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WO2019240310A1 - Formulation complexe comprenant de l'acéclofénac et de l'ésoméprazole et son procédé de préparation - Google Patents

Formulation complexe comprenant de l'acéclofénac et de l'ésoméprazole et son procédé de préparation Download PDF

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Publication number
WO2019240310A1
WO2019240310A1 PCT/KR2018/006720 KR2018006720W WO2019240310A1 WO 2019240310 A1 WO2019240310 A1 WO 2019240310A1 KR 2018006720 W KR2018006720 W KR 2018006720W WO 2019240310 A1 WO2019240310 A1 WO 2019240310A1
Authority
WO
WIPO (PCT)
Prior art keywords
layer
active ingredient
tablet
aceclofenac
coating
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2018/006720
Other languages
English (en)
Korean (ko)
Inventor
최연웅
장재상
이남송
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea United Pharm Inc
Original Assignee
Korea United Pharm Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea United Pharm Inc filed Critical Korea United Pharm Inc
Publication of WO2019240310A1 publication Critical patent/WO2019240310A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/20—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an anti-inflammatory analgesic agent aceclofenac and gastric acid secretion agent Someprazole two effective ingredients to minimize side effects and improve the convenience of the drug formulations and a preparation method thereof.
  • Nonsteroidal anti-inflammatory drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), which are mainly used for symptoms such as rheumatoid arthritis, ankylosing spondylitis and osteoarthritis (degenerative arthritis).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Aceclofenac has a short duration of 0.5 ⁇ 2 hours in nonsteroidal anti-inflammatory analgesic drugs, and its effect lasts about 4 hours. Therefore, it is used for acute pain such as postoperative pain and toothache.
  • the present applicant has developed a bilayer tablet consisting of an immediate release layer for expressing the fast analgesic effect of aceclofenac and a sustained release layer for maintaining the anti-inflammatory analgesic effect for a long time (Korean Patent No. 1234254). Has released a new improved drug.
  • Clanza CR tablet is a double-layer tablet structure of the immediate release layer and the sustained release layer that maintains the anti-inflammatory analgesic effect for a long time. By improving the patient's ease of taking it.
  • aceclofenac may cause side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • non-steroidal analgesics In the United States, there are 70,000 cases of gastrointestinal side effects caused by non-steroidal analgesics and about 7,000 deaths from gastrointestinal side effects.
  • NSAIDs inhibit the action of cyclooxygenase enzymes, which induce the synthesis of prostaglandins that are involved in gastric acid secretion of gastric mucosa. Excessive secretion of gastric acid in the gastrointestinal tract continues to occur, such as non-ulcer dyspepsia, peptic ulcer, Solinger syndrome, and reflux esophagitis.
  • PPI Proton Pump Inhibitors
  • the present inventors have invented a complex formulation of aceclofenac and eomeprazole.
  • a capsule, a two-layer tablet, a coated tablet, a nucleated tablet, and the like are known as a single-part composite formulation using two active ingredients.
  • the formulations have the following problems.
  • the tablets or granules are filled into the soft capsules, and the sufficient active ingredient content to exhibit pharmacological activity was not obtained due to the limitation of the capsule size.
  • the active ingredient of esomeprazole can be dissolved in a coating liquid and coated on a tablet containing aceclofenac, but the yield is low in the preliminary preparation step and the coating liquid manufacturing step due to the coating, which exceeds 20-40% of the active ingredient. It should be put in, and the content was not uniform problem appeared.
  • Nucleated tablets are prepared by the tableting method of the core-shell structure, and have the advantage of uniformly adjusting the content and relatively easy to separate coating, but the size of the shell portion is exponentially proportional to the active ingredient content and size of the core. Will increase. Therefore, in order to achieve an excellent pharmacological effect while preparing an effective amount of aceclofenac and esomeprazole in order to prevent side effects, there is a problem that the formulation size becomes very large so that oral administration is difficult.
  • the preparation of the aceclofenac and esomeprazole combination formulations according to the present invention is not preferable due to technical and economic factors. Accordingly, the present inventors have studied and invented a multi-layered tablet formulation having excellent long-term stability while exhibiting excellent pharmacological effects, including an inert layer and a protective coating layer, which prevent the interaction and stability deterioration between two components.
  • the present invention is an oral administration co-formulation comprising aceclofenac and eomeprazole, a multi-layered tablet formulation overcoming the disadvantages of conventional formulations by forming an inert layer, characterized by having excellent pharmacological effects and long-term stability.
  • the present invention comprises a first active ingredient layer containing aceclofenac or a pharmaceutically acceptable salt thereof; A second active ingredient layer containing esomeprazole or a pharmaceutically acceptable salt thereof; And it provides an oral administration multi-layered tablet combination comprising an inert layer containing no active ingredient.
  • the inactive layer is formed between the first active ingredient layer and the second active ingredient layer, and prevents the modification of the active ingredient due to physical contact between the first active ingredient layer and the second active ingredient side, the present multilayer Tablet formulations have superior long-term stability compared to other conventional formulations containing similar active ingredients.
  • the formulation according to the present invention is a three-layer tablet consisting of a first active ingredient layer, an inactive layer and a second active ingredient layer. It is important to adjust the weight ratio of each layer preferably in order to ensure stability in the three-layer tableting, the total weight of the first active ingredient layer is 80 to 120% by weight relative to the total weight of the inactive layer, When the total weight of the active ingredient layer is 80 to 120% by weight, the tableting property was good, and the hardness and stability in long-term storage were also excellent.
  • the first active ingredient layer of the multi-layered tablet composite preparation of the present invention comprises 40 to 60 wt% of aceclofenac and its pharmaceutically acceptable salts based on the total weight of the first active ingredient layer, and the second active ingredient layer Silver, based on the total weight of the second active ingredient layer may comprise 5 to 20% by weight of esomeprazole and its pharmaceutically acceptable salts.
  • the amount of the active ingredient is less than the range, the pharmacological activity by aceclofenac or the side effect prevention effect by esomeprazole may be reduced, when the content exceeds the above range, side effects of gastrointestinal diseases or indigestion may occur.
  • the second active ingredient layer may include 5 to 20 wt% stabilizer, 6 to 10 wt% binder, and 1 to 5 wt% disintegrant based on the total weight of the second active ingredient layer.
  • Multi-layered tablet composite preparation according to the present invention comprises a binder in order to improve granule flowability during tableting by wet granulation method.
  • the binder is in the above range, the flowability is most favorable.
  • the binder is less than the above range, the flowability is poor, and when the binder is exceeded, the release effect after oral administration may be reduced.
  • the disintegrant is to prevent the release inhibition that may occur as a binder is optimized according to the content of the binder. Therefore, the release effect may be lowered if the disintegrant is less than the above range, the stability of the tablet may be lowered if it exceeds the above range.
  • the stabilizer is intended to prevent the destabilization of the relatively unstable second active ingredient, if less than the above-mentioned range, long-term preservation is inferior, and even if more than the above range does not appear to have a significant effect, the economy is inferior.
  • the stabilizer may include one or two selected from the group consisting of L-arginine, calcium hydrogen phosphate dihydrate, and the active ingredient included in the second active ingredient layer is vulnerable to acids. Since it has a relatively good stability when using calcium hydrogen phosphate dihydrate that can act as a relatively alkalizing agent.
  • the active ingredient of the second active ingredient layer may include esomeprazole or a pharmaceutically acceptable salt thereof, and in particular, the use of esopeprazole magnesium trihydrate exhibits excellent effects and facilitates supply of materials. Preferred for production in large quantities.
  • the total weight of the inactive layer is preferably 150 to 300mg, the weight of each active ingredient layer is adjusted according to the weight of the inactive layer, the smaller the weight of the inactive layer, the smaller the size of the entire formulation, so Will increase.
  • the weight of the inactive layer is preferably at least 150 mg or more.
  • the total weight of the inert layer exceeds 300mg, the dosage form is too large, and the convenience of medication is lowered, and the economical efficiency is lowered because the input amount of the material is increased and the tableting process is lengthened.
  • the inert layer may include one or two selected from the group consisting of microcrystalline cellulose, hydroxypropyl methyl cellulose, by mixing a relatively small amount of hydroxypropyl methyl cellulose rather than using microcrystalline cellulose alone When used, a more preferable effect is obtained.
  • the inactive layer may include 80 to 99% by weight of microcrystalline cellulose and 1 to 20% by weight of hydroxypropylmethylcellulose based on the total weight of the inactive layer.
  • the orally administered multi-layered tablet complex preparations include a first coating layer formed by coating a coating solution containing a non-acidic coating agent on the oral-administered multi-layered tablet composite formulation; And a second coating layer formed by coating a coating solution containing a moisture barrier coating base on the first coating layer. Since the active ingredient of the second active ingredient layer is easily denatured by an acid, the first coating layer which is in direct contact with the multi-layered tablet complex preparation is made of a non-acidic coating base. On the coating layer may be formed a second coating layer made of a moisture barrier coating base to prevent the penetration of moisture.
  • the non-acidic coating base of the first coating layer may include hydroxypropylmethylcellulose, and corresponds to a sub-coating that blocks the contact between the second coating layer and the tablet so that the moisture barrier coating base component does not affect the tablet. do.
  • the moisture barrier coating base of the second coating layer may be selected from commercially known coating bases, but it is preferable to use a coating base containing no stearic acid component.
  • a coating base containing no stearic acid component As a result of the applicant's experiment, when the coating base containing stearic acid is used in the second coating layer, the tablet is partially blacked and the flexible material is generated despite the first coating layer blocking the contact between the tablet and the second coating layer. Was observed.
  • the moisture barrier coating base includes polyvinyl alcohol and hydroxypropyl methyl cellulose as the main component, and preferably includes one or two polymer substances as the main component.
  • the multi-layered tablet complex preparation according to the present invention comprises a first active ingredient layer containing aceclobenac or a pharmaceutically acceptable salt thereof, a second active ingredient layer and an active ingredient containing esomeprazole or a pharmaceutically acceptable salt thereof.
  • an inert layer that does not contain, due to the structure in which the first active ingredient layer and the second active ingredient layer are separated from each other by the inactive layer it is possible to prevent denaturation and decrease in content due to physical contact between the active ingredients. have.
  • by further forming a coating layer to block external moisture on the outside of the tablet it is characterized by ensuring long-term stability.
  • the first active ingredient layer according to the present invention is aceclofenac, an excipient microcrystalline cellulose and a disintegrant croscarmellose sodium 10-20 minutes in a speed mixer, and then mixed several times with the addition of the fed solution Can be prepared.
  • the association is postmixed with lubricant, disintegrant.
  • the postmixed mixture is mixed in a drum mixer to prepare final granules of the first active ingredient layer.
  • the second active ingredient layer according to the present invention contains an active ingredient, e. Smefra or a pharmaceutically acceptable salt thereof, and after mixing someprazole magnesium, an excipient microcrystalline cellulose, and a stabilizer, several times while adding an association solution Mix over to prepare the union.
  • an active ingredient e. Smefra or a pharmaceutically acceptable salt thereof
  • the association is dried in a dryer.
  • the dry matter is mixed with a lubricant and then mixed with a binder and a disintegrant.
  • the post-mixture prepares the final granules of the second active ingredient layer.
  • the inert layer according to the present invention is prepared by adding the fed solution to the excipient microcrystalline cellulose.
  • the union is dried to produce the final granules.
  • the first active ingredient layer granules, the second active ingredient layer granules and the granules of the inactive layer are compressed while applying pressure.
  • the tableted uncoated tablet is separated using a tablet debranching, and then coated with the three-layer uncoated tablet with a coating base containing glycerin using a coater.
  • the primary coating tablet is coated with a waterproof coating base such as a coating base including polyvinyl alcohol using a coating machine to prepare a coated triple layer composite formulation.
  • a waterproof coating base such as a coating base including polyvinyl alcohol

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation complexe qui comprend deux principes actifs, l'acéclofénac, un analgésique anti-inflammatoire, et l'ésoméprazole, un inhibiteur de pompe à protons, réduisant ainsi au minimum les effets secondaires provoqués par l'acéclofénac tout en améliorant l'adhérence et la stabilité des médicaments et son procédé de préparation. Une formulation complexe de comprimé multicouche selon la présente invention comprend une première couche d'ingrédient actif contenant de l'acéclofénac ou un sel pharmaceutiquement acceptable de celui-ci, une seconde couche d'ingrédient actif contenant de l'ésoméprazole ou un sel pharmaceutiquement acceptable de celui-ci et une couche inerte ne contenant aucun ingrédient actif, la structure dans laquelle la première couche d'ingrédient actif et la seconde couche d'ingrédient actif sont séparées l'une de l'autre par la couche inerte pouvant empêcher une dégradation et une perte de contenu attribuable aux ingrédients actifs respectifs qui sont en contact physique l'un avec l'autre. En outre, la formulation complexe de comprimé multicouche peut également comprendre une couche de revêtement, bloquant l'humidité externe sur l'extérieur d'un comprimé, ce qui permet de présenter une excellente stabilité à long terme.
PCT/KR2018/006720 2018-06-14 2018-06-14 Formulation complexe comprenant de l'acéclofénac et de l'ésoméprazole et son procédé de préparation Ceased WO2019240310A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20180067934 2018-06-14
KR10-2018-0067934 2018-06-14

Publications (1)

Publication Number Publication Date
WO2019240310A1 true WO2019240310A1 (fr) 2019-12-19

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100483870B1 (ko) * 1996-01-08 2005-09-30 아스트라제네카 악티에볼라그 양성자펌프억제제및비스테로이드성항염증약물을포함하는경구제약제형
US20050249811A1 (en) * 2001-06-01 2005-11-10 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
KR20130115593A (ko) * 2012-04-12 2013-10-22 한미약품 주식회사 비스테로이드성 항염증약물 및 프로톤 펌프 저해제를 포함하는 약제학적 복합제제 및 이의 제조방법
KR20150114657A (ko) * 2014-04-02 2015-10-13 일양약품주식회사 일라프라졸 및 비스테로이드성 항염증약물 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 복합제제 및 이의 제조방법
KR20160020625A (ko) * 2014-08-13 2016-02-24 영남대학교 산학협력단 비스테로이드성 항염증약물 및 프로톤 펌프 저해제를 포함하는 경구용 속방형 조성물 및 그 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100483870B1 (ko) * 1996-01-08 2005-09-30 아스트라제네카 악티에볼라그 양성자펌프억제제및비스테로이드성항염증약물을포함하는경구제약제형
US20050249811A1 (en) * 2001-06-01 2005-11-10 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
KR20130115593A (ko) * 2012-04-12 2013-10-22 한미약품 주식회사 비스테로이드성 항염증약물 및 프로톤 펌프 저해제를 포함하는 약제학적 복합제제 및 이의 제조방법
KR20150114657A (ko) * 2014-04-02 2015-10-13 일양약품주식회사 일라프라졸 및 비스테로이드성 항염증약물 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 복합제제 및 이의 제조방법
KR20160020625A (ko) * 2014-08-13 2016-02-24 영남대학교 산학협력단 비스테로이드성 항염증약물 및 프로톤 펌프 저해제를 포함하는 경구용 속방형 조성물 및 그 제조방법

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