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WO2021145622A1 - Composition pharmaceutique comprenant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci et un émulsifiant - Google Patents

Composition pharmaceutique comprenant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci et un émulsifiant Download PDF

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Publication number
WO2021145622A1
WO2021145622A1 PCT/KR2021/000341 KR2021000341W WO2021145622A1 WO 2021145622 A1 WO2021145622 A1 WO 2021145622A1 KR 2021000341 W KR2021000341 W KR 2021000341W WO 2021145622 A1 WO2021145622 A1 WO 2021145622A1
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Prior art keywords
tablet
thioctic acid
emulsifier
active ingredient
dissolution
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Ceased
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PCT/KR2021/000341
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English (en)
Korean (ko)
Inventor
김성엽
송희용
최연웅
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Korea United Pharm Inc
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Korea United Pharm Inc
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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising R-thioctic acid or a salt thereof and an emulsifier as an active ingredient.
  • Thiocic acid is an organic compound containing sulfur derived from octanoic acid, also called alpha-lipoic acid.
  • Thioctic acid is one of the powerful antioxidants, and it removes lipophilic free radicals and reduces oxidative stress in tissues in diabetic patients, through which it suppresses hepatocellular damage and inflammation caused by diabetic neuropathy, diabetes, insulin resistance, cataracts, neuropathy, and It is known to have a pharmacological effect to improve symptoms such as diabetic complications such as kidney disease.
  • Thioctic acid is classified as an enantiomer and divided into R-type and S-type. Among them, the R-type is the active form in the human body.
  • thioctic acid forms a disulfide bond in a pentagonal ring structure in the molecular structure.
  • the disulfide bond is an unstable bond and is easily broken by heat to form free radicals.
  • the pentagonal ring structure is also energetically unstable as a sterically unstable structure. As a result, the bond is easily broken by heat and moisture to form a water-insoluble polymer.
  • the degree of instability of R-thioctic acid which has been extracted only R-type from the existing thioctic acid, becomes more severe, and for this reason, when mixed with water, the solubility is very poor due to ring-opening and polymerization formation.
  • Patent Document 1 describes that the solubility and absorption rate of R-thioctic acid are increased, and the stability according to temperature is also improved, and a formulation using the same is currently on the market (Bugwang Pharmaceutical 'Dexid Tablet').
  • Patent Document 1 also did not solve the problem of instability when exposed to acidic conditions, and the commercially available formulations using this also did not disintegrate due to denaturation such as polymerization and gel formation when exposed to gastric acid after oral administration. It shows a phenomenon that the dissolution rate is low.
  • the present invention improves the problem of conventional formulations in which disintegration and dissolution are inhibited due to gelation by polymerizing the active ingredient when exposed to an acidic environment in a conventional thioctic acid pharmaceutical formulation, thereby achieving an excellent dissolution rate in acidic conditions, and the active ingredient in the body It aims to improve bioavailability by allowing it to be rapidly absorbed in
  • the pharmaceutical composition comprising R-thioctic acid of the present invention includes R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, an emulsifier, and an adsorbent, and optionally a binder, a disintegrant It may further include, and the emulsifier is characterized in that it is in the form of a tablet for oral administration containing 30 to 70% by weight based on the total weight of the active ingredient.
  • the active ingredient may be R-thioctic acid free base, but preferably R-thioctic acid tromethamine salt, preferably 30 to 60% by weight, more preferably 40 to 50% by weight, based on the total weight of the tablet. % may be included.
  • the total weight of the tablet may vary depending on the formulation design, preferably 300 to 800 mg, more preferably 400 to 600 mg.
  • the content of the active ingredient is less than 30% by weight based on the total weight of the tablet, the pharmacological activity does not appear sufficiently, and when it exceeds 60% by weight, the main ingredient is included in an excessive ratio, which causes an obstacle during the manufacturing process of the tablet due to an inappropriate formulation ratio. likely to appear.
  • the pharmaceutical composition according to the present invention does not contain a surfactant, which is due to the property of R-thioctic acid to gel in an acidic environment.
  • a surfactant which is due to the property of R-thioctic acid to gel in an acidic environment.
  • the pharmaceutical composition according to the present invention does not contain a surfactant, which is due to the property of R-thioctic acid to gel in an acidic environment.
  • a surfactant when a surfactant is usually included with the drug, the effect of increasing solubility appears. Therefore, when designing a formulation for the purpose of improving bioavailability, it is common to include a surfactant within an acceptable content range. However, formulations containing surfactants may cause side effects such as vomiting or abdominal pain in the body when administered orally.
  • the emulsifier may be used by mixing one or two selected from the group consisting of caprylocaproyl macrogol glyceride and mono-and-diglyceride.
  • the adsorbent may be a mixture of one or more selected from the group consisting of a silicon-based compound and a cellulose derivative, and may preferably include calcium silicate and magnesium aluminate silicate.
  • the weight ratio of calcium silicate and magnesium aluminate silicate included as the adsorbent may be 1:0.8 to 1:5.
  • the weight ratio range of the calcium silicate and the magnesium aluminate silicate is an optimal mixing ratio for increasing the adsorption efficiency while ensuring the tabletting property, and when it is out of the above range, the tabletting property or the adsorption efficiency may be deteriorated.
  • the content of the adsorbent is preferably 15 to 30% by weight based on the combined weight of the active ingredient and the emulsifier, and if the content of the adsorbent is too low outside the above range, the adsorption efficiency may decrease, and if it is too high, the size of the formulation increases Convenience may be reduced.
  • the binder is polyvinylpyrrolidone, hydroxypropylcellulose, acacia, alginic acid, microcrystalline cellulose, copovidone, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, maltodextrin, methylcellulose, polyethylene
  • One or more selected from the group consisting of oxide, corn starch, potato starch, pregelatinized starch and wheat starch may be used, and preferably 2 to 5% by weight based on the total weight of the tablet, more preferably may be 3 to 4% by weight.
  • the binder content is less than 2% by weight, the binding force between the particles is insufficient during tableting, and tableting disorders such as capping may appear, and when the binder content exceeds 5% by weight, a problem of delayed disintegration may occur.
  • the disintegrant is one selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, polyacrylin potassium, maltose, alginic acid, microcrystalline cellulose and sodium hydrogen carbonate, or A mixture of two or more may be used, in which case the content of the disintegrant may be preferably 5 to 20% by weight, more preferably 10 to 15% by weight, based on the total weight of the tablet. If the content of the disintegrant is less than 5% by weight based on the total weight of the tablet, the disintegration of the formulation may be delayed, which is not preferable because it may negatively affect the dissolution of the active ingredient. In addition, when the content of the disintegrant exceeds 20% by weight based on the total weight of the tablet, there is no significant difference in the effect of improving disintegration, and it is not preferable because the size of the formulation becomes unnecessarily large.
  • the present invention is to improve the problem that in the pharmaceutical composition containing R- thioctic acid as an active ingredient, the dissolution rate is lowered by denaturing the active ingredient into a gel form as the active ingredient is exposed to an acidic environment and polymerized.
  • the pharmaceutical composition of the present invention has the effect of significantly improving the dissolution environment of the active ingredient and increasing the bioavailability by reducing the degree of denaturation of the active ingredient in the form of a gel and significantly reducing the viscosity of the emulsifier included with the active ingredient in the tablet.
  • FIG. 1 is a graph showing the results of dissolution testing of currently commercially available R-thioctate tromethamine salt tablets (Bukwang Pharmaceutical 'Dexid Tablets') and powders obtained by pulverizing the same tablets in a pH 1.2 dissolution environment.
  • Figure 3 is a schematic view by comparing the denaturation phenomenon that appears in the conventional tablet of the prior art (Bukwang Pharmaceutical 'Dexid Tablet') and the tablet containing the emulsifier of the present invention when exposed to an acidic environment.
  • FIG. 6 is a graph showing the results of dissolution tests for the R-thioctic acid tromethamine salt tablet of Example 3 and the reference drug (Bugwang Pharmaceutical 'Dexid Tablet') in pH 1.2, pH 4.0, pH 6.8 eluate and water. it has been shown
  • the present invention provides an oral pharmaceutical composition comprising R-thioctic acid or a pharmaceutically acceptable salt thereof and an emulsifier as an active ingredient, and the pharmaceutical composition is a tablet formulation, and is stable compared to existing formulations. and excellent dissolution rate.
  • the pharmaceutical composition of the present invention is a tablet-type preparation comprising R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising an emulsifier as a pharmaceutically acceptable excipient.
  • R-thioctic acid When R-thioctic acid is exposed to an acidic environment, it is denatured into a gel with high viscosity resulting from polymerization. Therefore, in the case of a conventional R-thioctic acid formulation, when exposed to an acidic solution such as gastric acid at the initial stage of oral administration, the active ingredient in the form of a denatured gel surrounds the formulation, and the viscosity is also very high, thereby inhibiting the disintegration and dissolution of the formulation. .
  • the pharmaceutical composition of the present invention is to improve the problems of these conventional formulations, and the emulsifier contained in the tablet reduces the degree of formation of the gel and the viscosity of the formed gel even during the dissolution test under acidic conditions, and the gel does not surround the tablet surface. to be distributed smoothly. That is, the pharmaceutical composition of the present invention is characterized in that it greatly improved the phenomenon of reducing the permeability of the solution into the formulation by enclosing the surface of the tablet as the gel was formed, which was a problem of the commercial formulation.
  • the bioavailability of thioctic acid when administered orally is about 30%.
  • the first is denaturation such as polymerization due to low stability
  • the second is the rapid metabolic rate in the liver
  • the third is low stability in acidic conditions.
  • the first and third except for the metabolic rate in the liver, seem to be able to be improved pharmaceuticalally.
  • poor disintegration and dissolution may affect the bioavailability. considered to be significantly affected.
  • the present invention provides a pharmaceutical composition comprising an emulsifier together with an active ingredient in order to achieve the above effects.
  • the dispersion of the formulation was successfully achieved due to the inhibition of the formation of the polymer gel and the decrease in viscosity due to the mixing of the active ingredient and the emulsifier, and thus a fast disintegration rate and excellent initial dissolution rate could achieve
  • FIG. 1 a comparative dissolution graph for the reference drug when exposed to an acidic environment in the form of a tablet or powder is shown in FIG. 1 , and the denatured appearance of the reference drug tablet after dissolution in an acidic environment is completed in FIG. 2 , and in an acidic environment 3 schematically shows the change in dissolution behavior for the tablet of the present invention including the conventional control drug tablet and the emulsifier when exposed to .
  • the present invention suppresses the formation of a polymer gel formed upon exposure to an acidic environment and reduces the viscosity, thereby causing smooth disintegration of the pharmaceutical composition formulation and improving the dissolution rate in an acidic environment. do.
  • the pharmaceutical composition of the present invention has a very excellent initial dissolution rate compared to conventional formulations on the market, and furthermore, increases the drug absorption rate and reduces the liver first-pass effect in vivo due to rapid drug absorption (receptor saturation). An additional effect of increasing bioavailability can also be expected.
  • An emulsifier is usually used as a substance to prevent the separation of immiscible substances in an emulsion, and serves to help the substance to be uniformly distributed.
  • a gel formed when R-thioctic acid tromethamine salt tablets are exposed to an acidic environment they have high viscosity. Therefore, when a certain level of external force is applied, dispersion in the pH 1.2 solution is achieved, but the general dissolution test and the standard test for the tablet (Korean Pharmacopoeia dissolution test method 2, 50 rpm) and gastrointestinal movement Due to its high viscosity, it does not disperse smoothly with relatively mild agitation and remains wrapped around the tablet surface.
  • an emulsifier is additionally included, it is mixed with the gel to promote mixing with the pH 1.2 solution, and it has been confirmed that it has a relatively low viscosity and reduces the viscosity when included in the formed gel.
  • monoandiglyceride and caprylocaproyl macrogol glyceride have strong affinity for R-thioctic acid tromethamine salt, and R-thioctic acid tromethamine salt binds with an acidic solution. It can primarily prevent denaturation by reacting. This plays a significant role in maintaining stability without polymerization and gel formation.
  • the active ingredient of R-thioctate tromethamine salt and the emulsifier are mixed in a ratio of 1:3 to sufficiently dissolve the active ingredient, and then the adsorbent until the mixture becomes a dry powder. was administered and mixed, and further dried by heating in an oven for a certain period of time. The dried powder was weighed so that it could contain 300 mg as R-thioctic acid, and a dissolution test was performed with a solution of pH 1.2 (Korean Pharmacopoeia 11th revision dissolution test method 1 solution) for 1 hour.
  • a dissolution test was performed under the same conditions, and the dissolution pattern was compared with that of the preparation example, and the results are shown in FIG. 4 .
  • the conditions of the adsorbent to be used for refining the mixture in a liquid state include high adsorption efficiency, the dissolution rate should not be reduced or reduced to a minimum, and the powder formed by adsorption should not cause problems during tableting.
  • Calcium silicate has a high adsorption efficiency and a relatively low degree of decrease in dissolution rate, but has a problem in that it easily causes a tableting disorder due to its very low tabletting property. That is, considering the tabletting property for tablet manufacturing, it is preferable to use a mixture of magnesium aluminate silicate or microcrystalline cellulose 101, which has advantageous properties for tableting, and among them, it is preferable to mix with magnesium aluminate silicate, which has relatively higher adsorption efficiency. it is most preferable
  • the weight ratio of calcium silicate and magnesium aluminate silicate is preferably in the range of 1:0.8 to 1:5, more preferably in the range of 1:1 to 1:3, and most preferably in the range of 1:1 to 1:2.
  • the weight ratio of calcium silicate and magnesium aluminate to 1:1 was used in manufacturing the tablet. judged to be the most desirable.
  • Example 4 comparative example 2 comparative example 3 note active ingredient R-thioctic acid tromethamine salt 240.0 240.0 240.0 240.0 240.0 240.0 300mg as R-thioctic acid interface activator polysorbate 80 - - - - 15.0 - interface activator Sodium Lauryl Sulfate - - - - - 15.0 emulsifier mono and D glycerides 100.0 120.0 140.0 160.0 140.0 140.0 binder Povidone K-30 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 absorbent silicate aluminic acid magnesium 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 Neusilin ® US2 absorbent calcium silicate 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 FLORITE® PS-200 disintegrant low substituted hydroxy Propyl Cellulose 25.0 25.0 25.0 25.0 25.0 25.0 disintegrant croscarmellose salt 45.0 45.0 45.0 45.0 45.0 lubric
  • Example 4 In the case of Example 4, when the tableting process was continued, some tableting failures due to sticking occurred.
  • test Method 2 As the test conditions, 900mL of the dissolution test method 1st solution of the 11th revision of the Korean Pharmacopoeia (pH 1.2, the 1st solution of the 11th revision dissolution test method of the Korean Pharmacopoeia) is used as the dissolution solution, and the paddle method at 50 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution) is used as the dissolution solution. Test Method 2) was applied. The test results are shown in FIG. 5 .
  • the preferred content range of the emulsifier may be 30 to 70% by weight, more preferably 50 to 60% by weight, based on the total weight of the active ingredient that can cause denaturation.
  • the preferred amount of the adsorbent may be 15 to 30% by weight, more preferably 20 to 25% by weight.
  • tromethamine R-thioctate is a drug with high solubility in water, it is judged that the change in dissolution rate does not change significantly depending on the presence or absence of a solubility enhancing agent such as a surfactant. Therefore, unlike conventional active ingredients, in the case of R-thioctic acid, it is a drug with strong properties of being denatured under acidic conditions, and drug dissolution is greatly reduced due to denaturation, so a method of increasing the dissolution rate by preventing denaturation may be the most effective. . That is, it was confirmed that the surfactant commonly used for solubilizing the drug has a negative effect on the dissolution of the formulation according to the present invention.
  • a comparative dissolution test was carried out on the tablets prepared in Example 3 using 'Dexid Tablet', a currently commercially available product, as a reference drug. The test was carried out for 1 hour with 4 phases of elution using water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution, and the preparation method of each eluate is as follows.
  • pH 4.0 Eluent: 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid, 0.05 mol/L sodium acetate mixture (82 : 18)] is used.
  • pH 6.8 dissolution solution Use the 2nd solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.
  • Example 3 As a result of the test, in the case of Example 3, it was confirmed that all four dissolutions showed a fast dissolution rate, and a dissolution rate of about 80% in an acidic condition.
  • the control drug showed a dissolution rate of less than 20% in a dissolution test in a pH 1.2 solution, and as a result of visual observation, it was confirmed that there was a denatured gel. That is, it can be seen that Example 3 has an excellent dissolution rate in acidic conditions compared to the reference drug.
  • the test results are shown in FIG. 6 .
  • Example 3 For the tablets prepared in Example 3, dissolution tests were performed after 1 month, 2 months, and 3 months after manufacture to confirm the stability of the tablet. The test was carried out for 1 hour with 4 phases of elution using water, pH 1.2 eluate, pH 4.0 eluate, and pH 6.8 eluate, and the preparation method of each eluate is as follows.
  • pH 4.0 Eluent: 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid, 0.05 mol/L sodium acetate mixture (82 : 18)] is used.
  • pH 6.8 dissolution solution Use the 2nd solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.

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Abstract

La présente invention concerne une composition pharmaceutique sous forme de comprimé, la composition comprenant de l'acide R-thioctique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif et une huile en tant qu'émulsifiant et caractérisée par une désintégration rapide et une dissolution de principe actif in vivo. De plus, la composition est caractérisée en ce que l'ingrédient émulsifiant diminue efficacement le degré de formation de gel et la viscosité apportée par le principe actif pour diminuer remarquablement l'activité inhibitrice du gel entourant la surface du comprimé afin d'empêcher qu'une solution ne pénètre à l'intérieur du comprimé et d'améliorer le taux de dissolution du principe actif dans un environnement à faible pH.
PCT/KR2021/000341 2020-01-13 2021-01-11 Composition pharmaceutique comprenant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci et un émulsifiant Ceased WO2021145622A1 (fr)

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KR10-2020-0004414 2020-01-13
KR1020200004414A KR102381839B1 (ko) 2020-01-13 2020-01-13 R-치옥트산 또는 이의 약학적으로 허용되는 염 및 유화제를 포함하는 약학조성물

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006296315A (ja) * 2005-04-21 2006-11-02 T Hasegawa Co Ltd α−リポ酸含有乳化組成物および飲食品
KR20070036450A (ko) * 2005-09-29 2007-04-03 전북대학교산학협력단 리포산을 함유하는 염증 질환 치료용 약제조성물
JP2010189337A (ja) * 2009-02-19 2010-09-02 Asahi Breweries Ltd 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法
JP5085329B2 (ja) * 2005-09-12 2012-11-28 協和発酵バイオ株式会社 α−リポ酸含有組成物
KR20160013511A (ko) * 2014-07-25 2016-02-04 연세대학교 산학협력단 알파 리포산을 포함하는 갑상선 안병증의 예방 또는 치료용 약제학적 조성물

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100705199B1 (ko) 2005-09-02 2007-04-06 부광약품 주식회사 Ｄ-(+)-α-리포산 트로메타민염을 포함하는 간섬유화 억제 및 치료용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006296315A (ja) * 2005-04-21 2006-11-02 T Hasegawa Co Ltd α−リポ酸含有乳化組成物および飲食品
JP5085329B2 (ja) * 2005-09-12 2012-11-28 協和発酵バイオ株式会社 α−リポ酸含有組成物
KR20070036450A (ko) * 2005-09-29 2007-04-03 전북대학교산학협력단 리포산을 함유하는 염증 질환 치료용 약제조성물
JP2010189337A (ja) * 2009-02-19 2010-09-02 Asahi Breweries Ltd 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法
KR20160013511A (ko) * 2014-07-25 2016-02-04 연세대학교 산학협력단 알파 리포산을 포함하는 갑상선 안병증의 예방 또는 치료용 약제학적 조성물

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KR20210090980A (ko) 2021-07-21

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