WO2021145618A1 - Composition pharmaceutique incluant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci, de l'huile, et un auxiliaire de dispersion - Google Patents

Composition pharmaceutique incluant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci, de l'huile, et un auxiliaire de dispersion Download PDF

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WO2021145618A1
WO2021145618A1 PCT/KR2021/000330 KR2021000330W WO2021145618A1 WO 2021145618 A1 WO2021145618 A1 WO 2021145618A1 KR 2021000330 W KR2021000330 W KR 2021000330W WO 2021145618 A1 WO2021145618 A1 WO 2021145618A1
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pharmaceutical composition
oil
active ingredient
thioctic acid
weight
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PCT/KR2021/000330
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English (en)
Korean (ko)
Inventor
김성엽
송희용
최연웅
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한국유나이티드제약 주식회사
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Publication of WO2021145618A1 publication Critical patent/WO2021145618A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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 as an active ingredient and an oil for improving the bioavailability of the active ingredient and a dispersing aid.
  • Patent Document 1 In order to improve the low stability of R-thioctic acid, in Korean Patent Application Laid-Open No. 10-2007-0025426 (Patent Document 1), R-thioctic acid and tromethamine are combined in a 1:1 ratio. methamine salts are presented. According to Patent Document 1, the solubility and absorption rate of R-thioctic acid were increased compared to the conventional formulation, and the stability according to temperature was also improved. Also, a formulation using it is currently on the market (Bukwang Pharmaceutical's Dexid Tablet).
  • Patent Document 1 also did not sufficiently solve the instability that appears in acidic conditions, and this causes denaturation such as polymerization and resulting gel formation, resulting in poor disintegration or insufficient dissolution of the active ingredient, resulting in a low dissolution rate. show the phenomenon
  • Patent Document 2 proposes a formulation in the form of a soft capsule with improved stability including thioctic acid.
  • Patent Document 2 proposes a method for improving the stability of the soft capsule formulation, such as improving the mixing phenomenon that occurs when the liquid inside the soft capsule is transferred to the film.
  • the present invention improves the problem of the conventional formulation in which the active ingredient is polymerized and denatured into a gel form when exposed to an acidic environment, thereby reducing the bioavailability, and further improving the dispersibility of the pharmaceutical formulation containing thioctic acid.
  • An object of the present invention is to provide a pharmaceutical composition that maintains a high absorption rate in the body and is rapidly dispersed in the gastrointestinal tract.
  • the pharmaceutical composition of the present invention contains R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and contains 100 to 300% by weight of oil and 150 to 350% by weight of a dispersing aid based on the total weight of the active ingredient characterized.
  • the pharmaceutical composition may have a total weight of 600 to 1500 mg, preferably 800 to 1200 mg.
  • the active ingredient may be included in 5 to 25% by weight based on the total weight of the pharmaceutical composition in order to exhibit pharmacological activity.
  • the content of the active ingredient is less than 5% by weight based on the total weight of the pharmaceutical composition, the pharmacological activity does not appear sufficiently, and when it exceeds 25% by weight, the ratio of the main ingredient in the formulation is excessively high, and incomplete encapsulation and dissolution of the pharmaceutical composition in the oil during the dissolution test It may exhibit pharmaceutical inappropriate functions, such as insufficient dispersing power.
  • the pharmaceutical composition contains R-thioctic acid free base as an active ingredient, it suppresses the denaturation of the active ingredient in the body to form a gel, and thus exhibits high bioavailability.
  • the oil is propylene glycol monocaprylate Type I, propylene glycol monocaprylate Type II, glycerol / glyceryl monolinoleic acid, medium chain triglycerides, propylene glycol monolaurate, propylene glycol dicaprylate, from the group consisting of castor oil It may be one selected or a mixture of two or more, and serves to prevent denaturation of the active ingredient by encapsulating the active ingredient in oil.
  • the dispersing aid is an amphiphilic excipient, and one or two or more selected from the group consisting of linoleoyl, caprylocaproyl macrogol glyceride, polysorbate 20, and polysorbate 80 may be used.
  • an amphiphilic excipient having a relatively high viscosity is included as a surfactant
  • an amphiphilic excipient having a relatively low viscosity is included as an auxiliary surfactant
  • an excellent effect was obtained.
  • the difference between the hydrophilicity-lipophilicity balance (HLB) value of the oil and the dispersing aid may be preferably 4 or more, more preferably 7 or more.
  • the difference in the hydrophilicity-lipophilic balance (HLB) value is less than 4, the active ingredient is not sufficiently encapsulated in the oil, and a significant amount of the active ingredient is mixed in the dispersion aid, and may be exposed to an external acid and denatured.
  • the pharmaceutical composition of the present invention may be prepared in the form of a soft capsule or tablet, and in the case of a tablet, an adsorbent may be further included to improve tabletting performance.
  • the adsorbent may be included in an amount of 60 to 200% by weight based on the combined weight of the oil and the dispersing aid.
  • the content of the adsorbent is less than 60% by weight based on the combined weight of the oil and the dispersing aid, the tabletting property is low, and defects may occur during tablet manufacture.
  • the content of the adsorbent is less than 60% by weight based on the combined weight of the oil and the dispersing aid, the tabletting property is low, and defects may occur during tablet manufacture.
  • there is no significant tabletting improvement effect and only the size of the formulation is unnecessarily large, which is not preferable because the convenience of taking it may decrease.
  • the adsorbent may be a silicon-based compound, and preferably, may be one or a mixture of two or more selected from the group consisting of calcium silicate, magnesium metasilicate, and colloidal silicon dioxide.
  • the pharmaceutical composition according to the present invention is characterized in that it is self-emulsifying in the body. That is, since it is emulsified so as not to be exposed to an acidic environment during oral administration, active ingredients that are easily denatured by acid are not easily exposed, and thus bioavailability is high.
  • the present invention is to improve the dissolution rate reduction that occurs when the active ingredient is polymerized in an acidic environment to form a gel in a pharmaceutical composition containing R-thioctic acid as an active ingredient.
  • the pharmaceutical composition of the present invention forms a protective layer in which the oil contained together with the active ingredient in the soft capsule surrounds the active ingredient, and the internal solution is smoothly dispersed into the eluate through the dispersion aid containing the surfactant and the auxiliary surfactant, It has the effect of suppressing the polymerization of the active ingredient and smoothly releasing the drug in the eluate to improve the dissolution rate and increase the bioavailability.
  • 1 is a graph showing the results of a dissolution test for commercially available R-thioctate tromethamine salt tablets (Bugwang Pharmaceutical 'Dexid Tablets') under pH 1.2 dissolution conditions.
  • Figure 2 is a schematic diagram of the denaturation phenomenon of commercially available R-thioctate tromethamine salt tablets (Bukwang Pharmaceutical 'Dexid Tablets') as they are eluted under pH 1.2 eluent conditions and photos of the actually denatured properties.
  • FIG. 6 schematically shows whether or not a polymerization phenomenon occurs when the R-thioctic acid active ingredient is encapsulated by oil and when not encapsulated.
  • Example 7 shows the dissolution profiles of Example 3, Comparative Example 1, and the reference drug (Bugwang Pharmaceutical 'Dexid Tablet') formulations compared and dissolution profiles under each dissolution condition.
  • Example 8 shows a comparative dissolution graph between the R-thioctic acid tablet prepared in Example 9 and Comparative Example 2 and the reference drug (Bugwang Pharmaceutical 'Dexid Tablet').
  • the present invention provides an oral formulation having improved stability and dissolution rate compared to conventional formulations, and containing R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present invention includes R-thioctic acid or a pharmaceutically acceptable salt thereof as an active ingredient, an oil for blocking the active ingredient from an acidic environment, and a dispersing aid for improving dispersibility.
  • 'dispersion aid' refers to a pharmaceutically acceptable excipient used to increase dispersibility in an acidic environment when the R-thioctic acid active ingredient is eluted from the body.
  • the dispersing aid comprises a specific surfactant suitable for increasing the dispersibility of R-thioctic acid and an additional auxiliary surfactant.
  • the bioavailability of thioctic acid when orally administered as an active ingredient appears to be about 30%.
  • the first is denaturation such as polymerization due to low stability
  • the second is a fast intrahepatic metabolic rate
  • the third is low solubility in acidic conditions.
  • the pharmaceutical improvement is expected to be effective in improving the bioavailability. It is found that this bioavailability has a significant effect on degradation.
  • the pharmaceutical composition of the present invention prevents the formation of a polymer gel under acidic conditions by first encapsulating R-thioctic acid in oil.
  • a dispersing aid comprising a surfactant and an auxiliary surfactant
  • the dissolution rate in acidic conditions was remarkably improved compared to the conventional formulation.
  • the pharmaceutical composition of the present invention was able to significantly increase the dissolution rate and dissolution rate under acidic conditions in the stomach at the beginning of oral administration compared to the existing commercial formulations, and furthermore, through reduction of the liver first-pass effect in vivo (receptor saturation) An additional effect of increasing bioavailability can also be expected.
  • the pharmaceutical technology mainly used in the present invention is the self-emulsifying drug delivery system (SEDDS), in which the drug encapsulated in oil obtains sufficient dispersing power by a dispersing agent including surfactants and auxiliary surfactants to achieve homogeneity with body fluids under in vivo conditions.
  • SEDDS self-emulsifying drug delivery system
  • It is a formulation method that induces an emulsion state of one type.
  • self-emulsification an emulsion is formed even with relatively mild agitation such as gastrointestinal movement, ensuring the complete dissolution of poorly soluble preparations or drugs that are unstable under certain conditions, and facilitates rapid release of drugs, gastrointestinal permeation and absorption in vivo when taken. .
  • the oil excipients of the components listed in Table 1 below are added to 100 mg of R-thioctic acid in a weight ratio of 1:1, mixed uniformly, and the drug is dissolved in oil for a sufficient time using a sonicator to prepare a solution.
  • the prepared solution was filtered with a 0.45 ⁇ m filter, diluted 1:100 in ethanol, and then the peak value of the diluted solution was checked using HPLC, so that the solubility of R-thioctic acid according to the oil type of each preparation example was confirmed.
  • amphiphilic excipients of the components listed in Table 2 below were added 1:1:1 with R-thioctic acid and propylene glycol monocaprylate Type II oil having an HLB value of 5 and uniformly mixed with an ultrasonic dispersing device (sonicator) Disperse for a sufficient time using to prepare a mixture.
  • the mixture was filtered with a 0.45 ⁇ m filter, diluted 1:100 in ethanol, and the peak value of the diluted solution was checked using HPLC to confirm the solubility of each oil in R-thioctic acid. .
  • the mixture was administered to a pH 1.2 solution to determine whether the mixture formed polymer gel formation.
  • the HLB value of the oil excipient used as a surfactant such as Transcutol and the amphipathic excipient used as a dispersing aid is similar, the encapsulation effect of R-thioctic acid encapsulated in the oil is weakened by the amphiphilic excipient, and the pH 1.2 It is easily exposed to the solution to form a polymer gel, and it is judged that the dispersion in the solution is poor.
  • the HLB values of the oil excipient and the amphiphilic excipient show a difference of more than a certain level, the state of R-thioctic acid encapsulated in the oil is maintained, so that it is not directly exposed to a pH 1.2 solution. Dispersion was confirmed.
  • each component was mixed in the ratio shown in Table 3 below. After that, 1 mL of the mixture was added to 10 mL of a pH 1.2 solution, and the dispersion state before and after stirring through a vortexing machine was visually compared. The test results are shown in FIG. 3 .
  • Preparation 25 containing the highest ratio of propylene glycol monocaprylate Type II among the completely emulsified preparations was selected as the optimal ratio of the self-emulsifying drug delivery system base.
  • the components included in the internal solution and the capsule base were separately and uniformly mixed to prepare the internal solution and the capsule base solution, respectively.
  • the prepared mixture was prepared into soft capsules using a capsule base and a rotary soft capsule molding machine.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Comparative Example 1 note active ingredient R-thioctic acid 100.0 125.0 150.0 175.0 200.0 150.0 oil propylene glycol Monocaprylate Type II 270.0 270.0 270.0 270.0 270.0 595.0
  • Example 5 In light of these results, when the viscosity is higher than a certain level, it is difficult to disperse the solution according to stirring in the dissolution test, and it can be interpreted that the dissolution rate and final dissolution rate are also low. In addition, in the case of Example 5, some polymerization occurred during the dissolution test. As the ratio of R-thioctic acid to oil increased, drug encapsulation in oil was not completely completed, and R-thioctic acid was exposed to a pH 1.2 solution. It is considered that polymerization has occurred. The state of the eluate after the test and a schematic diagram of the relationship between drug encapsulation and polymerization in oil, which is the cause of the phenomenon, is shown in FIG. 5 . As a result of the test, it was found that Example 3 was a preferred R-thioctic acid soft capsule pharmaceutical composition containing the largest amount of active ingredient and dissolution of all drugs in 1 hour.
  • a comparative dissolution test was performed with the R-thioctic acid soft capsule prepared in Example 3 and Comparative Example 1 with 'Dexid Tablet' of Bukwang Pharmaceutical, a currently commercially available product.
  • the test was conducted for 1 hour with four dissolutions using 900 mL of water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution as the eluent, and the paddle method at 75 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2 method) ) was applied.
  • 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 solution Use the second solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.
  • test results are graphically shown in FIG. 7 .
  • Example 3 In the case of Example 3, each dissolution solution showed a fast dissolution rate and a final dissolution rate of 90% or more, whereas 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 excellent stability and dissolution rate in acidic conditions compared to the reference drug. On the other hand, in Comparative Example 1, although polymerization did not occur under acidic conditions, it can be confirmed that the final dissolution rate of all four dissolutions was 50% or less. This is considered to be because Comparative Example 1, unlike Example 3, was not sufficiently miscible with the eluate because it did not contain an appropriate ratio of surfactant and auxiliary surfactant capable of dispersing oil.
  • the components except for the adsorbent, disintegrant, and lubricant were added and uniformly mixed to make a solution, and then the prepared solution was adsorbed using an adsorbent and then dried sufficiently. Thereafter, the dried powder, disintegrant, and lubricant were uniformly mixed, and then tablets were prepared using a rotary tablet press.
  • adsorbent other known adsorbents other than calcium silicate may be used, and the amount may be increased up to 200% by weight to exhibit a desirable effect.
  • calcium silicate it is more preferable to minimize the size of the dosage form because it is sufficiently effective to use 100 wt% or less.
  • a comparative dissolution test was conducted with the R-thioctic acid tablet prepared in Example 9 and Comparative Example 2 with 'Dexid Tablet', a currently commercially available product, Bukwang Pharmaceutical.
  • the test was conducted for 1 hour with four dissolutions using 900 mL of water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution as the eluent, and the paddle method at 75 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2 method) ) was applied.
  • the preparation method of each solution is as follows.
  • pH 1.2 solution Use the first solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.
  • pH 4.0 solution 0.05 mol/L sodium acetate buffer
  • pH 6.8 solution Use the second solution of the 11th revision dissolution test method of the Korean Pharmacopoeia.
  • test results are graphically shown in FIG. 8 .
  • Example 9 has excellent stability and dissolution rate in acidic conditions compared to the reference drug.
  • Comparative Example 2 although polymerization did not occur under acidic conditions, it can be confirmed that the final dissolution rate of all four phases of dissolution was 50% or less. This can be determined because Comparative Example 2 is not miscible with the eluate because the surfactant and auxiliary surfactant that can disperse the oil are not included in an appropriate ratio, unlike Example 9.

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Abstract

La présente invention concerne une composition pharmaceutique caractérisée en ce qu'elle contient de l'acide R-thioctique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif, et en ce qu'elle contient également une huile et un auxiliaire de dispersion. Dans la composition pharmaceutique selon la présente invention, l'huile forme une couche protectrice entourant le principe actif pour protéger le principe actif contre une exposition à un environnement acide, ce qui permet d'empêcher la dégradation du principe actif tandis que l'auxiliaire de dispersion améliore la dispersibilité dans un liquide de dissolution, ce qui permet au principe actif de présenter une vitesse de dissolution élevée même dans un environnement à faible pH.
PCT/KR2021/000330 2020-01-13 2021-01-11 Composition pharmaceutique incluant de l'acide r-thioctique ou un sel pharmaceutiquement acceptable de celui-ci, de l'huile, et un auxiliaire de dispersion WO2021145618A1 (fr)

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KR10-2020-0004401 2020-01-13
KR1020200004401A KR102329411B1 (ko) 2020-01-13 2020-01-13 R-치옥트산 또는 이의 약학적으로 허용되는 염, 오일 및 분산보조제를 포함하는 약학조성물

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Citations (4)

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Publication number Priority date Publication date Assignee Title
JP2006257010A (ja) * 2005-03-16 2006-09-28 Yokohama Yushi Kogyo Kk α−リポ酸水溶性組成物、それを含む飲食品、化粧料及びその製造方法
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
JP2007016000A (ja) * 2005-07-11 2007-01-25 Taiyo Kagaku Co Ltd チオクト酸含有組成物
KR20100075599A (ko) * 2007-10-03 2010-07-02 아사히비루 가부시키가이샤 과립, 정제 및 이들의 제조 방법

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KR20060100117A (ko) 2005-03-16 2006-09-20 건일제약 주식회사 알파-리포산을 포함한 안정성이 증진된 경구 투여용 약제조성물
KR100705199B1 (ko) 2005-09-02 2007-04-06 부광약품 주식회사 Ｄ-(+)-α-리포산 트로메타민염을 포함하는 간섬유화 억제 및 치료용 조성물

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JP2006257010A (ja) * 2005-03-16 2006-09-28 Yokohama Yushi Kogyo Kk α−リポ酸水溶性組成物、それを含む飲食品、化粧料及びその製造方法
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
JP2007016000A (ja) * 2005-07-11 2007-01-25 Taiyo Kagaku Co Ltd チオクト酸含有組成物
KR20100075599A (ko) * 2007-10-03 2010-07-02 아사히비루 가부시키가이샤 과립, 정제 및 이들의 제조 방법

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HU CAIBIAO; ZHAO GUODONG; XIA QIANG; SUN RUI: "Development and characterization of a self-double-emulsifying drug delivery system containing both epigallocatechin-3-gallate and α-lipoic", JOURNAL OF MATERIAL SCIENCE, vol. 50, no. 20, 14 July 2015 (2015-07-14), pages 6567 - 6577, XP035519616, ISSN: 0022-2461, DOI: 10.1007/s10853-015-9194-7 *
NEKKANTI VIJAYKUMAR, KARATGI PRADEEP, PRABHU RAGHAVENDRA, PILLAI RAVIRAJ: "Solid Self-Microemulsifying Formulation for Candesartan Cilexetil", AAPS PHARMSCITECH, vol. 11, no. 1, 1 March 2010 (2010-03-01), pages 9 - 17, XP055829678, DOI: 10.1208/s12249-009-9347-6 *

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