이물감, 4)함량불균일 발생, 5)경시적 안정성 (경화, 침전, 상분리) 문제가 발생하게 된다. 이 때문에 상품성이 뛰어난 약제학적 액상현탁조성물 제조가 불가능하여, 상업적으로 이용가능한 대량생산의 제조공정을 찾고자 하였다. In the case of producing a liquid suspension containing agglomeration as it is, 1) it is difficult to maintain a uniform viscosity of the liquid suspension composition, 2) poor properties, 3) foreign body feeling when taking, 4) content unevenness, 5) stability over time (Curing, precipitation, phase separation) problems arise. For this reason, it is impossible to manufacture a pharmaceutical liquid suspension composition having excellent commercial properties, and therefore, the present invention seeks to find a commercially available mass production process.
하기 표6에 기재된 바와 같이 아래에 설명하는 비교예20 내지 비교예23 및 실시예35와 같은 공정으로 분지쇄아미노산 3종을 포함하는 약제학적 액상현탁액을 제조비교하고, 이에 발생하는 문제를 가지고 평가하였다. 비교예20 내지 비교예23은 실온 또는 미온에서 용해되었던 히드록시프로필셀룰로오스가 물질자체의 특이적 성질 때문에 공정도중 다시 뭉치는 현상이 발생되었다.As shown in Table 6 below, a pharmaceutical liquid suspension containing three branched chain amino acids was prepared and compared with the same procedures as in Comparative Examples 20 to 23 and 35, which were described below. It was. In Comparative Examples 20 to 23, the hydroxypropyl cellulose dissolved at room temperature or lukewarm occurred again during the process due to the specific properties of the material itself.
표 6
비교예 20 비교예 21 비교예 22 비교예 23 실시예 35
제조공정 1 D-소르비톨액과 승온된(50℃ 이상)정제수에 점증제 3종 용해 실온 또는 미온의 정제수 및 D-소르비톨액에 점증제 3종 용해 실온 또는 미온의 정제수 및 D-소르비톨액에 HPC-L, Avicel RC591용해 실온 또는 미온의 정제수 및 D-소르비톨액에 점증제 3종 용해 실온 또는 미온의 정제수 및 D-소르비톨액에 점증제 3종 용해
2 승온(90±5℃설비셋팅) 승온(90±5℃설비셋팅) 아미노산 1종 투입 아미노산 1종 투입
3 PVPK-30 용해 승온(90±5℃설비셋팅) 아미노산 2종 투입 50℃이하)
4 아미노산 2종 투입(50~70 ℃ 부근) 승온(90±5℃설비셋팅)
문제점 HPC-L뭉침현상 발생 HPC-L뭉침현상 발생 HPC-L뭉침현상 발생 70-90℃에서 HPC-L뭉침현상 발생 뭉침현상 없음
Table 6
Comparative Example 20 Comparative Example 21 Comparative Example 22 Comparative Example 23 Example 35
Manufacture process One Dissolve three types of thickener in purified water heated to D-sorbitol solution and heated to 50 ℃ or higher. 3 types of thickeners dissolved in purified water and D-sorbitol solution at room temperature or Dissolve HPC-L, Avicel RC591 in purified water and D-sorbitol solution at room temperature or in warm 3 types of thickeners dissolved in purified water and D-sorbitol solution at room temperature or 3 types of thickeners dissolved in purified water and D-sorbitol solution at room temperature or
2 Temperature rise (90 ± 5 ℃ equipment setting) Temperature rise (90 ± 5 ℃ equipment setting) 1 amino acid 1 amino acid
3 PVPK-30 Melt Temperature rise (90 ± 5 ℃ equipment setting) 2 amino acids below 50 ℃)
4 2 kinds of amino acids (at around 50 ~ 70 ℃) Temperature rise (90 ± 5 ℃ equipment setting)
problem HPC-L agglomeration phenomenon HPC-L agglomeration phenomenon HPC-L agglomeration phenomenon HPC-L agglomeration occurs at 70-90 ℃ No agglomeration
비교예20 내지 23의 결과 및 히드록시프로필셀룰로오스의 고온 가열시 뭉침현상이라는 공지 사실에서는 전혀 예기치 않았음에도 불구하고, 아래의 실시예35에 기재된 제조공정으로 제조하였을 때에는, 그 문제를 해결할 뿐 아니라, 상업적으로 이용가능한 제품을 수득할 수 있음을 발견하였다. 실시예35의 제조공정을 설명하기 위하여 그림1로 도식화하여 나타내었고, 히드록시프로필셀룰로오스의 뭉침현상을 그림 2의 (a)에 나타내었고, 이를 해결한 약제학적 액상현탁조성물의 실시예35의 제조과정을 도 3에 나타내었다. Although the results of Comparative Examples 20 to 23 and the known fact of agglomeration at high temperature heating of hydroxypropyl cellulose were not unexpected at all, when manufactured by the manufacturing process described in Example 35 below, the problem was not only solved. It has been found that commercially available products can be obtained. In order to explain the manufacturing process of Example 35 is shown in Figure 1, the aggregation phenomenon of hydroxypropyl cellulose is shown in Figure 2 (a), the preparation of Example 35 of the pharmaceutical liquid suspension composition The process is shown in FIG. 3.
아래에는 비교예20 내지 비교예23 및 실시예35의 제조방법을 나타내었다. 여기에 사용한 분지쇄아미노산 3종의 입도는 35메쉬 내지 100메쉬로 분급한 원료를 사용하였다. 본 발명의 범위는 비교예 및 실시예의 범위로 한정되는 것은 아니며 35메쉬보다 큰 입자나 100메쉬보다 작은 입자가 상대적으로 소량 혼합된 것으로도 유사한 효과를 얻을 수 있다. 그러나 아미노산의 입자도 범위는 상기한 35메쉬에서 100메쉬 사이의 입자도를 가진 것을 사용하는 것이 가장 바람직하다.The preparation methods of Comparative Examples 20 to 23 and 35 are shown below. The particle size of three branched chain amino acids used here used the raw material classified into 35 mesh-100 mesh. The scope of the present invention is not limited to the ranges of the comparative examples and examples, and similar effects can be obtained by mixing relatively small amounts of particles larger than 35 mesh or particles smaller than 100 mesh. However, the particle size range of the amino acid is most preferably used having a particle size of the above 35 mesh to 100 mesh.
비교예20Comparative Example 20
표6의 제조공정 1 Manufacturing Process 1 of Table 6
세척한 조제탱크에 D-sorbitol 72kg 및 미리 승온시킨 50℃ 이상의 정제수 130kg을 넣고 교반하면서, 여기에 히드록시프로필셀룰로오스4kg, 폴리비닐피롤리돈8kg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨9kg를 넣고 교반한다. 상기 조제탱크 내부에서 뭉침현상이 발생하였다. 분지쇄아미노산 3종 (L-이소류신 14.280kg, 28.560kg 및 17.160kg)을 추가하여도 뭉침 덩어리가 붕해되지 않아 더 이상 공정을 진행할 수 없다. 승온과정은 덩어리 뭉침과 밀접한 관계가 있으나 멸균적 조건으로 제조해야하는 공업적 특성상 반드시 거쳐야하는 과정이다.72 kg of D-sorbitol and 130 kg of purified water of 50 ° C. or higher previously heated were added to the prepared tank, followed by stirring. . Agglomeration phenomenon occurred inside the preparation tank. The addition of three branched chain amino acids (14.280 kg L-isoleucine, 28.560 kg and 17.160 kg) does not disintegrate the mass and can no longer proceed. The temperature increase process is closely related to the agglomeration but it is a process that must be passed due to the industrial characteristics that must be manufactured under sterile conditions.
비교예21Comparative Example 21
표6의 제조공정 1 Manufacturing Process 1 of Table 6
세척한 조제탱크에 실온 또는 미온의 정제수 130kg 및 D-sorbitol 72kg 를 넣고 교반하면서, 여기에 히드록시프로필셀룰로오스4kg, 폴리비닐피롤리돈8kg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨9kg를 넣고 교반한다.130 kg of purified water and 72 kg of D-sorbitol and room temperature or lukewarm purified water were added to the washed preparation tank and stirred, while 4 kg of hydroxypropyl cellulose, 8 kg of polyvinylpyrrolidone and 9 kg of microcrystalline cellulose and carboxymethyl cellulose sodium were added thereto and stirred.
표6의 제조공정 2Manufacturing Process 2 of Table 6
온도를 90±5℃로 셋팅하여 승온시킨다. 상기 조제탱크 내부의 조제액의 온도가 45~50℃ 부근에서 뭉침현상이 발생하기 시작한다. 분지쇄아미노산 3종 (L-이소류신 14.280kg, 28.560kg 및 17.160kg)을 추가하여도 뭉침 덩어리가 붕해되지 않아 더 이상 공정을 진행할 수 없다.The temperature is increased by setting the temperature to 90 ± 5 ℃. Agglomeration phenomenon starts to occur when the temperature of the preparation liquid in the preparation tank is around 45 ~ 50 ℃. The addition of three branched chain amino acids (14.280 kg L-isoleucine, 28.560 kg and 17.160 kg) does not disintegrate the mass and can no longer proceed.
비교예22Comparative Example 22
표6의 제조공정 1 Manufacturing Process 1 of Table 6
세척한 조제탱크에 실온 또는 미온의 정제수 130kg 및 D-sorbitol 72kg 를 넣고 교반하면서, 여기에 히드록시프로필셀룰로오스4kg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨9kg를 넣고 교반한다.130 kg of purified water and 72 kg of D-sorbitol and room temperature or lukewarm purified water were added to the washed preparation tank, and 4 kg of hydroxypropyl cellulose and 9 kg of microcrystalline cellulose and carboxymethyl cellulose sodium were added thereto and stirred.
표6의 제조공정 2Manufacturing Process 2 of Table 6
온도를 90±5℃로 셋팅하여 승온시킨다.The temperature is increased by setting the temperature to 90 ± 5 ℃.
표6의 제조공정 3Manufacturing Process 3 of Table 6
상기의 조제탱크에 폴리비닐피롤리돈8kg넣고 교반한다. (40℃ 부근) 상기 조제탱크 내부의 조제액의 온도가 45~50℃ 부근에서 뭉침현상이 발생하기 시작한다. 분지쇄아미노산 3종 (L-이소류신 14.280kg, 28.560kg 및 17.160kg)을 추가하여도 뭉침 덩어리가 붕해되지 않아 더 이상 공정을 진행할 수 없다.8 kg of polyvinylpyrrolidone was put into the said preparation tank, and it stirred. (40 ° C.) Agglomeration occurs at a temperature of 45 ° C. to 50 ° C. in the preparation tank. The addition of three branched chain amino acids (14.280 kg L-isoleucine, 28.560 kg and 17.160 kg) does not disintegrate the mass and can no longer proceed.
비교예23Comparative Example 23
표6의 제조공정 1 Manufacturing Process 1 of Table 6
세척한 조제탱크에 실온 또는 미온의 정제수 130kg 및 D-sorbitol 72kg 를 넣고 교반하면서, 여기에 히드록시프로필셀룰로오스4kg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨9kg를 넣고 교반한다.130 kg of purified water and 72 kg of D-sorbitol and room temperature or lukewarm purified water were added to the washed preparation tank, and 4 kg of hydroxypropyl cellulose and 9 kg of microcrystalline cellulose and carboxymethyl cellulose sodium were added thereto and stirred.
표6의 제조공정 2Manufacturing Process 2 of Table 6
상기의 조제탱크에 분지쇄아미노산 1종을 투입하고 교반한다.1 type of branched chain amino acid is thrown into the said preparation tank, and it stirs.
표6의 제조공정 3Manufacturing Process 3 of Table 6
온도를 90±5℃로 셋팅하여 승온시킨다.The temperature is increased by setting the temperature to 90 ± 5 ℃.
표6의 제조공정 4Manufacturing Process 4 of Table 6
상기의 조제탱크 내의 조제액의 온도가 50~70℃인 부근에서 분지쇄아미노산 2종을 투입하고 교반한다. 상기 조제탱크 내부의 조제액의 온도가 70~90℃ 부근에서 뭉침현상이 발생하기 시작한다.Two kinds of branched chain amino acids are added and stirred in the vicinity of the temperature of the preparation liquid in the preparation tank of 50 to 70 ° C. Agglomeration phenomenon starts to occur when the temperature of the preparation liquid in the preparation tank is around 70 ~ 90 ℃.
실시예35Example 35
표6의 제조공정 1 Manufacturing Process 1 of Table 6
세척한 조제탱크에 실온 또는 미온의 정제수 130kg 및 D-sorbitol 72kg 를 넣고 교반하면서, 여기에 히드록시프로필셀룰로오스4kg, 폴리비닐피롤리돈8kg 및 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨9kg를 넣고 교반한다.130 kg of purified water and 72 kg of D-sorbitol and room temperature or lukewarm purified water were added to the washed preparation tank and stirred, while 4 kg of hydroxypropyl cellulose, 8 kg of polyvinylpyrrolidone and 9 kg of microcrystalline cellulose and carboxymethyl cellulose sodium were added thereto and stirred.
표6의 제조공정 2Manufacturing Process 2 of Table 6
상기의 조제탱크에 분지쇄아미노산 1종 (L-이소류신) 을 투입하고 교반한다.One branched chain amino acid (L-isoleucine) is added to the preparation tank and stirred.
표6의 제조공정 3Manufacturing Process 3 of Table 6
상기의 조제탱크에 분지쇄아미노산 2종 (L-류신, L-발린) 을 투입하고 교반한다. (50℃ 이하)Two branched chain amino acids (L-leucine and L-valine) are added to the preparation tank and stirred. (Less than 50 ℃)
표6의 제조공정 4Manufacturing Process 4 of Table 6
온도를 90±5℃로 셋팅하여 승온시킨다. 상기 조제탱크 내부의 조제액의 온도가 90℃ 까지 상승해도 뭉침현상이 발생하지 않는다. 상기의 제조공정 2 및 3에 투입하는 분지쇄아미노산 3종의 순서를 상호 바꾸었을 때에도 동일한 성상의 약제학적 액상현탁조성물을 얻을 수 있다. The temperature is increased by setting the temperature to 90 ± 5 ℃. Agglomeration does not occur even when the temperature of the preparation liquid inside the preparation tank rises to 90 ° C. A pharmaceutical liquid suspension composition of the same properties can be obtained even when the order of the three branched chain amino acids to be added to the above-described production steps 2 and 3 is changed.
본 발명은, 상기한 실시례들에서 설명된 바와 같이 입도분포를 조절한 분지쇄아미노산 3종 이소류신, 류신 및 발린을 유효성분으로 함유하고, 특정의 점증제 또는 특정의 점증제의 조합, 특정의 감미제 그리고, 특정범위의 pH를 조절함으로써 쓴맛과 이물감을 은폐하면서도 환자가 복용하기에 적절한 용적으로 약제학적 액상현탁조성물을 제공한다. 또한 본 발명은, 상업적 이용을 위한 대량생산에서 발생한 점증제의 뭉침현상을 해결하여 멸균적 조건으로 상업화 가능한 약제학적 액상현탁조성물의 바람직한 제조 공정을 제공한다.The present invention contains three branched chain amino acid isoleucine, leucine, and valine as effective ingredients in which the particle size distribution is adjusted as described in the above embodiments, and a specific thickener or a combination of specific thickeners, specific A sweetening agent and a pharmaceutical liquid suspension composition are provided in a volume suitable for the patient's intake while concealing bitter taste and foreign body by adjusting a specific range of pH. The present invention also provides a preferred process for the preparation of a pharmaceutical liquid suspension composition commercially available under sterile conditions by solving the agglomeration of thickeners arising from mass production for commercial use.
본 발명의 약제학적 조성물 및 이의 제조방법을 이용하면, 고미를 지닌 다양한 아미노산류를 함유한 액상현탁조성물을 환자에게 투여하기 용이한 맛과 용적이 개선된 우수한 약제학적 액상현탁조성물을 구성할 수 있으며, 공업적 규모로 생산할 수 있다. By using the pharmaceutical composition of the present invention and a method for preparing the same, an excellent pharmaceutical liquid suspension composition having improved taste and volume, which is easy to administer to the patient, can be easily prepared. It can be produced on an industrial scale.

Claims (6)

  1. 이소류신, 류신 및 발린의 3종의 분지쇄 아미노산, 점증제, pH 조절제 및 약제학적으로 허용가능한 첨가제를 포함하는 경구투여 가능한 액상현탁조성물에 있어서, 상기 분지쇄 아미노산의 입도가 35메쉬 내지 100메쉬인 것을 특징으로 하는 액상현탁조성물.In an orally administrable liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, a thickener, a pH adjusting agent and a pharmaceutically acceptable additive, the branched chain amino acids have a particle size of 35 mesh to 100 mesh. Liquid suspension composition, characterized in that.
  2. 제 1항에 있어서, 상기 점증제는 히드록시프로필셀룰로오스, 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 및 폴리비닐피롤리돈으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 액상현탁조성물.The liquid suspension composition according to claim 1, wherein the thickener is selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, and polyvinylpyrrolidone.
  3. 제 1항 또는 제 2항에 있어서, 상기 pH 조절제는 시트르산 및 무수인산수소나트륨으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 액상현탁조성물.The liquid suspension composition according to claim 1 or 2, wherein the pH adjusting agent is selected from the group consisting of citric acid and sodium hydrogen phosphate anhydride.
  4. 제 1항 또는 2항에 있어서, 상기 조성물의 pH범위가 5 내지 7인 것을 특징으로 하는 액상현탁조성물.The liquid suspension composition according to claim 1 or 2, wherein the pH range of the composition is 5 to 7.
  5. 제 2항에 있어서, 히드록시프로필셀룰로오스를 액상현탁조성물 중량대비 0.2 내지 2.0% (w/w), 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨을 액상현탁조성물 중량대비 1.0 내지 3.4% (w/w), 폴리비닐피롤리돈을 액상현탁조성물 중량대비 2.0 내지 4.0% (w/w) 를 함유하는 액상현탁조성물.The method according to claim 2, wherein the hydroxypropyl cellulose is 0.2 to 2.0% (w / w) relative to the weight of the liquid suspension composition, and the microcrystalline cellulose-carboxymethylcellulose sodium is 1.0 to 3.4% (w / w) relative to the weight of the liquid suspension composition, poly A liquid suspension composition containing 2.0% to 4.0% (w / w) of vinylpyrrolidone by weight of the liquid suspension composition.
  6. 실온 또는 미온의 정제수에 히드록시프로필셀룰로오스, 미결정셀룰로오스·카르복시메칠셀룰로오스나트륨 및 폴리비닐피롤리돈으로 이루어지는 군으로부터 선택되는 점증제를 용해 또는 현탁시키는 단계;Dissolving or suspending a thickener selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose, carboxymethyl cellulose sodium, and polyvinylpyrrolidone in purified water at room temperature or lukewarm water;
    상기 현탁용액에 이소류신, 류신 및 발린으로부터 선택되는 1종의 아미노산을 첨가하고 분산시키는 단계;Adding and dispersing one amino acid selected from isoleucine, leucine and valine to the suspension solution;
    상기 현탁용액에 나머지 아미노산 2종을 50℃이하에서 첨가하고, 70 내지 90℃로 승온 및 분산시키는 단계;Adding the remaining two amino acids to the suspension solution at 50 ° C. or lower, and heating and dispersing at 70 to 90 ° C .;
    상기 현탁용액에 보존제, 감미제, pH조절제를 첨가하여 용해시키는 단계Dissolving by adding a preservative, a sweetener, and a pH adjusting agent to the suspension solution
    를 포함하는 것을 특징으로 하는 이소류신, 류신 및 발린의 3종의 분지쇄아미노산을 포함하는 경구투여 가능한 액상현탁조성물의 제조방법.Method for producing an orally administrable liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, characterized in that it comprises a.
PCT/KR2013/002304 2012-03-30 2013-03-20 Pharmaceutical composition containing branched chain amino acid, and production method therefor WO2013147451A1 (en)

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JP2002187840A (en) * 2000-10-10 2002-07-05 Ajinomoto Co Inc Medicinal suspension containing branched chain amino acid
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