WO2023224358A1 - Soft capsule having improved pharmaceutical stability - Google Patents

Soft capsule having improved pharmaceutical stability Download PDF

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Publication number
WO2023224358A1
WO2023224358A1 PCT/KR2023/006614 KR2023006614W WO2023224358A1 WO 2023224358 A1 WO2023224358 A1 WO 2023224358A1 KR 2023006614 W KR2023006614 W KR 2023006614W WO 2023224358 A1 WO2023224358 A1 WO 2023224358A1
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Prior art keywords
soft capsule
oil
gelatine
capsule composition
composition according
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PCT/KR2023/006614
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French (fr)
Korean (ko)
Inventor
유희원
배성수
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부광약품 주식회사
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Publication of WO2023224358A1 publication Critical patent/WO2023224358A1/en

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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
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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

Definitions

  • the present invention relates to a soft capsule with improved pharmaceutical stability, and more specifically, to a film containing a content with self-emulsifying properties and a low molecular weight gelatin hydrolyzate with a high primary amine content. It relates to a soft capsule containing improved pharmaceutical stability.
  • Soft capsules are composed of contents (filling), which is the core ingredient, and gelatin film (outer shell), which is the shell ingredient.
  • the capsule contents are composed of one or more active ingredients and bases (excipients), and the film is made up of gelatin and a certain amount of It consists of plasticizer and water.
  • Gelatin the main component of the skin, is a substance obtained by hydrolyzing collagen, which makes up the connective tissue of animals, and is a polymer in which polypeptide chains are complexly entangled.
  • the polypeptide chain contains highly reactive active groups (-COOH, -NH 2 , -SH, -OH) that can bind.
  • the active groups between gelatin molecules form covalent bonds over time, gradually forming a large network structure (network molecule). Due to this phenomenon, gelatin becomes insoluble (insoluble) in water, which causes the entire shell of the soft capsule to become insoluble, delaying disintegration.
  • Factors that affect the formation of a network between gelatin molecules include high temperature, high moisture content of the film, aldehyde or ketone compounds contained in active ingredients or excipients, tannin, iron or chromium, and aluminum metal ions.
  • the insolubilization mechanism of gelatin is mainly achieved by carbonylamine reaction, and this reaction proceeds quickly when an aldehyde compound is present inside the film and contains a lot of moisture.
  • the contents of soft capsules have the advantage of being able to be easily filled in liquid or paste form, so the main ingredients are suspended or dissolved in oil or a hydrophilic base and used as capsule contents.
  • oil base is used as the capsule content, physical stability is superior to soft capsules using a hydrophilic base, but it has the disadvantage of being poor in pharmaceutical bioavailability and rapid efficacy.
  • the dissolution rate or bioavailability is generally low.
  • the active ingredient is dissolved in a mixture of surfactants, solubilizing agents, lipid substances, etc. to achieve self-emulsification.
  • this content has the property of being easily dispersed in water, so when formulated into a soft capsule, the problem of film insolubilization (delayed disintegration) of the active ingredient is likely to occur as it is dispersed and transferred into the moisture within the gelatin film.
  • the object of the present invention is to provide a pharmaceutically stable soft capsule formulation with self-emulsifying properties, significantly reduced migration of active ingredients into the capsule membrane due to moisture in the capsule shell, and improved disintegration delay. will be.
  • a core comprising a lipophilic compound and a vehicle with a log P of at least 5;
  • the vehicle comprises (a) at least 500 mg of a fatty component sufficient to achieve lymphatic uptake in a mammal and (b) a hydrophilic surfactant;
  • the fatty component is selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids;
  • the long-chain fatty acids in the monoglycerides are selected from fatty acid chains having 14 to 24 carbon atoms, and the long-chain fatty acids in the triglycerides are selected from fatty acid chains having 14 to 24 carbon atoms;
  • the weight ratio of triglycerides to monoglycerides ranges from 2.8:1 to 1:5;
  • the weight ratio (a):(b) is 10:1 to 1:2,
  • the gelatine hydrolyzate has an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 ⁇ 10 -3 to 1.0 ⁇ 10 -2 ⁇ Mol per 1 ⁇ g of gelatine hydrolyzate,
  • the gelatine composition includes 1 to 20% of gelatine hydrolyzate and 80 to 99% of gelatin by weight by weight of the gelatine composition,
  • a soft capsule composition is provided.
  • the fatty component comprises mono-glycerides and tri-glycerides of long chain fatty acids, and the weight ratio of tri-glycerides to mono-glycerides may range from 2:1 to 1:3. there is.
  • the core may exhibit an AUC(0-inf)(fasted)/AUC(0-inf)(fed) of at least 0.8.
  • the weight ratio of (a):(b) may range from 4:1 to 1:2.
  • the long-chain fatty acid in the mono-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid
  • the long-chain fatty acid in the tri-glyceride may be selected from linolenic acid, oleic acid, and palmitic acid. , linoleic acid, and stearic acid.
  • the fat component containing tri-glycerides of long-chain fatty acids may be a naturally derived oil
  • the naturally derived oil may be soybean oil, olive oil, sesame oil, safflower oil, It may be selected from peanut oil, rapeseed oil, sunflower oil, coconut oil, corn oil, sunflower seed oil, cotton seed oil, palm oil, peanut oil (arachidis oil), and mixtures thereof.
  • the vehicle is self-emulsifying.
  • the lipophilic compound is abiraterone acetate, acitretin, allylestrenol, alpha tocopherol, amidarone, and aprepitant.
  • atorvastatin bexarotene, bromocriptine
  • candesartan cinacalcet
  • clomiphene diethyl stilbestrol
  • diethyl stilbestrol diethyl stilbestrol, dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fucidic acid
  • halofantrine halofantrine, irbesartan, isotretinoin, itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, Nel nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, r
  • the capsule shell may include 30 to 60% by weight of gelatin hydrolyzate and one or more of the gelatin composition, 20 to 40% by weight of plasticizer, and 20 to 40% by weight of water.
  • the gelatin hydrolyzate may have a degree of hydrolysis exceeding 13%.
  • the average molecular weight of the gelatine hydrolyzate may range from 100 to 1500 Da, and in a further aspect from 400 to 1200 Da.
  • the gelatin composition may include 5 to 10% of gelatin hydrolyzate and 90 to 95% of gelatin by weight.
  • the jelly strength of one or more of the gelatine hydrolyzate and gelatine composition may be 160 to 200 blooms.
  • the plasticizer may be selected from glycerin, sorbitol, sorbitan, maltitol, polyglycitol, propylene glycol, polyethylene glycol and mixtures thereof, and in a further aspect glycerin, sorbitol, sorbitan and mixtures thereof. and, in a further embodiment, a mixture of sorbitol and sorbitan or a mixture of glycerin and sorbitol.
  • the capsule shell may further include one or more selected from colorants, light-shielding agents, flavoring agents, sweeteners, acidulants, antioxidants, and preservatives.
  • the soft capsule according to the present invention contains a low-molecular-weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby preventing the delayed disintegration of the active ingredient that generally occurs in soft capsules containing contents with self-emulsifying properties. It has formulation stability.
  • the present invention relates to a pharmaceutically stable soft capsule containing content with self-emulsifying properties, significantly reducing migration of active ingredients into the capsule shell due to moisture in the capsule shell, and improving disintegration delay.
  • a core comprising a lipophilic compound and a vehicle with a log P of at least 5;
  • the vehicle comprises (a) at least 500 mg of a fatty component sufficient to achieve lymphatic uptake in a mammal and (b) a hydrophilic surfactant;
  • the fatty component is selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids;
  • the long-chain fatty acids in the monoglycerides are selected from fatty acid chains having 14 to 24 carbon atoms, and the long-chain fatty acids in the triglycerides are selected from fatty acid chains having 14 to 24 carbon atoms;
  • the weight ratio of triglycerides to monoglycerides ranges from 2.8:1 to 1:5;
  • the weight ratio (a):(b) is 10:1 to 1:2,
  • the gelatine hydrolyzate has an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 ⁇ 10 -3 to 1.0 ⁇ 10 -2 ⁇ Mol per 1 ⁇ g of gelatine hydrolyzate,
  • the gelatin composition provides a soft capsule composition comprising 1 to 20% by weight of gelatine hydrolyzate and 80 to 99% by weight of gelatin.
  • the fatty component is present in an amount sufficient to enhance or promote intestinal lymphatic transport of the lipophilic compound by oral administration in the fasted and fed state compared to a composition without the fatty component.
  • the fatty component may be selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids, specifically mono-glycerides of long-chain fatty acids. and tri-glycerides, wherein the weight ratio of triglycerides to monoglycerides may range from 2:1 to 1:3.
  • the long-chain fatty acid in the mono-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid.
  • the long-chain fatty acid in the tri-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid.
  • the fat component containing tri-glycerides of long-chain fatty acids may be a naturally derived oil.
  • the natural oils include, for example, soybean oil, olive oil, sesame oil, safflower oil, peanut oil, rapeseed oil, sunflower oil, coconut oil, corn oil, sunflower seed oil, cotton seed oil, and palm oil. , peanut oil (arachidis oil), and mixtures thereof.
  • the fat component is selected from olive oil, soybean oil, mixtures of olive oil and glycerol mono-oleate, and mixtures of soybean oil and glycerol mono-oleate.
  • the fatty component does not include any triglycerides but only mono-glycerides, such as glycerol mono-oleate.
  • the weight ratio of (a):(b) may range from 4:1 to 1:2.
  • the vehicle has self-emulsifying properties.
  • the core exhibits an AUC(0-inf)(fasted)/AUC(0-inf)(fed) of at least 0.8.
  • the lipophilic compound having a log P of at least 5 is 0.1 to 60% by weight, 0.1 to 50% by weight, 0.1 to 40% by weight, 0.1 to 30% by weight, and 0.5 to 60% by weight based on the weight of the composition. , may be present in an amount of 0.5 to 50% by weight, 0.5 to 40% by weight, or 0.5 to 30% by weight.
  • log P refers to the partition coefficient of the substance.
  • the log P of a substance is the base 10 logarithm of the ratio of the substance's solubility in n-octanol to its solubility in water.
  • the lipophilic compounds include, for example, abiraterone acetate, acitretin, allylestrenol, alpha tocopherol, amidarone, and aprepitant. , atorvastatin, bexarotene, bromocriptine, candesartan, cinacalcet, clomiphene, diethyl stilbestrol , dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fucidic acid, halofantrine, Irbesartan, isotretinoin, itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, nelfinavir ( nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, ritonavir, tamoxifen,
  • the lipophilic compound may be in the form of a free acid, free base, or base, and mixtures of lipophilic compounds may be used if they are therapeutically effective.
  • the lipophilic compound can be solubilized in the vehicle prior to filling into the capsule.
  • the hydrophilic surfactant may be any described herein. Suitable hydrophilic surfactants include hydrogenated castor oil ethoxylates (e.g. polyoxyl 35 castor oil), polysorbates (e.g. polysorbate 80) or any other hydrophilic surfactant with a hydrophilic-lipophilic balance (HLB) value of 10 or greater. It may include a surfactant, and any combination of any of the above.
  • HLB hydrophilic-lipophilic balance
  • the capsule shell may include 30 to 60% by weight of one or more of gelatin hydrolyzate and gelatin composition, 20 to 40% by weight of plasticizer, and 20 to 40% by weight of water, specifically 35 to 40% by weight. It may include 55% by weight of gelatine hydrolyzate and one or more of the gelatin composition, 20 to 35% by weight of plasticizer and 20 to 35% by weight of water, and more specifically, 40 to 50% by weight of gelatine hydrolyzate and gelatin.
  • the composition may include one or more of 20 to 30% by weight of a plasticizer and 20 to 35% by weight of water.
  • the gelatine hydrolyzate may have a degree of hydrolysis (DH) exceeding 13%.
  • DH is the percentage of the total number of peptide bonds present in the gelatin starting material hydrolyzed by proteolytic enzymes.
  • DH can be calculated by a method well known in the technical field to which the present invention pertains, for example, the Adler-Nissen method.
  • the gelatine hydrolyzate is a mixture of peptides of different lengths with a lower average molecular weight and higher primary amine content compared to the gelatin starting material, and an increased amount of free glycine, other amino acids and small peptides compared to the gelatin starting material. Including, it is possible to prevent the cross-linking-forming reaction. Accordingly, insolubilization (delayed disintegration) of the coating (e.g., capsule shell) of the active ingredient (e.g., lipophilic compound), which tends to occur in a soft capsule composition containing self-emulsifying contents (e.g., core), can be improved.
  • the coating e.g., capsule shell
  • the active ingredient e.g., lipophilic compound
  • the gelatine hydrolyzate may have an average molecular weight of 100 to 2000 Da, more specifically, may have an average molecular weight of 100 to 1500 Da, and even more specifically may have an average molecular weight of 400 to 1200 Da.
  • the average molecular weight is that of the gelatine hydrolyzate measured by electro-spray ionization liquid chromatography mass spectrometry (ESI-LC/MS).
  • the gelatine hydrolyzate may have an average primary amine content of 1.0 ⁇ 10 -3 to 1.0 ⁇ 10 -2 ⁇ Mol per 1 ⁇ g of gelatine hydrolyzate.
  • the gelatine hydrolyzate may have an average polypeptide length of 20 amino acids or less, specifically 6 to 18 amino acids, and more specifically 4 to 18 amino acids. It may have an average polypeptide length consisting of .
  • the length of a polypeptide chain can be determined indirectly by size-exclusion chromatography/high performance liquid chromatography (SEC/HPLC).
  • the gelatine composition comprises the gelatine hydrolyzate and higher molecular weight pharmaceutical grade gelatin.
  • the gelatine composition may include 1 to 20% by weight of gelatine hydrolyzate and 80 to 99% by weight of gelatin, and more specifically, 5 to 10% of gelatine hydrolyzate and 90 to 99% by weight. May contain 95% gelatin.
  • the gelatin typically has a high average molecular weight. Specifically, the gelatin may have an average molecular weight greater than 200,000 Da, may have an average molecular weight greater than 150,000 Da, or may have an average molecular weight of 100,000 Da to 200,000 Da.
  • gelatine hydrolyzate can be blended with several types of gelatin with a wide range of physical and functional properties.
  • the selection of a particular gelatin can vary greatly depending on the intended use of the gelatin composition.
  • gelatin is derived from collagen or collagen rich tissue, which is typically available from a variety of suitable raw materials such as animal skin and bone.
  • the gelatin may be Type A gelatin, Type B gelatin, or a mixture of Type A gelatin and Type B gelatin.
  • Gelatin prepared by enzymatic methods can be used to replace Type A and/or Type B gelatin.
  • the jelly strength of one or more of the gelatine hydrolyzate and gelatine composition may be 160 to 200 blooms.
  • the plasticizer may be selected from glycerin, sorbitol, sorbitan, maltitol, polyglycitol, propylene glycol, polyethylene glycol, and mixtures thereof, and specifically may be selected from glycerin, sorbitol, sorbitan, and mixtures thereof. And, more specifically, it may be a mixture of sorbitol and sorbitan or a mixture of glycerin and sorbitol.
  • the capsule shell may further include one or more selected from colorants, light blocking agents, flavoring agents, sweeteners, acidulants, antioxidants, and preservatives.
  • the bursting strength of the soft capsule composition may be 6.0 to 9.0 N.
  • the method for producing the soft capsule composition may adopt a method commonly used in the art for producing a soft capsule formulation or may be modified appropriately, and thus a detailed description thereof will be omitted in the present invention.
  • a soft capsule film was manufactured through swelling, heating dissolution (70 to 80°C), and defoaming processes.
  • Example 1 Example 2
  • Example 3 Example 4 Gelatin 150 LB gelatin 42.25% - - - - Glycerin plasticizer 11.70% - - - - Sorbitol Special plasticizer 11.05% - - - - RXL Gelatin hydrolyzate - 43.20% 43.20% 30.00% RXL R2 Gelatin hydrolyzate and gelatin blend - - - 49.00% 10.00% polysorb plasticizer - - 24.80% 27.00% 26.00% A-810 plasticizer - 24.80% Purified water 35.00% 32.00% 32.00% 24.00% 34.00%
  • Gelatin 150 LB Commercially available general gelatin with a molecular weight of 2000 to 4000 Da (product of Rousselot)
  • RXL Gelatin hydrolyzate with an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 Decomposition product (gelita product)
  • RXL R2 A gelatin composition (product of gelita) in which the gelatin hydrolyzate and gelatin are mixed at 1 to 20% and 80 to 99% by weight, respectively.
  • Sorbitol Special Sorbitol Special ® by SPI Pharma
  • SEDDS self-emulsifying drug delivery systems
  • the oil component of SEDDS was dispersed and mixed to obtain a transparent mono-phase placebo vehicle system.
  • Abiraterone acetate as one of the lipophilic compounds was added and dissolved in the placebo vehicle system.
  • Soft capsules were manufactured by filling and molding the soft capsule shell prepared in step 1 above and the soft capsule contents prepared in step 2 into a rotary die type automatic soft capsule molding machine.
  • the soft capsule membrane prepared in step 1 above and the soft capsule contents prepared using S3 as SEDDS in step 2 above were filled and molded in a rotary die type soft capsule automatic forming machine to obtain 60.5 mg of parenteral content per soft capsule.
  • the dissolution rate of the prepared soft capsules was evaluated over a long period of time.
  • 900 ml of water (3% SLS (Sodium Lauryl Sulfate), solubilizer) was used as the dissolution medium, and the test was conducted according to the dissolution test method 2 among the general test methods of the Korean Pharmacopoeia.
  • the rotation speed of the paddle was 75 rpm and the sinker was used. used.
  • 5 mL of the eluate was collected, filtered through a 10 um filter, and about 2 mL of the solution was discarded and the remaining solution was used as the sample solution.
  • approximately 68 mg of abiraterone acetate standard was precisely weighed and dissolved in 900 ml of the above eluate, and then the content was measured using liquid chromatography using the standard solution.
  • the eluate was collected at 15, 30, 45, and 60 minutes after the start of the dissolution test, and quantified using liquid chromatography at a wavelength of 254 nm.
  • the mobile phase was a mixture of 800 mL of HPLC-grade water and 200 mL of Acetonitrile containing 1 mL of acetic acid, the flow rate was 2 mL/min, and the sample injection volume was 10 ⁇ l.
  • the soft capsules of Examples 1 to 4 contained low molecular weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby increasing the amount of free glycine, other amino acids and small peptides, thereby promoting crosslinking of gelatin. It can be seen that the disintegration delay is improved and the lipophilic compound is eluted stably.
  • the soft capsule according to the present invention contains a low-molecular-weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby preventing the delayed disintegration of the active ingredient that generally occurs in soft capsules containing contents with self-emulsifying properties. Since it has formulation stability, it can be usefully used as a soft capsule with improved pharmaceutical stability.

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Abstract

The present invention relates to a soft capsule having improved pharmaceutical stability and, more specifically, to a soft capsule having improved pharmaceutical stability, comprising: contents with a self-emulsifying property; and a coating comprising a low molecular weight gelatin hydrolysate having a high primary amine content, and thus the delayed disintegration of active ingredients, which generally occurs in soft capsules comprising contents with a self-emulsifying property, can be prevented.

Description

제제학적으로 안정성이 향상된 연질 캡슐Soft capsule with improved pharmaceutical stability
본 발명은 제제학적으로 안정성이 향상된 연질 캡슐에 관한 것으로, 더욱 상세하게는 자기-유화(self-emulsifying) 특성의 내용물 및 높은 일차 아민(primary amine) 함량을 갖는 저분자량 젤라틴 가수분해물을 포함하는 피막을 포함하는, 제제학적으로 안정성이 향상된 연질 캡슐에 관한 것이다.The present invention relates to a soft capsule with improved pharmaceutical stability, and more specifically, to a film containing a content with self-emulsifying properties and a low molecular weight gelatin hydrolyzate with a high primary amine content. It relates to a soft capsule containing improved pharmaceutical stability.
연질 캡슐은 코어 성분인 내용물(충전물)과 쉘 성분인 젤라틴 피막(외피)으로 구성되어 있으며 이때 캡슐 내용물은 활성을 지닌 1종 이상의 유효성분과 기제(부형제, Excipients)로 구성되고, 피막은 젤라틴과 일정량의 가소제 및 물로 이루어진다.Soft capsules are composed of contents (filling), which is the core ingredient, and gelatin film (outer shell), which is the shell ingredient. In this case, the capsule contents are composed of one or more active ingredients and bases (excipients), and the film is made up of gelatin and a certain amount of It consists of plasticizer and water.
피막의 주요 구성 성분인 젤라틴은 동물의 결합조직을 구성하는 콜라겐(Collagen)을 가수분해시켜 얻는 물질로 폴리펩타이드(Polypeptide) 사슬이 복잡하게 엉겨있는 폴리머이다. 폴리펩타이드 사슬에는 결합할 수 있는 반응성이 큰 활성기(-COOH, -NH2, -SH, -OH)가 포함되어 있다. 젤라틴 분자들 간의 활성기는 시간이 경과함에 따라 공유결합을 형성하여 점차적으로 거대한 그물 구조(네트워크 분자, Network molecule) 형태를 가지게 된다. 이 현상으로 인해 젤라틴은 물에 용해되지 않게(불용화) 되며, 이로 인해 연질 캡슐의 피막 전체가 불용화 되어, 붕해가 지연되게 된다.Gelatin, the main component of the skin, is a substance obtained by hydrolyzing collagen, which makes up the connective tissue of animals, and is a polymer in which polypeptide chains are complexly entangled. The polypeptide chain contains highly reactive active groups (-COOH, -NH 2 , -SH, -OH) that can bind. The active groups between gelatin molecules form covalent bonds over time, gradually forming a large network structure (network molecule). Due to this phenomenon, gelatin becomes insoluble (insoluble) in water, which causes the entire shell of the soft capsule to become insoluble, delaying disintegration.
젤라틴 분자간의 네트워크 형성에 영향을 주는 요인으로는 높은 온도, 피막 의 높은 수분 함량, 유효성분 또는 부형제에 함유된 알데히드 또는 케톤 화합물, 탄닌, 철 또는 크롬, 알루미늄 금속이온 등을 들 수 있다.Factors that affect the formation of a network between gelatin molecules include high temperature, high moisture content of the film, aldehyde or ketone compounds contained in active ingredients or excipients, tannin, iron or chromium, and aluminum metal ions.
젤라틴의 불용화 기전은 주로 카르보닐아민 반응에 의해 이루어지며, 이 반응은 알데히드 화합물이 피막 내부에 존재하고 수분을 많이 함유할 경우 신속히 진행된다. The insolubilization mechanism of gelatin is mainly achieved by carbonylamine reaction, and this reaction proceeds quickly when an aldehyde compound is present inside the film and contains a lot of moisture.
연질 캡슐의 내용물은 액상 또는 페이스트상 형태를 간편하게 충전할 수 있는 장점을 가지고 있어 주성분을 오일이나 친수성기제에 현탁 또는 용해시켜 캡슐 내용물로 사용한다. 캡슐 내용물로 오일 기제를 사용한 경우 친수성 기제를 사용한 연질 캡슐보다 물리적 안정성은 우수하나 제제학적으로 생체이용률 및 속효성이 떨어지는 단점이 있다.The contents of soft capsules have the advantage of being able to be easily filled in liquid or paste form, so the main ingredients are suspended or dissolved in oil or a hydrophilic base and used as capsule contents. When an oil base is used as the capsule content, physical stability is superior to soft capsules using a hydrophilic base, but it has the disadvantage of being poor in pharmaceutical bioavailability and rapid efficacy.
특히, 약리학적 유효성분이 친유성이거나 또는 불용성인 경우에는 일반적으로 용출률이나 생체이용률이 낮기 때문에, 이를 개선하기 위하여 계면활성제, 용해보조제, 지질성 물질 등의 혼합물에 유효성분을 용해시켜 자기-유화의 특성을 갖는 충전물로 제조한다. 그러나, 이 내용물은 물에 쉽게 분산이 되는 성질을 가지고 있어 연질 캡슐로 제형화할 경우 젤라틴 피막 내의 수분 속으로 분산·이행됨에 따라 유효성분의 피막불용화(붕해지연) 문제가 발생하기 쉽다.In particular, when the pharmacologically active ingredient is lipophilic or insoluble, the dissolution rate or bioavailability is generally low. To improve this, the active ingredient is dissolved in a mixture of surfactants, solubilizing agents, lipid substances, etc. to achieve self-emulsification. Manufactured with fillers with special properties. However, this content has the property of being easily dispersed in water, so when formulated into a soft capsule, the problem of film insolubilization (delayed disintegration) of the active ingredient is likely to occur as it is dispersed and transferred into the moisture within the gelatin film.
본 발명자들은 연질 캡슐에 포함되는 약리학적 유효성분의 용출 또는 생체 이용률을 높이기 위해 예의 연구한 결과, 자기-유화 특성의 내용물을 포함하는 연질 캡슐에서 발생하기 쉬운 유효성분의 피막불용화(붕해지연) 문제를 개선할 수 있음을 확인하고 본 발명을 완성하기에 이르렀다.As a result of intensive research to increase the dissolution or bioavailability of pharmacologically active ingredients contained in soft capsules, the present inventors found that film insolubilization (delayed disintegration) of the active ingredients is likely to occur in soft capsules containing contents with self-emulsifying properties. After confirming that the problem could be improved, the present invention was completed.
따라서, 본 발명의 목적은 자기-유화 특성의 내용물을 포함하면서, 캡슐 피막의 수분으로 인한 유효성분의 피막으로의 이행이 현저히 감소되고, 붕해지연이 개선된 제제학적으로 안정된 연질 캡슐 제제를 제공하는 것이다.Therefore, the object of the present invention is to provide a pharmaceutically stable soft capsule formulation with self-emulsifying properties, significantly reduced migration of active ingredients into the capsule membrane due to moisture in the capsule shell, and improved disintegration delay. will be.
본 발명의 목적을 달성하기 위하여, 본 발명은In order to achieve the purpose of the present invention, the present invention
i) 적어도 5의 log P를 가지는 친유성 화합물 및 비히클을 포함하는 코어(core); 및i) a core comprising a lipophilic compound and a vehicle with a log P of at least 5; and
ii) 젤라틴 가수분해물 및 젤라틴 가수분해물과 젤라틴을 포함하는 젤라틴 조성물 중 1종 이상, 가소제 및 물을 포함하는 캡슐(capsule) 쉘을 포함하고,ii) a capsule shell containing at least one of a gelatin hydrolyzate and a gelatine composition containing a gelatin hydrolyzate and gelatin, a plasticizer and water,
여기에서, 상기 비히클은 (a) 포유동물에서 림프 흡수를 달성하기에 충분한 적어도 500 mg의 지방 성분 및 (b) 친수성 계면활성제를 포함하며; 상기 지방 성분은 장쇄 지방산의 모노-글리세라이드, 장쇄 지방산의 트리-글리세라이드, 및 장쇄 지방산의 모노- 및 트리-글리세라이드로부터 선택되고; 상기 모노글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되며, 상기 트리글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되고; 트리글리세라이드 대 모노글리세라이드의 중량비는 2.8:1 내지 1:5의 범위이며; 중량비 (a):(b)는 10:1 내지 1:2이고,wherein the vehicle comprises (a) at least 500 mg of a fatty component sufficient to achieve lymphatic uptake in a mammal and (b) a hydrophilic surfactant; The fatty component is selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids; The long-chain fatty acids in the monoglycerides are selected from fatty acid chains having 14 to 24 carbon atoms, and the long-chain fatty acids in the triglycerides are selected from fatty acid chains having 14 to 24 carbon atoms; The weight ratio of triglycerides to monoglycerides ranges from 2.8:1 to 1:5; The weight ratio (a):(b) is 10:1 to 1:2,
상기 젤라틴 가수분해물은 100 내지 2000 Da의 평균 분자량 및 1 ㎍의 젤라틴 가수분해물 당 1.0 × 10-3 ~ 1.0 × 10-2 μMol의 평균 일차 아민 함량을 갖는 것이며,The gelatine hydrolyzate has an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 × 10 -3 to 1.0 × 10 -2 μMol per 1 μg of gelatine hydrolyzate,
상기 젤라틴 조성물은 젤라틴 조성물 중량 기준으로 1 내지 20%의 젤라틴 가수분해물 및 중량 기준으로 80 내지 99%의 젤라틴을 포함하는 것인,The gelatine composition includes 1 to 20% of gelatine hydrolyzate and 80 to 99% of gelatin by weight by weight of the gelatine composition,
연질 캡슐 조성물을 제공한다.A soft capsule composition is provided.
본 발명의 일 양태에서, 상기 지방 성분은 장쇄 지방산의 모노-글리세라이드 및 트리-글리세라이드를 포함하고, 트리-글리세라이드 대 모노-글리세라이드의 중량비는 2:1 내지 1:3의 범위일 수 있다.In one aspect of the invention, the fatty component comprises mono-glycerides and tri-glycerides of long chain fatty acids, and the weight ratio of tri-glycerides to mono-glycerides may range from 2:1 to 1:3. there is.
본 발명의 일 양태에서, 상기 코어는 적어도 0.8의 AUC(0-inf)(절식) / AUC(0-inf)(섭식)을 나타낼 수 있다.In one aspect of the invention, the core may exhibit an AUC(0-inf)(fasted)/AUC(0-inf)(fed) of at least 0.8.
본 발명의 일 양태에서, (a):(b)의 중량비는 4:1 내지 1:2의 범위일 수 있다.In one aspect of the present invention, the weight ratio of (a):(b) may range from 4:1 to 1:2.
본 발명의 일 양태에서, 상기 모노-글리세라이드 내 장쇄 지방산은 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택될 수 있고, 상기 트리-글리세라이드 내 장쇄 지방산은 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택될 수 있다.In one aspect of the present invention, the long-chain fatty acid in the mono-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid, and the long-chain fatty acid in the tri-glyceride may be selected from linolenic acid, oleic acid, and palmitic acid. , linoleic acid, and stearic acid.
본 발명의 일 양태에서, 상기 장쇄 지방산의 트리-글리세라이드를 포함하는 지방 성분이 자연 유래 오일(naturally derived oil)일 수 있고, 상기 자연 유래 오일은 대두유(soybean oil), 올리브유, 참기름, 홍화유, 땅콩유, 유채유(rapeseed oil), 해바라기유, 코코넛유, 옥수수유, 해바라기씨유, 면실유(cotton seed oil), 팜유, 땅콩 오일(arachidis oil) 및 이의 혼합물로부터 선택될 수 있다.In one aspect of the present invention, the fat component containing tri-glycerides of long-chain fatty acids may be a naturally derived oil, and the naturally derived oil may be soybean oil, olive oil, sesame oil, safflower oil, It may be selected from peanut oil, rapeseed oil, sunflower oil, coconut oil, corn oil, sunflower seed oil, cotton seed oil, palm oil, peanut oil (arachidis oil), and mixtures thereof.
본 발명의 일 양태에서, 상기 비히클은 자기-유화성(self-emulsifying)을 갖는다.In one aspect of the invention, the vehicle is self-emulsifying.
본 발명의 일 양태에서, 상기 친유성 화합물은 아비라테론 아세테이트(abiraterone acetate), 아시트레틴(acitretin), 알릴에스트레놀(allylestrenol), 알파 토코페롤(alpha tocopherol), 아미다론(amidarone), 아프레피탄트(aprepitant), 아트로바스타틴(atorvastatin), 벡사로텐(bexarotene), 브로모크립틴(bromocriptine), 칸데사르탄(candesartan), 시나칼세트(cinacalcet), 클로미펜(clomiphene), 디에틸 스틸베스트롤(diethyl stilbestrol), 디호모-감마-리놀레산(dihomo-gamma-linoleic acid), 에바스틴(ebastine), 에르고칼시페롤(ergocalciferol), 페노피브레이트(fenofibrate), 푸시드산(fucidic acid), 할로판트린(halofantrine), 이르베사르탄(irbesartan), 이소트레티노인(isotretinoin), 이트라코나졸(itraconazole), 라파티닙(lapatinib), 리라글루티드(liraglutide), 로라티딘(loratidine), 난드롤론 데카노에이트(nandrolone decanoate), 넬피나비르(nelfinavir), 올메사르탄(olmesartan), 오르리스타트(orlistat), 포사코나졸(posaconazole), 프로부콜(probucol), 랄록시펜(raloxifene), 리토나비르(ritonavir), 타목시펜(tamoxifen), 텔미사르탄(telmisartan), 테프레논(teprenone), 티프라나비르(tipranavir), 발사르탄(valsartan) 및 주클로펜틱솔(zuclopenthixol)로부터 선택될 수 있다.In one aspect of the invention, the lipophilic compound is abiraterone acetate, acitretin, allylestrenol, alpha tocopherol, amidarone, and aprepitant. (aprepitant), atorvastatin, bexarotene, bromocriptine, candesartan, cinacalcet, clomiphene, diethyl stilbestrol ( diethyl stilbestrol, dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fucidic acid, halofantrine ( halofantrine, irbesartan, isotretinoin, itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, Nel nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, ritonavir, tamoxifen, Telmi It may be selected from telmisartan, teprenone, tipranavir, valsartan and zuclopenthixol.
본 발명의 일 양태에서, 상기 캡슐 쉘은 30 내지 60 중량%의 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상, 20 내지 40 중량%의 가소제 및 20 내지 40 중량%의 물을 포함할 수 있다.In one aspect of the present invention, the capsule shell may include 30 to 60% by weight of gelatin hydrolyzate and one or more of the gelatin composition, 20 to 40% by weight of plasticizer, and 20 to 40% by weight of water.
본 발명의 일 양태에서,상기 젤라틴 가수분해물은 13%를 초과하는 가수분해 정도(degree of hydrolysis)를 갖는 것일 수 있다.In one aspect of the present invention, the gelatin hydrolyzate may have a degree of hydrolysis exceeding 13%.
본 발명의 일 양태에서, 상기 젤라틴 가수분해물의 평균 분자량은 100 내지 1500 Da의 범위일 수 있고, 추가 양태에서 400 내지 1200 Da의 범위일 수 있다.In one aspect of the invention, the average molecular weight of the gelatine hydrolyzate may range from 100 to 1500 Da, and in a further aspect from 400 to 1200 Da.
본 발명의 일 양태에서, 상기 젤라틴 조성물은 중량 기준으로 5 내지 10%의 젤라틴 가수분해물 및 90 내지 95%의 젤라틴을 포함할 수 있다.In one aspect of the present invention, the gelatin composition may include 5 to 10% of gelatin hydrolyzate and 90 to 95% of gelatin by weight.
본 발명의 일 양태에서, 상기 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상 의 젤리 강도(jelly strength)가 160 내지 200 블룸(bloom)일 수 있다.In one aspect of the present invention, the jelly strength of one or more of the gelatine hydrolyzate and gelatine composition may be 160 to 200 blooms.
본 발명의 일 양태에서, 상기 가소제는 글리세린, 소르비톨, 소르비탄, 말티톨, 폴리글리시톨, 프로필렌글리콜, 폴리에틸렌글리콜 및 이의 혼합물로부터 선택될 수 있고, 추가 양태에서 글리세린, 소르비톨, 소르비탄 및 이의 혼합물로부터 선택될 수 있으며, 추가 양태에서 소르비톨과 소르비탄의 혼합물 또는 글리세린과 소르비톨의 혼합물일 수 있다.In one aspect of the invention, the plasticizer may be selected from glycerin, sorbitol, sorbitan, maltitol, polyglycitol, propylene glycol, polyethylene glycol and mixtures thereof, and in a further aspect glycerin, sorbitol, sorbitan and mixtures thereof. and, in a further embodiment, a mixture of sorbitol and sorbitan or a mixture of glycerin and sorbitol.
본 발명의 일 양태에서, 상기 캡슐 쉘은 착색제, 차광제, 착향제, 감미제, 산미제, 산화방지제 및 보존제로부터 선택되는 하나 이상을 추가로 포함할 수 있다.In one aspect of the present invention, the capsule shell may further include one or more selected from colorants, light-shielding agents, flavoring agents, sweeteners, acidulants, antioxidants, and preservatives.
본 발명에 따른 연질 캡슐은 피막의 주성분으로 높은 일차 아민 함량을 갖는 저분자량 젤라틴 가수분해물을 포함하여 자기-유화 특성의 내용물을 포함하는 연질 캡슐에서 일반적으로 발생하는 유효성분의 붕해지연을 방지함으로써 우수한 제형 안정성을 갖는다.The soft capsule according to the present invention contains a low-molecular-weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby preventing the delayed disintegration of the active ingredient that generally occurs in soft capsules containing contents with self-emulsifying properties. It has formulation stability.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 자기-유화 특성의 내용물을 포함하면서, 캡슐 피막의 수분으로 인한 유효성분의 피막으로의 이행이 현저히 감소되고, 붕해지연이 개선된 제제학적으로 안정된 연질 캡슐에 관한 것이다.The present invention relates to a pharmaceutically stable soft capsule containing content with self-emulsifying properties, significantly reducing migration of active ingredients into the capsule shell due to moisture in the capsule shell, and improving disintegration delay.
따라서, 본 발명은Therefore, the present invention
i) 적어도 5의 log P를 가지는 친유성 화합물 및 비히클을 포함하는 코어(core); 및i) a core comprising a lipophilic compound and a vehicle with a log P of at least 5; and
ii) 젤라틴 가수분해물 및 젤라틴 가수분해물과 젤라틴을 포함하는 젤라틴 조성물 중 1종 이상, 가소제 및 물을 포함하는 캡슐(capsule) 쉘을 포함하고,ii) a capsule shell containing at least one of a gelatin hydrolyzate and a gelatine composition containing a gelatin hydrolyzate and gelatin, a plasticizer and water,
여기에서, 상기 비히클은 (a) 포유동물에서 림프 흡수를 달성하기에 충분한 적어도 500 mg의 지방 성분 및 (b) 친수성 계면활성제를 포함하며; 상기 지방 성분은 장쇄 지방산의 모노-글리세라이드, 장쇄 지방산의 트리-글리세라이드, 및 장쇄 지방산의 모노- 및 트리-글리세라이드로부터 선택되고; 상기 모노글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되며, 상기 트리글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되고; 트리글리세라이드 대 모노글리세라이드의 중량비는 2.8:1 내지 1:5의 범위이며; 중량비 (a):(b)는 10:1 내지 1:2이고,wherein the vehicle comprises (a) at least 500 mg of a fatty component sufficient to achieve lymphatic uptake in a mammal and (b) a hydrophilic surfactant; The fatty component is selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids; The long-chain fatty acids in the monoglycerides are selected from fatty acid chains having 14 to 24 carbon atoms, and the long-chain fatty acids in the triglycerides are selected from fatty acid chains having 14 to 24 carbon atoms; The weight ratio of triglycerides to monoglycerides ranges from 2.8:1 to 1:5; The weight ratio (a):(b) is 10:1 to 1:2,
상기 젤라틴 가수분해물은 100 내지 2000 Da의 평균 분자량 및 1 ㎍의 젤라틴 가수분해물 당 1.0 × 10-3 ~ 1.0 × 10-2 μMol의 평균 일차 아민 함량을 갖는 것이며,The gelatine hydrolyzate has an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 × 10 -3 to 1.0 × 10 -2 μMol per 1 μg of gelatine hydrolyzate,
상기 젤라틴 조성물은 중량 기준으로 1 내지 20%의 젤라틴 가수분해물 및 중량 기준으로 80 내지 99%의 젤라틴을 포함하는 것인, 연질 캡슐 조성물을 제공한다.The gelatin composition provides a soft capsule composition comprising 1 to 20% by weight of gelatine hydrolyzate and 80 to 99% by weight of gelatin.
본 발명에서, 상기 지방 성분은 상기 지방 성분이 없는 조성물과 비교하여 절식 상태에서 그리고 섭식 상태에서 경구 투여에 의해 상기 친유성 화합물의 장 림프 수송을 향상 또는 촉진시키기에 충분한 양으로 존재한다.In the present invention, the fatty component is present in an amount sufficient to enhance or promote intestinal lymphatic transport of the lipophilic compound by oral administration in the fasted and fed state compared to a composition without the fatty component.
본 발명에서, 상기 지방 성분은 장쇄 지방산의 모노-글리세라이드, 장쇄 지방산의 트리-글리세라이드, 및 장쇄 지방산의 모노- 및 트리-글리세라이드로부터 선택될 수 있고, 구체적으로 장쇄 지방산의 모노-글리세라이드 및 트리-글리세라이드를 포함하며, 트리글리세라이드 대 모노글리세라이드의 중량비는 2:1 내지 1:3의 범위일 수 있다.In the present invention, the fatty component may be selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids, specifically mono-glycerides of long-chain fatty acids. and tri-glycerides, wherein the weight ratio of triglycerides to monoglycerides may range from 2:1 to 1:3.
본 발명에서, 상기 모노-글리세라이드 내 장쇄 지방산은 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택될 수 있다.In the present invention, the long-chain fatty acid in the mono-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid.
본 발명에서, 상기 트리-글리세라이드 내 장쇄 지방산은 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택될 수 있다.In the present invention, the long-chain fatty acid in the tri-glyceride may be selected from linolenic acid, oleic acid, palmitic acid, linoleic acid, and stearic acid.
본 발명에서, 상기 장쇄 지방산의 트리-글리세라이드를 포함하는 지방 성분이 자연 유래 오일(naturally derived oil)일 수 있다. 또한, 상기 자연 유래 오일은 예컨대 대두유(soybean oil), 올리브유, 참기름, 홍화유, 땅콩유, 유채유(rapeseed oil), 해바라기유, 코코넛유, 옥수수유, 해바라기씨유, 면실유(cotton seed oil), 팜유, 땅콩 오일(arachidis oil) 및 이의 혼합물로부터 선택될 수 있다. 본 발명의 일 구체예에서 상기 지방 성분은 올리브유, 대두유, 올리브유 및 글리세롤 모노-올레에이트의 혼합물, 및 대두유 및 글리세롤 모노-올레에이트의 혼합물로부터 선택된다. 또한, 일 구체예에서 상기 지방 성분은 어떠한 트리글리세라이드도 포함하지 않지만 단지 모노-글리세라이드, 예컨대 글리세롤 모노-올레에이트를 포함한다.In the present invention, the fat component containing tri-glycerides of long-chain fatty acids may be a naturally derived oil. In addition, the natural oils include, for example, soybean oil, olive oil, sesame oil, safflower oil, peanut oil, rapeseed oil, sunflower oil, coconut oil, corn oil, sunflower seed oil, cotton seed oil, and palm oil. , peanut oil (arachidis oil), and mixtures thereof. In one embodiment of the invention the fat component is selected from olive oil, soybean oil, mixtures of olive oil and glycerol mono-oleate, and mixtures of soybean oil and glycerol mono-oleate. Additionally, in one embodiment the fatty component does not include any triglycerides but only mono-glycerides, such as glycerol mono-oleate.
본 발명에서, 상기 (a):(b)의 중량비는 4:1 내지 1:2의 범위일 수 있다.In the present invention, the weight ratio of (a):(b) may range from 4:1 to 1:2.
본 발명에서, 상기 비히클은 자기-유화성(self-emulsifying)을 갖는다.In the present invention, the vehicle has self-emulsifying properties.
본 발명에서, 상기 코어는 적어도 0.8의 AUC(0-inf)(절식) / AUC(0-inf)(섭식)을 나타낸다.In the present invention, the core exhibits an AUC(0-inf)(fasted)/AUC(0-inf)(fed) of at least 0.8.
본 발명에서, 상기 적어도 5의 log P를 가지는 친유성 화합물은 상기 조성물 중량 기준으로 0.1 내지 60 중량%, 0.1 내지 50 중량%, 0.1 내지 40 중량%, 0.1 내지 30 중량%, 0.5 내지 60 중량%, 0.5 내지 50 중량%, 0.5 내지 40 중량% 또는 0.5 내지 30 중량% 양으로 존재할 수 있다. 여기서 "log P"는 물질의 분배계수를 지칭한다. 물질의 log P는 n-옥탄올 내 물질의 용해도 대 물 내 물질의 용해도의 비의 밑이 10인 로그값이다.In the present invention, the lipophilic compound having a log P of at least 5 is 0.1 to 60% by weight, 0.1 to 50% by weight, 0.1 to 40% by weight, 0.1 to 30% by weight, and 0.5 to 60% by weight based on the weight of the composition. , may be present in an amount of 0.5 to 50% by weight, 0.5 to 40% by weight, or 0.5 to 30% by weight. Here “log P” refers to the partition coefficient of the substance. The log P of a substance is the base 10 logarithm of the ratio of the substance's solubility in n-octanol to its solubility in water.
또한, 상기 친유성 화합물은 예컨대, 아비라테론 아세테이트(abiraterone acetate), 아시트레틴(acitretin), 알릴에스트레놀(allylestrenol), 알파 토코페롤(alpha tocopherol), 아미다론(amidarone), 아프레피탄트(aprepitant), 아트로바스타틴(atorvastatin), 벡사로텐(bexarotene), 브로모크립틴(bromocriptine), 칸데사르탄(candesartan), 시나칼세트(cinacalcet), 클로미펜(clomiphene), 디에틸 스틸베스트롤(diethyl stilbestrol), 디호모-감마-리놀레산(dihomo-gamma-linoleic acid), 에바스틴(ebastine), 에르고칼시페롤(ergocalciferol), 페노피브레이트(fenofibrate), 푸시드산(fucidic acid), 할로판트린(halofantrine), 이르베사르탄(irbesartan), 이소트레티노인(isotretinoin), 이트라코나졸(itraconazole), 라파티닙(lapatinib), 리라글루티드(liraglutide), 로라티딘(loratidine), 난드롤론 데카노에이트(nandrolone decanoate), 넬피나비르(nelfinavir), 올메사르탄(olmesartan), 오르리스타트(orlistat), 포사코나졸(posaconazole), 프로부콜(probucol), 랄록시펜(raloxifene), 리토나비르(ritonavir), 타목시펜(tamoxifen), 텔미사르탄(telmisartan), 테프레논(teprenone), 티프라나비르(tipranavir), 발사르탄(valsartan) 및 주클로펜틱솔(zuclopenthixol)로부터 선택될 수 있으나, 이에 제한되지 않는다. In addition, the lipophilic compounds include, for example, abiraterone acetate, acitretin, allylestrenol, alpha tocopherol, amidarone, and aprepitant. , atorvastatin, bexarotene, bromocriptine, candesartan, cinacalcet, clomiphene, diethyl stilbestrol , dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fucidic acid, halofantrine, Irbesartan, isotretinoin, itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, nelfinavir ( nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, ritonavir, tamoxifen, telmisartan ( It may be selected from, but is not limited to, telmisartan, teprenone, tipranavir, valsartan, and zuclopenthixol.
또한, 상기 친유성 화합물은 유리 산, 유리 염기 또는 염기 형태일 수 있고, 치료적으로 효과적인 경우 친유성 화합물의 혼합물이 사용될 수 있다.Additionally, the lipophilic compound may be in the form of a free acid, free base, or base, and mixtures of lipophilic compounds may be used if they are therapeutically effective.
또한, 상기 친유성 화합물은 캡슐제 내로 충전 이전에 상기 비히클 내에서 가용화될 수 있다.Additionally, the lipophilic compound can be solubilized in the vehicle prior to filling into the capsule.
본 발명에서, 상기 친수성 계면활성제는 본 명세서에 기술된 어느 것일 수 있다. 적합한 친수성 계면활성제는 수소화된 피마자유 에톡실레이트(예컨대, 폴리옥실 35 피마자유), 폴리소르베이트(예컨대, 폴리소르베이트 80) 또는 10 이상의 친수성-친유성 밸런스(HLB) 값을 가지는 어떠한 기타 친수성 계면활성제, 및 상기 중 어느 하나의 어느 조합을 포함할 수 있다.In the present invention, the hydrophilic surfactant may be any described herein. Suitable hydrophilic surfactants include hydrogenated castor oil ethoxylates (e.g. polyoxyl 35 castor oil), polysorbates (e.g. polysorbate 80) or any other hydrophilic surfactant with a hydrophilic-lipophilic balance (HLB) value of 10 or greater. It may include a surfactant, and any combination of any of the above.
본 발명에서, 상기 캡슐 쉘은 30 내지 60 중량%의 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상, 20 내지 40 중량%의 가소제 및 20 내지 40 중량%의 물을 포함할 수 있고, 구체적으로 35 내지 55 중량%의 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상, 20 내지 35 중량%의 가소제 및 20 내지 35 중량%의 물을 포함할 수 있으며, 보다 구체적으로 40 내지 50 중량%의 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상, 20 내지 30 중량%의 가소제 및 20 내지 35 중량%의 물을 포함할 수 있다.In the present invention, the capsule shell may include 30 to 60% by weight of one or more of gelatin hydrolyzate and gelatin composition, 20 to 40% by weight of plasticizer, and 20 to 40% by weight of water, specifically 35 to 40% by weight. It may include 55% by weight of gelatine hydrolyzate and one or more of the gelatin composition, 20 to 35% by weight of plasticizer and 20 to 35% by weight of water, and more specifically, 40 to 50% by weight of gelatine hydrolyzate and gelatin. The composition may include one or more of 20 to 30% by weight of a plasticizer and 20 to 35% by weight of water.
본 발명에서, 상기 젤라틴 가수분해물은 13%를 초과하는 가수분해 정도(degree of hydrolysis; DH)를 갖을 수 있다. 여기서 DH는 단백질 분해효소에 의해 가수분해된 젤라틴 출발 물질에 존재하는 펩티드 결합의 총수에 대한 백분율이다. DH는 본 발명이 속하는 기술분야에서 널리 알려진 방법, 예를 들면, 애들러-니센 (Adler-Nissen) 방법에 의해 계산될 수 있다.In the present invention, the gelatine hydrolyzate may have a degree of hydrolysis (DH) exceeding 13%. where DH is the percentage of the total number of peptide bonds present in the gelatin starting material hydrolyzed by proteolytic enzymes. DH can be calculated by a method well known in the technical field to which the present invention pertains, for example, the Adler-Nissen method.
또한, 상기 젤라틴 가수분해물은 젤라틴 출발물질에 비해 보다 낮은 평균 분자량 및 보다 높은 일차 아민 함량을 가지는 것으로, 젤라틴 출발 물질에 비해 유리 글리신, 기타 아미노산 및 작은 펩티드의 양이 증가된 상이한 길이의 펩티드의 혼합물을 포함하여 가교-형성 반응을 방지할 수 있다. 이에 자기-유화성의 내용물(예컨대, 코어)를 포함하는 연질 캡슐 조성물에서 발생하기 쉬운 유효성분(예컨대, 친유성 화합물)의 피막(예컨대, 캡슐 쉘) 불용화(붕해지연)를 개선할 수 있다.Additionally, the gelatine hydrolyzate is a mixture of peptides of different lengths with a lower average molecular weight and higher primary amine content compared to the gelatin starting material, and an increased amount of free glycine, other amino acids and small peptides compared to the gelatin starting material. Including, it is possible to prevent the cross-linking-forming reaction. Accordingly, insolubilization (delayed disintegration) of the coating (e.g., capsule shell) of the active ingredient (e.g., lipophilic compound), which tends to occur in a soft capsule composition containing self-emulsifying contents (e.g., core), can be improved.
구체적으로, 상기 젤라틴 가수분해물은 100 내지 2000 Da의 평균 분자량을 가질 수 있고, 보다 구체적으로 100 내지 1500 Da의 평균 분자량을 가질 수 있으며, 보다 더 구체적으로 400 내지 1200 Da의 평균 분자량을 가질 수 있다. 상기 평균 분자량은 전자-분무 이온화 액체 크로마토그래피 질량 분석법(ESI-LC/MS)에 의해 측정된 젤라틴 가수분해 물의 분자량이다. Specifically, the gelatine hydrolyzate may have an average molecular weight of 100 to 2000 Da, more specifically, may have an average molecular weight of 100 to 1500 Da, and even more specifically may have an average molecular weight of 400 to 1200 Da. . The average molecular weight is that of the gelatine hydrolyzate measured by electro-spray ionization liquid chromatography mass spectrometry (ESI-LC/MS).
또한, 상기 젤라틴 가수분해물은 1 ㎍의 젤라틴 가수분해물 당 1.0 × 10-3 ~ 1.0 × 10-2 μMol의 평균 일차 아민 함량을 가질 수 있다. Additionally, the gelatine hydrolyzate may have an average primary amine content of 1.0 × 10 -3 to 1.0 × 10 -2 μMol per 1 μg of gelatine hydrolyzate.
또한, 상기 젤라틴 가수분해물은 20개 이하의 아미노산으로 구성된 평균 폴리펩티드 길이를 가질 수 있고, 구체적으로 6개 내지 18개의의 아미노산으로 구성된 평균 폴리펩티드 길이를 가질 수 있으며, 보다 구체적으로 4개 내지 18개의 아미노산으로 구성된 평균 폴리펩티드 길이를 가질 수 있다. 폴리펩티드 사슬의 길이는 크기-배제 크로마토그래피/고성능 액체 크로마토그래피(SEC/HPLC)에 의해 간접적으로 결정될 수 있다.In addition, the gelatine hydrolyzate may have an average polypeptide length of 20 amino acids or less, specifically 6 to 18 amino acids, and more specifically 4 to 18 amino acids. It may have an average polypeptide length consisting of . The length of a polypeptide chain can be determined indirectly by size-exclusion chromatography/high performance liquid chromatography (SEC/HPLC).
본 발명에서, 상기 젤라틴 조성물은 상기 젤라틴 가수분해물 및 보다 높은 분자량의 약학 등급 젤라틴을 포함한다. 구체적으로, 젤라틴 조성물은 중량 기준으로 1 내지 20%의 젤라틴 가수분해물 및 중량 기준으로 80 내지 99%의 젤라틴을 포함할 수 있고, 보다 구체적으로 중량 기준으로 5 내지 10%의 젤라틴 가수분해물 및 90 내지 95%의 젤라틴을 포함할 수 있다.In the present invention, the gelatine composition comprises the gelatine hydrolyzate and higher molecular weight pharmaceutical grade gelatin. Specifically, the gelatine composition may include 1 to 20% by weight of gelatine hydrolyzate and 80 to 99% by weight of gelatin, and more specifically, 5 to 10% of gelatine hydrolyzate and 90 to 99% by weight. May contain 95% gelatin.
상기 젤라틴은 통상적으로 높은 평균 분자량을 가진다. 구체적으로, 상기 젤라틴은 200,000 Da보다 큰 평균 분자량을 가질 수 있고, 150,000 Da보다 큰 평균 분자량을 가질 수 있으며, 또는 100,000 Da 내지 200,000 Da의 평균 분자량을 가질 수 있다.The gelatin typically has a high average molecular weight. Specifically, the gelatin may have an average molecular weight greater than 200,000 Da, may have an average molecular weight greater than 150,000 Da, or may have an average molecular weight of 100,000 Da to 200,000 Da.
상기 젤라틴 가수분해물은 광범위한 물리적 특성 및 기능적 특성을 갖는 수 개의 타입의 젤라틴과 혼합될 수 있다. 특정한 젤라틴의 선택은 젤라틴 조성물의 의도된 용도에 따라 크게 변할 수 있다. 일반적으로, 젤라틴은 통상적으로 동물의 피부 및 뼈와 같은 여러 적합한 원재료로부터 입수가능한 콜라겐 또는 콜라겐 풍부 조직(collagen rich tissue)으로부터 유래된다. 예컨대, 젤라틴은 타입 A 젤라틴, 타입 B 젤라틴, 또는 타입 A 젤라틴 및 타입 B 젤라틴의 혼합물일 수 있다. 효소적 방법에 의해 제조된 젤라틴은 타입 A 및/또는 타입 B 젤라틴을 대체하기 위해 이용될 수 있다.The gelatine hydrolyzate can be blended with several types of gelatin with a wide range of physical and functional properties. The selection of a particular gelatin can vary greatly depending on the intended use of the gelatin composition. In general, gelatin is derived from collagen or collagen rich tissue, which is typically available from a variety of suitable raw materials such as animal skin and bone. For example, the gelatin may be Type A gelatin, Type B gelatin, or a mixture of Type A gelatin and Type B gelatin. Gelatin prepared by enzymatic methods can be used to replace Type A and/or Type B gelatin.
상기 젤라틴 가수분해물 또는 젤라틴 조성물의 제조방법은 국제공개번호 WO 2006/128685를 참조한다.For a method of producing the gelatin hydrolyzate or gelatin composition, refer to International Publication No. WO 2006/128685.
본 발명에서, 상기 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상의 젤리 강도(jelly strength)는 160 내지 200 블룸(bloom)일 수 있다. In the present invention, the jelly strength of one or more of the gelatine hydrolyzate and gelatine composition may be 160 to 200 blooms.
본 발명에서, 상기 가소제는 글리세린, 소르비톨, 소르비탄, 말티톨, 폴리글리시톨, 프로필렌글리콜, 폴리에틸렌글리콜 및 이의 혼합물로부터 선택될 수 있고, 구체적으로 글리세린, 소르비톨, 소르비탄 및 이의 혼합물로부터 선택될 수 있으며, 보다 구체적으로 소르비톨과 소르비탄의 혼합물 또는 글리세린과 소르비톨의 혼합물일 수 있다.In the present invention, the plasticizer may be selected from glycerin, sorbitol, sorbitan, maltitol, polyglycitol, propylene glycol, polyethylene glycol, and mixtures thereof, and specifically may be selected from glycerin, sorbitol, sorbitan, and mixtures thereof. And, more specifically, it may be a mixture of sorbitol and sorbitan or a mixture of glycerin and sorbitol.
본 발명에서, 상기 캡슐 쉘은 착색제, 차광제, 착향제, 감미제, 산미제, 산화방지제 및 보존제로부터 선택되는 하나 이상을 추가로 포함할 수 있다.In the present invention, the capsule shell may further include one or more selected from colorants, light blocking agents, flavoring agents, sweeteners, acidulants, antioxidants, and preservatives.
본 발명에서, 상기 연질 캡슐 조성물의 파열 강도는 6.0 내지 9.0 N일 수 있다.In the present invention, the bursting strength of the soft capsule composition may be 6.0 to 9.0 N.
한편, 상기 연질 캡슐 조성물을 제조하는 방법은 당업계에서 연질 캡슐 제제의 제조를 위해 통상적으로 사용되는 방법을 채용하거나 또는 이를 적절히 변경할 수 있으므로 본 발명은 이에 대한 구체적인 설명은 생략한다.Meanwhile, the method for producing the soft capsule composition may adopt a method commonly used in the art for producing a soft capsule formulation or may be modified appropriately, and thus a detailed description thereof will be omitted in the present invention.
이하, 본 발명을 실시예 및 비교예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and comparative examples.
단, 하기 실시예 및 비교예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 비교예에 한정되는 것은 아니다.However, the following examples and comparative examples only illustrate the present invention, and the content of the present invention is not limited to the following examples and comparative examples.
실시예 1 ~ 4, 비교예 1: 연질 캡슐의 제조Examples 1 to 4, Comparative Example 1: Preparation of soft capsules
1. 연질 캡슐 피막의 제조1. Preparation of soft capsule shell
표 1에 나타낸 조성으로 원료를 피막 제조용 멜팅 탱크에 투입한 후, 팽윤, 가온 용해(70 ~ 80℃), 탈포 공정을 거쳐 연질 캡슐 피막을 제조하였다.After putting the raw materials with the composition shown in Table 1 into a melting tank for film production, a soft capsule film was manufactured through swelling, heating dissolution (70 to 80°C), and defoaming processes.
성분ingredient 종류type 비교예 1Comparative Example 1 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4
Gelatin 150 LBGelatin 150 LB 젤라틴gelatin 42.25%42.25% -- -- -- --
GlycerinGlycerin 가소제plasticizer 11.70%11.70% -- -- -- --
Sorbitol SpecialSorbitol Special 가소제plasticizer 11.05%11.05% -- -- -- --
RXLRXL 젤라틴 가수분해물Gelatin hydrolyzate -- 43.20%43.20% 43.20%43.20% 30.00%30.00%
RXL R2RXL R2 젤라틴 가수분해물 및 젤라틴 혼합Gelatin hydrolyzate and gelatin blend -- -- -- 49.00%49.00% 10.00%10.00%
polysorbpolysorb 가소제plasticizer -- -- 24.80%24.80% 27.00%27.00% 26.00%26.00%
A-810A-810 가소제plasticizer -- 24.80%24.80%
정제수Purified water 35.00%35.00% 32.00%32.00% 32.00%32.00% 24.00%24.00% 34.00%34.00%
여기서, 원료는 아래의 것을 사용하였다.Gelatin 150 LB: 2000 ~ 4000 Da 분자량을 갖는 시판되는 일반 젤라틴(Rousselot사 제품)Here, the following raw materials were used: Gelatin 150 LB: Commercially available general gelatin with a molecular weight of 2000 to 4000 Da (product of Rousselot)
RXL: 국제공개번호 WO 2006/128685에 개시된 방법으로 획득 100 ~ 2000 Da의 평균 분자량 및 1 ㎍의 젤라틴 가수분해물 당 1.0 × 10-3 ~ 1.0 × 10-2 μMol의 평균 일차 아민 함량을 갖는 젤라틴 가수분해물(gelita사 제품)RXL: Gelatin hydrolyzate with an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 Decomposition product (gelita product)
RXL R2: 상기 젤라틴 가수분해물 및 젤라틴이 각각 중량 기준으로 1 내지 20% 및 80 내지 99%로 혼합된 젤라틴 조성물(gelita사 제품)RXL R2: A gelatin composition (product of gelita) in which the gelatin hydrolyzate and gelatin are mixed at 1 to 20% and 80 to 99% by weight, respectively.
Sorbitol Special: SPI Pharma사 Sorbitol Special® Sorbitol Special: Sorbitol Special ® by SPI Pharma
polysorb: Roquette사 polysorb® 85/70/00polysorb: Roquette polysorb ® 85/70/00
A-810: SPI Pharma사 Sorbitol Special® A-810A-810: Sorbitol Special ® A-810 from SPI Pharma
2. 연질 캡슐 내용물의 제조2. Preparation of soft capsule contents
표 2에 요약된 바와 같이 여섯 개의 자기-유화 약물 송달 시스템(SEDDS)에 친유성 화합물이 부가된 연질 캡슐 내용물을 표 3에 나타낸 조성으로 하여 제조하였다. SEDDS의 오일 성분을 분산 및 혼합하여 투명한 모노-상 플라시보 비히클 시스템을 얻었다. 친유성 화합물의 하나로 아비라테론 아세테이트를 부가하고 플라시보 비히클 시스템 내에 용해하였다.As summarized in Table 2, six self-emulsifying drug delivery systems (SEDDS) with lipophilic compounds added to the soft capsule contents were prepared with the compositions shown in Table 3. The oil component of SEDDS was dispersed and mixed to obtain a transparent mono-phase placebo vehicle system. Abiraterone acetate as one of the lipophilic compounds was added and dissolved in the placebo vehicle system.
종류type SEDDS 성분의 요약Summary of SEDDS ingredients
S1S1 60% 지방(올리브유, 글리세롤 모노-올레에이트 1:3)
40% 가용화제(폴리소르베이트 80, 폴리옥실 35 피마자유 1:1) 60% fat (olive oil, glycerol mono-oleate 1:3)
40% solubilizer (polysorbate 80, polyoxyl 35 castor oil 1:1)
S2S2 60% 지방(대두유, 글리세롤 모노-올레에이트 1:1)
40% 가용화제(폴리옥실 35 피마자유)60% fat (soybean oil, glycerol mono-oleate 1:1)
40% solubilizer (polyoxyl 35 castor oil)
S3S3 80% 지방(대두유, 글리세롤 모노-올레에이트 1:1)
20% 가용화제(폴리옥실 35 피마자유)80% fat (soybean oil, glycerol mono-oleate 1:1)
20% solubilizer (polyoxyl 35 castor oil)
S4S4 60% 지방(올리브유, 글리세롤 모노-올레에이트 65:35)
40% 가용화제(폴리소르베이트 80, 폴리옥실 35 피마자유 1:1)60% fat (olive oil, glycerol mono-oleate 65:35)
40% solubilizer (polysorbate 80, polyoxyl 35 castor oil 1:1)
S5S5 60% 지방(글리세롤 모노-올레에이트)
40% 가용화제(폴리옥실 35 피마자유)60% fat (glycerol mono-oleate)
40% solubilizer (polyoxyl 35 castor oil)
S6S6 70% 지방(대두유, 글리세롤 모노-올레에이트 1:1)
30% 가용화제(폴리옥실 35 피마자유)70% fat (soybean oil, glycerol mono-oleate 1:1)
30% solubilizer (polyoxyl 35 castor oil)
성분ingredient SEDDS(mg)SEDDS (mg)
S1S1 S2S2 S3S3 S4S4 S5S5 S6S6
올리브유olive oil 9.009.00 -- -- 34.434.4 -- --
대두유soybean oil -- 54.054.0 18.018.0 -- -- 54.054.0
글리세롤 모노-올레에이트Glycerol mono-oleate 27.027.0 54.054.0 18.018.0 12.612.6 36.036.0 54.054.0
폴리소르베이트 80Polysorbate 80 12.012.0 -- -- -- -- --
폴리옥실 35 피마자유Polyoxyl 35 Castor Oil 12.012.0 72.072.0 9.09.0 24.024.0 24.024.0 46.346.3
합계Sum 60.060.0 180.0180.0 45.045.0 60.060.0 60.060.0 154.3154.3
3. 연질 캡슐의 제조3. Preparation of soft capsules
상기 1.에서 제조한 연질 캡슐 피막 및 상기 2.에서 제조한 연질 캡슐 내용물을 로터리다이 방식의 연질 캡슐 자동성형기에 충전하고 성형하여 연질 캡슐을 제조하였다.Soft capsules were manufactured by filling and molding the soft capsule shell prepared in step 1 above and the soft capsule contents prepared in step 2 into a rotary die type automatic soft capsule molding machine.
실험예 1: 연질 캡슐의 안정성 및 용출률 평가Experimental Example 1: Evaluation of stability and dissolution rate of soft capsules
상기 3.에서 제조한 연질 캡슐의 안정성을 평가하였다. The stability of the soft capsule prepared in step 3 above was evaluated.
구체적으로, 상기 1.에서 제조한 연질 캡슐 피막 및 상기 2.에서 SEDDS로 S3을 이용하여 제조한 연질 캡슐 내용물을 로터리다이 방식의 연질 캡슐 자동성형기에 충전하고 성형하여 연질 캡슐 1개당 60.5 mg의 친유성 화합물, 80% 지방 SEDDS에 대해 1100 mg SEDDS, 306 mg의 젤라틴 성분을 함유하도록 제조하였다. 제조한 연질 캡슐의 안정성 평가를 위해 성상 변화를 확인하였다.Specifically, the soft capsule membrane prepared in step 1 above and the soft capsule contents prepared using S3 as SEDDS in step 2 above were filled and molded in a rotary die type soft capsule automatic forming machine to obtain 60.5 mg of parenteral content per soft capsule. Oily compound, formulated to contain 1100 mg SEDDS and 306 mg of gelatin for 80% fat SEDDS. Changes in properties were confirmed to evaluate the stability of the manufactured soft capsules.
그 결과, 실시예 1 내지 실시예 4의 성상에 큰 변화가 없음을 확인하였다.As a result, it was confirmed that there was no significant change in the properties of Examples 1 to 4.
또한, 제조한 연질 캡슐의 용출률을 장기간에 걸쳐 평가하였다. 용출매질로 물 900 ml(3% SLS(Sodium Lauryl Sulfate), 가용화제)를 사용하였고, 대한약전 일반시험법 중 용출시험법 제 2법에 따라 시험하였으며, 패들의 회전 속도는 75 rpm이며 싱커를 사용하였다. 정해진 시간에 용출액 5mL를 취하여 채취하고, 이를 10 um 필터로 여과한 액 약 2 mL를 버리고 잔여액을 검액으로 하였다. 따로 아비라테론 아세테이트 표준품 약 68 mg을 정밀히 달아 위의 용출액 900 ml에 녹인 다음 표준액으로 하여 액체크로마토그래프법으로 함량을 측정하였다.Additionally, the dissolution rate of the prepared soft capsules was evaluated over a long period of time. 900 ml of water (3% SLS (Sodium Lauryl Sulfate), solubilizer) was used as the dissolution medium, and the test was conducted according to the dissolution test method 2 among the general test methods of the Korean Pharmacopoeia. The rotation speed of the paddle was 75 rpm and the sinker was used. used. At a designated time, 5 mL of the eluate was collected, filtered through a 10 um filter, and about 2 mL of the solution was discarded and the remaining solution was used as the sample solution. Separately, approximately 68 mg of abiraterone acetate standard was precisely weighed and dissolved in 900 ml of the above eluate, and then the content was measured using liquid chromatography using the standard solution.
용출시험 시작 후 15분, 30분, 45분 및 60분에서 용출액을 채취하고, 액체크로마토그래피법으로 254 nm 파장에서 정량하였다. 이동상은 1 mL 아세트산이 포함된 HPLC급 물 800 mL과 200 mL의 Acetonitrile의 혼합액이었고, 유속은 2 mL/min이었으며, 시료 주입량은 10 ㎕이었다.The eluate was collected at 15, 30, 45, and 60 minutes after the start of the dissolution test, and quantified using liquid chromatography at a wavelength of 254 nm. The mobile phase was a mixture of 800 mL of HPLC-grade water and 200 mL of Acetonitrile containing 1 mL of acetic acid, the flow rate was 2 mL/min, and the sample injection volume was 10 ㎕.
그 결과, 표 4 내지 표 8에 나타낸 바와 같이, 비교예 1은 실시예 1 내지 실시예 4에 비해 15개월에서 용출시험의 초기 결과값(15분)이 제조시점(T=0)보다 현저히 저하되어 있음을 확인하였으며, 이는 붕해지연에 의한 것으로 보인다. 반면, 실시예 1 내지 실시예 4에서는, 초기 결과값(45분)이 제조시점(T=0) 수준으로 향상된 것, 즉 시험기간 동안 용출률의 변화가 적음을 확인하였다. As a result, as shown in Tables 4 to 8, the initial result of the dissolution test (15 minutes) in Comparative Example 1 at 15 months was significantly lower than the time of manufacture (T = 0) compared to Examples 1 to 4. This was confirmed to be due to delayed disintegration. On the other hand, in Examples 1 to 4, it was confirmed that the initial result (45 minutes) was improved to the level at the time of manufacture (T = 0), that is, there was little change in the dissolution rate during the test period.
장기시험long-term test 비교예 1Comparative Example 1
개월month T=0T=0 T=2T=2 T=3T=3 T=6T=6
Dissolution
testDissolution
test 		1515 85.3(11.5)85.3(11.5) 74.9(7.1)74.9(7.1) 49.6(8.3)49.6(8.3) 20.9(19.2)20.9(19.2)
3030 87.9(10.6)87.9(10.6) 94.9(4.7)94.9(4.7) 104.7(12.9)104.7(12.9) 90.2(11.1)90.2(11.1)
4545 94.3(3.5)94.3(3.5) 95.9(2.5)95.9(2.5) 97.9(3.8)97.9(3.8) 98.6(4.4)98.6(4.4)
6060 96.6(6.5)96.6(6.5) 97(2.0)97(2.0) 96.4(1.2)96.4(1.2) 100.7(2.2)100.7(2.2)
장기시험long-term test 실시예 1Example 1
개월month T=0T=0 T=1T=1 T=5T=5 T=6T=6
Dissolution
testDissolution
test 		1515 84(3.8)84(3.8) 73(1.8)73(1.8) 81(4.5)81(4.5) 80(1.6)80(1.6)
3030 92(1.9)92(1.9) 94(1.1)94(1.1) 94(2.6)94(2.6) 96(1.4)96(1.4)
4545 96(1.0)96(1.0) 97(0.7)97(0.7) 98(0.7)98(0.7) 99(0.7)99(0.7)
6060 97(0.5)97(0.5) 98(0.3)98(0.3) 98(0.6)98(0.6) 99(0.5)99(0.5)
장기시험long-term test 실시예 2Example 2
개월month T=0T=0 T=1T=1 T=5T=5 T=6T=6
Dissolution
testDissolution
test 		1515 82(5.1)82(5.1) 83(5.5)83(5.5) 70(9.1)70(9.1) 76(3.5)76(3.5)
3030 93(2.4)93(2.4) 96(1.3)96(1.3) 86(7.7)86(7.7) 89(42)89(42)
4545 96(1.2)96(1.2) 97(0.4)97(0.4) 93(4.1)93(4.1) 92(3.9)92(3.9)
6060 97(0.8)97(0.8) 98(0.4)98(0.4) 95(2.2)95(2.2) 95(1.5)95(1.5)
장기시험long-term test 실시예 3Example 3
개월month T=0T=0 T=1T=1 T=5T=5 T=6T=6
Dissolution
testDissolution
test 		1515 90(3.6)90(3.6) 82(5.0)82(5.0) 83(3.4)83(3.4) 99(2.0)99(2.0)
3030 96(1.3)96(1.3) 96(1.2)96(1.2) 94(1.0)94(1.0) 99(1.0)99(1.0)
4545 98(0.6)98(0.6) 98(0.5)98(0.5) 97(0.6)97(0.6) 100(0.9)100(0.9)
6060 97(0.7)97(0.7) 99(0.5)99(0.5) 97(0.6)97(0.6) 101(0.9)101(0.9)
장기시험long-term test 실시예 4Example 4
개월month T=0T=0 T=1T=1 T=5T=5 T=6T=6
Dissolution
testDissolution
test 		1515 87(2.6)87(2.6) 83(7.6)83(7.6) 78(4.4)78(4.4) 74(6.1)74(6.1)
3030 93(2.1)93(2.1) 96(2.3)96(2.3) 93(2.3)93(2.3) 88(4.9)88(4.9)
4545 95(1.2)95(1.2) 97(0.9)97(0.9) 96(1.4)96(1.4) 96(0.8)96(0.8)
6060 97(0.7)97(0.7) 98(0.5)98(0.5) 97(0.8)97(0.8) 97(0.3)97(0.3)
상기 결과를 통해 실시예 1 내지 4의 연질 캡슐은 피막의 주성분으로 높은 일차 아민 함량을 갖는 저분자량 젤라틴 가수분해물을 포함함으로써, 유리글리신, 기타 아미노산 및 작은 펩티드의 양이 증가하여 젤라틴의 가교형성이 감소하고, 이로 인해 붕해지연이 개선되어 친유성 화합물을 안정적으로 용출하는 것을 알 수 있다.From the above results, the soft capsules of Examples 1 to 4 contained low molecular weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby increasing the amount of free glycine, other amino acids and small peptides, thereby promoting crosslinking of gelatin. It can be seen that the disintegration delay is improved and the lipophilic compound is eluted stably.
본 발명에 따른 연질 캡슐은 피막의 주성분으로 높은 일차 아민 함량을 갖는 저분자량 젤라틴 가수분해물을 포함하여 자기-유화 특성의 내용물을 포함하는 연질 캡슐에서 일반적으로 발생하는 유효성분의 붕해지연을 방지함으로써 우수한 제형 안정성을 가지므로, 제제학적으로 안정성이 향상된 연질 캡슐로 유용하게 이용될 수 있다.The soft capsule according to the present invention contains a low-molecular-weight gelatin hydrolyzate with a high primary amine content as the main component of the shell, thereby preventing the delayed disintegration of the active ingredient that generally occurs in soft capsules containing contents with self-emulsifying properties. Since it has formulation stability, it can be usefully used as a soft capsule with improved pharmaceutical stability.

Claims (21)

  1. i) 적어도 5의 log P를 가지는 친유성 화합물 및 비히클을 포함하는 코어(core); 및i) a core comprising a lipophilic compound and a vehicle with a log P of at least 5; and
    ii) 젤라틴 가수분해물 및 젤라틴 가수분해물과 젤라틴을 포함하는 젤라틴 조성물 중 1종 이상, 가소제 및 물을 포함하는 캡슐(capsule) 쉘을 포함하고,ii) a capsule shell containing at least one of a gelatin hydrolyzate and a gelatine composition containing a gelatin hydrolyzate and gelatin, a plasticizer and water,
    여기에서, 상기 비히클은 (a) 포유동물에서 림프 흡수를 달성하기에 충분한 적어도 500 mg의 지방 성분 및 (b) 친수성 계면활성제를 포함하며; 상기 지방 성분은 장쇄 지방산의 모노-글리세라이드, 장쇄 지방산의 트리-글리세라이드, 및 장쇄 지방산의 모노- 및 트리-글리세라이드로부터 선택되고; 상기 모노글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되며, 상기 트리글리세라이드 내 장쇄 지방산은 14 내지 24 탄소 원자를 가지는 지방산 사슬로부터 선택되고; 트리글리세라이드 대 모노글리세라이드의 중량비는 2.8:1 내지 1:5의 범위이며; 중량비 (a):(b)는 10:1 내지 1:2이고,wherein the vehicle comprises (a) at least 500 mg of a fatty component sufficient to achieve lymphatic uptake in a mammal and (b) a hydrophilic surfactant; The fatty component is selected from mono-glycerides of long-chain fatty acids, tri-glycerides of long-chain fatty acids, and mono- and tri-glycerides of long-chain fatty acids; The long-chain fatty acids in the monoglycerides are selected from fatty acid chains having 14 to 24 carbon atoms, and the long-chain fatty acids in the triglycerides are selected from fatty acid chains having 14 to 24 carbon atoms; The weight ratio of triglycerides to monoglycerides ranges from 2.8:1 to 1:5; The weight ratio (a):(b) is 10:1 to 1:2,
    상기 젤라틴 가수분해물은 100 내지 2000 Da의 평균 분자량 및 1 ㎍의 젤라틴 가수분해물 당 1.0 × 10-3 ~ 1.0 × 10-2 μMol의 평균 일차 아민 함량을 갖는 것이며,The gelatine hydrolyzate has an average molecular weight of 100 to 2000 Da and an average primary amine content of 1.0 × 10 -3 to 1.0 × 10 -2 μMol per 1 μg of gelatine hydrolyzate,
    상기 젤라틴 조성물은 젤라틴 조성물 중량 기준으로 1 내지 20%의 젤라틴 가수분해물 및 중량 기준으로 80 내지 99%의 젤라틴을 포함하는 것인,The gelatine composition includes 1 to 20% of gelatine hydrolyzate and 80 to 99% of gelatin by weight by weight of the gelatine composition,
    연질 캡슐 조성물.Soft capsule composition.
  2. 제1항에 있어서, 상기 지방 성분이 장쇄 지방산의 모노-글리세라이드 및 트리-글리세라이드를 포함하고, 트리-글리세라이드 대 모노-글리세라이드의 중량비는 2:1 내지 1:3의 범위인 것을 특징으로 하는, 연질 캡슐 조성물.The method of claim 1, wherein the fat component comprises mono-glycerides and tri-glycerides of long-chain fatty acids, and the weight ratio of tri-glycerides to mono-glycerides is in the range of 2:1 to 1:3. A soft capsule composition comprising:
  3. 제1항에 있어서, 상기 코어가 적어도 0.8의 AUC(0-inf)(절식) / AUC(0-inf)(섭식)을 나타내는 것을 특징으로 하는, 연질 캡슐 조성물.2. The soft capsule composition of claim 1, wherein the core exhibits an AUC(0-inf) (fasted)/AUC(0-inf) (fed) of at least 0.8.
  4. 제1항에 있어서, (a):(b)의 중량비가 4:1 내지 1:2의 범위인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the weight ratio of (a):(b) is in the range of 4:1 to 1:2.
  5. 제1항에 있어서, 상기 모노-글리세라이드 내 장쇄 지방산이 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the long-chain fatty acid in the mono-glyceride is selected from linolenic acid, oleic acid, palmitic acid, linoleic acid and stearic acid.
  6. 제1항에 있어서, 상기 트리-글리세라이드 내 장쇄 지방산이 리놀렌산, 올레산, 팔미트산, 리놀레산 및 스테아르산으로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the long-chain fatty acids in the tri-glyceride are selected from linolenic acid, oleic acid, palmitic acid, linoleic acid and stearic acid.
  7. 제1항에 있어서, 상기 장쇄 지방산의 트리-글리세라이드를 포함하는 지방 성분이 자연 유래 오일(naturally derived oil)인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the fat component containing tri-glycerides of long-chain fatty acids is a naturally derived oil.
  8. 제7항에서 있어서, 상기 자연 유래 오일이 대두유(soybean oil), 올리브유, 참기름, 홍화유, 땅콩유, 유채유(rapeseed oil), 해바라기유, 코코넛유, 옥수수유, 해바라기씨유, 면실유(cotton seed oil), 팜유, 땅콩 오일(arachidis oil) 및 이의 혼합물로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.The method of claim 7, wherein the natural oil is soybean oil, olive oil, sesame oil, safflower oil, peanut oil, rapeseed oil, sunflower oil, coconut oil, corn oil, sunflower seed oil, and cotton seed oil. ), a soft capsule composition, characterized in that it is selected from palm oil, peanut oil (arachidis oil) and mixtures thereof.
  9. 제1항에 있어서, 상기 비히클이 자기-유화성(self-emulsifying)인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the vehicle is self-emulsifying.
  10. 제1항에 있어서, 상기 친유성 화합물이 아비라테론 아세테이트(abiraterone acetate), 아시트레틴(acitretin), 알릴에스트레놀(allylestrenol), 알파 토코페롤(alpha tocopherol), 아미다론(amidarone), 아프레피탄트(aprepitant), 아트로바스타틴(atorvastatin), 벡사로텐(bexarotene), 브로모크립틴(bromocriptine), 칸데사르탄(candesartan), 시나칼세트(cinacalcet), 클로미펜(clomiphene), 디에틸 스틸베스트롤(diethyl stilbestrol), 디호모-감마-리놀레산(dihomo-gamma-linoleic acid), 에바스틴(ebastine), 에르고칼시페롤(ergocalciferol), 페노피브레이트(fenofibrate), 푸시드산(fucidic acid), 할로판트린(halofantrine), 이르베사르탄(irbesartan), 이소트레티노인(isotretinoin), 이트라코나졸(itraconazole), 라파티닙(lapatinib), 리라글루티드(liraglutide), 로라티딘(loratidine), 난드롤론 데카노에이트(nandrolone decanoate), 넬피나비르(nelfinavir), 올메사르탄(olmesartan), 오르리스타트(orlistat), 포사코나졸(posaconazole), 프로부콜(probucol), 랄록시펜(raloxifene), 리토나비르(ritonavir), 타목시펜(tamoxifen), 텔미사르탄(telmisartan), 테프레논(teprenone), 티프라나비르(tipranavir), 발사르탄(valsartan) 및 주클로펜틱솔(zuclopenthixol)로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.The method of claim 1, wherein the lipophilic compound is abiraterone acetate, acitretin, allylestrenol, alpha tocopherol, amidarone, aprepitant ( aprepitant, atorvastatin, bexarotene, bromocriptine, candesartan, cinacalcet, clomiphene, diethyl stilbestrol stilbestrol, dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fucidic acid, halofantrine ), irbesartan, isotretinoin, itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, nelfina nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, ritonavir, tamoxifen, telmisar A soft capsule composition selected from telmisartan, teprenone, tipranavir, valsartan and zuclopenthixol.
  11. 제1항에 있어서, 상기 캡슐 쉘은 30 내지 60 중량%의 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상, 20 내지 40 중량%의 가소제 및 20 내지 40 중량%의 물을 포함하는 것을 특징으로 하는, 연질 캡슐 조성물. The method of claim 1, wherein the capsule shell comprises 30 to 60% by weight of one or more of a gelatine hydrolyzate and a gelatine composition, 20 to 40% by weight of a plasticizer, and 20 to 40% by weight of water. Soft capsule composition.
  12. 제1항에 있어서, 상기 젤라틴 가수분해물은 13%를 초과하는 가수분해 정도(degree of hydrolysis)를 갖는 것을 특징으로 하는, 연질 캡슐 조성물.2. Soft capsule composition according to claim 1, wherein the gelatine hydrolyzate has a degree of hydrolysis exceeding 13%.
  13. 제1항에 있어서, 상기 젤라틴 가수분해물의 평균 분자량은 100 내지 1500 Da의 범위인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the gelatine hydrolyzate has an average molecular weight in the range of 100 to 1500 Da.
  14. 제13항에 있어서, 상기 평균 분자량은 400 내지 1200 Da의 범위인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 13, wherein the average molecular weight is in the range of 400 to 1200 Da.
  15. 제1항에 있어서, 상기 젤라틴 조성물은 중량 기준으로 5 내지 10%의 젤라틴 가수분해물 및 90 내지 95%의 젤라틴을 포함하는 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the gelatine composition comprises 5 to 10% of gelatine hydrolyzate and 90 to 95% of gelatin by weight.
  16. 제1항에 있어서, 상기 젤라틴 가수분해물 및 젤라틴 조성물 중 1종 이상 의 젤리 강도(jelly strength)가 160 내지 200 블룸(bloom)인 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein at least one of the gelatine hydrolyzate and the gelatine composition has a jelly strength of 160 to 200 blooms.
  17. 제1항에 있어서, 상기 가소제가 글리세린, 소르비톨, 소르비탄, 말티톨, 폴리글리시톨, 프로필렌글리콜, 폴리에틸렌글리콜 및 이의 혼합물로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.2. Soft capsule composition according to claim 1, wherein the plasticizer is selected from glycerin, sorbitol, sorbitan, maltitol, polyglycitol, propylene glycol, polyethylene glycol and mixtures thereof.
  18. 제17항에서 있어서, 상기 가소제가 글리세린, 소르비톨, 소르비탄 및 이의 혼합물로부터 선택되는 것을 특징으로 하는, 연질 캡슐 조성물.18. Soft capsule composition according to claim 17, wherein the plasticizer is selected from glycerin, sorbitol, sorbitan and mixtures thereof.
  19. 제18항에서 있어서, 상기 가소제가 소르비톨과 소르비탄의 혼합물인 것을 특징으로 하는, 연질 캡슐 조성물.19. The soft capsule composition according to claim 18, wherein the plasticizer is a mixture of sorbitol and sorbitan.
  20. 제18항에서 있어서, 상기 가소제가 글리세린과 소르비톨의 혼합물인 것을 특징으로 하는, 연질 캡슐 조성물.19. The soft capsule composition according to claim 18, wherein the plasticizer is a mixture of glycerin and sorbitol.
  21. 제1항에 있어서, 상기 캡슐 쉘이 착색제, 차광제, 착향제, 감미제, 산미제, 산화방지제 및 보존제로부터 선택되는 하나 이상을 추가로 포함하는 것을 특징으로 하는, 연질 캡슐 조성물.The soft capsule composition according to claim 1, wherein the capsule shell further comprises one or more selected from colorants, light-shielding agents, flavoring agents, sweeteners, acidulants, antioxidants, and preservatives.
PCT/KR2023/006614 2022-05-18 2023-05-16 Soft capsule having improved pharmaceutical stability WO2023224358A1 (en)

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