WO2005123052A1 - Composition medicamenteuse contenant de l'ambroxol et de l'erdosteine ou de l'acetylcysteine - Google Patents

Composition medicamenteuse contenant de l'ambroxol et de l'erdosteine ou de l'acetylcysteine Download PDF

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Publication number
WO2005123052A1
WO2005123052A1 PCT/CN2005/000789 CN2005000789W WO2005123052A1 WO 2005123052 A1 WO2005123052 A1 WO 2005123052A1 CN 2005000789 W CN2005000789 W CN 2005000789W WO 2005123052 A1 WO2005123052 A1 WO 2005123052A1
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WO
WIPO (PCT)
Prior art keywords
ambroxol
acetylcysteine
erdosteine
pharmaceutically acceptable
content
Prior art date
Application number
PCT/CN2005/000789
Other languages
English (en)
Chinese (zh)
Inventor
Piaoyang Sun
Kaihong Yuan
Original Assignee
Jiangsu Hengrui Medicine Co., Ltd.
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 Jiangsu Hengrui Medicine Co., Ltd. filed Critical Jiangsu Hengrui Medicine Co., Ltd.
Publication of WO2005123052A1 publication Critical patent/WO2005123052A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants

Definitions

  • composition containing ambroxol and erdosteine or acetylcysteine and application thereof
  • the invention relates to a pharmaceutical composition and an application thereof.
  • the pharmaceutical composition contains ambroxol and erdosteine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may further include ambroxol and Application of acetylcysteine or a pharmaceutically acceptable salt of the two, and the combination of such drugs for the preparation of drugs for the prevention and treatment of various diseases such as respiratory congestion and infection, inflammation and expectoration, especially for expectoration . Background technique
  • Ambroxol is the active metabolite of bromhexine. It has low toxicity and accurate curative effect. Its expectorant effect is stronger than that of bromhexine. In 1984, the drug was used as a hydrochloride in the clinic. Ambroxol hydrochloride has been widely used in many countries such as the United States, Britain, Germany, Japan and other countries for the treatment of respiratory diseases with excellent clinical effects and almost no toxic side effects. Ambroxol hydrochloride is widely used clinically for acute and chronic respiratory diseases with abnormal sputum secretion and poor sputum excretion, such as acute and chronic bronchitis, asthma-type bronchitis, bronchiectasis and tracheal asthma, and lung surgery. Preventive and adjuvant treatment of complications of posterior lung symphony, sticky sputum caused by lung structure, difficulty in expectoration, and treatment of respiratory distress syndrome (IRDS) in premature and newborn infants.
  • IRDS respiratory distress syndrome
  • Ambroxol hydrochloride is quickly absorbed orally and its elimination half-life is 2 to 3 hours. Its main preparations are tablets, sustained-release pellets, solutions, syrups, water injections and other compound preparations. However, due to the water solubility of ambroxol hydrochloride, It is not ideal, and its application and clinical application are limited.
  • Erdosteine is a prodrug with a non-free blocked thiol group in its structure and has no active effect on local mucin. After oral administration, three metabolites containing free thiol groups are metabolized to exert pharmacological effects. No obvious gastrointestinal side effects after oral administration. Experiments prove that Erdosteine metabolites can break the disulfide bonds of mucin in bronchial secretions, and change the composition and rheological properties of secretions, reduce the viscosity of sputum and improve the inhibited respiratory function. This product can remove free radicals, Effectively protect al-antitrypsin from smoke and dust-induced oxidative inactivation and prevent damage to lung elastin and neutrophils.
  • This product can also significantly increase the ratio of IgA / albumin, lactoferrin / albumin, reduce local inflammation, increase and improve the penetration of antibiotics into the bronchial mucosa, and is beneficial to the treatment of various inflammations of the respiratory tract.
  • Acetylcysteine is the most commonly used phlegm-soluble sputum expectorant. It is mainly used for spray inhalation.
  • the inventors of the present application have surprisingly found that the drug combination of ambroxol with erdosteine, ambroxol and acetylcysteine can provide a particularly beneficial expectorant effect without observing side effects.
  • this kind of drug combination is particularly suitable for treating various inflammations such as chronic bronchitis, asthma, etc., which are difficult to cough in patients with respiratory tract congestion and infection.
  • Simultaneous administration includes administration of ambroxol and erdosteine or ambroxol and acetylcysteine, or separate formulations of each active agent are administered substantially simultaneously.
  • ambroxol and erdosteine, ambroxol and acetylcysteine are administered as pharmaceutically active agents in their pharmaceutically acceptable forms, respectively, and their pharmaceutically acceptable forms include pharmaceutically acceptable Accepted salts, esters and solvates.
  • “Pharmaceutically acceptable” for the present invention includes human and veterinary use.
  • the scalar amounts of ambroxol or erdosteine or acetylcysteine in the pharmaceutically acceptable form given in the present invention are given for the compound itself: for example 50 mg of salt
  • Ambroxol in the acid salt form refers to the amount of the hydrochloride salt containing 50 mg of ambroxol; for example, Erdosteine in the form of 200 mg hydrochloride means the amount of the hydrochloride salt containing 200 mg of Erdosteine.
  • the pharmaceutical combination comprises 1-2000 mg of ambroxol administered daily.
  • the pharmaceutical combination contains 1-500 mg, 500-1000 mg, or 1000-2000 mg of ambroxol administered daily.
  • the pharmaceutical combination comprises 100-1000 mg of ambroxol administered daily.
  • the pharmaceutical combination comprises 1-2000 mg of erdosteine administered daily.
  • the pharmaceutical combination comprises erdosteine administered at 1-500 mg, 500-1000 mg, or 1000-2000 mg per day.
  • the pharmaceutical combination comprises 1-1000 mg of erdosteine administered daily.
  • the pharmaceutical combination comprises 1-2000 mg of acetylcysteine administered daily.
  • the pharmaceutical combination contains 1-500 mg, 500-1000 mg, or 1000-2000 mg of acetylcysteine per day.
  • the pharmaceutical combination comprises 1-1000 mg of acetylcysteine administered daily.
  • the invention proves through experiments that the combination of ambroxol and erdosteine, ambroxol and acetylcysteine can provide particularly beneficial prevention and treatment of respiratory congestion and inflammation of infections such as chronic bronchitis, asthma, and sputum. Effect and exhibit a synergistic effect relative to a control that is expected to be the sum of the effects of the individual active agents.
  • the expectorant effect can be characterized by conventional methods, for example by measuring an increase in the amount of expectorant.
  • the dose level of the two active agents of the pharmaceutical combination of the invention will be less than the dose required to achieve the expectorant effect of pure addition.
  • the active drug is preferably administered in the form of a pharmaceutical composition.
  • the two compositions may include multiple drugs or only one drug. Therefore, another object of the present invention is to provide a pharmaceutical composition containing 1-2000 mg of ambroxol and 1-2000 mg of erdosteine or 1-2000 mg of ambroxol and 1-2000 mg of Acetylcysteine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition for preventing and treating various inflammations of respiratory tract congestion and infection, and for expectoration.
  • the pharmaceutical composition comprises sequential or simultaneous administration of ambroxol in a pharmaceutically acceptable form and It is selected from Erdostein and acetylcysteine, wherein the content of ambroxol is 1-2000mg, the content of Erdostein is 1-2000mg, and the content of acetylcysteine is 1-2000mg.
  • the ambroxol is a base or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention is in the form of injections, powder injections, sprays, tablets, sustained-release agents, dripping pills, granules, capsules or sustained-release pellets.
  • the present invention also provides an application of the pharmaceutical composition of the present invention in the preparation of an expectorant.
  • composition of the present invention can be obtained by mixing 1-2000 mg of ambroxol and 1-2000 mg of erdostan After mixing with a pharmaceutically acceptable carrier, it is prepared according to a conventional preparation method.
  • compositions are generally suitable for oral and injection administration, as well as other methods of administration, such as transdermal administration.
  • composition can be in the form of tablets, capsules, powders, sprays, granules, dragees, suppositories, or liquid preparations such as oral solutions or sterile parenteral solutions or suspensions.
  • the composition may be in the form of a large or small volume injection, a lyophilized powder injection, a sterile powder portion, and the like.
  • the composition of the present invention is preferably in a single-dose form.
  • Single-dose representations for oral administration may be tablets and capsules, and may contain conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; Or a pharmaceutically acceptable wetting agent, such as sodium lauryl sulfate.
  • binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine
  • compositions are preferably made into unit doses in an amount appropriate to the relevant daily dose.
  • Suitable unit doses of ambroxol include various doses ranging from 1 to 2000 mg. It can be administered 1-6 times a day, but most preferably it is administered once (injection) or three times (orally).
  • Suitable doses of Erdostan include various doses of 1-2000 mg per day, but optimally it is administered once a day (injection) or three times (orally).
  • Suitable doses of acetylcysteine include various doses of 1-2000 mg per day, but most preferably are administered once (injection) or 3 times (orally) per day.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated blending operations can be used to distribute the active agent sufficiently into a composition using a large amount of filler. Such operations are of course routine in the art.
  • the tablets can be made into coated or plain tablets according to a conventional method.
  • Oral liquid preparations can be in the form of, for example, emulsions, syrups or elixirs, or they can be present as dry products and reconstituted with water or other suitable carriers before use.
  • This liquid formulation may contain conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated food fat; emulsification; Agents, such as lecithin, sorbitan monooleate, or gum arabic; anhydrous carriers (which can include edible oils), such as almond oil, distilled coconut oil, or oily esters, where the oily esters include glycerides, propylene glycol Or ethanol; preservatives, such as methyl or propyl parabens, or sorbic acid; if desired, conventional flavoring or coloring agents can also be added.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin,
  • Bacterial carriers are prepared in unit liquid dosage form and are suspended or dissolved in the carrier depending on the concentration used.
  • the active ingredient can be dissolved in water for injection and filtered for sterilization, then poured into a vial or ampoule and sealed.
  • adjuvants such as a local anesthetic, preservatives and buffering agents can be dissolved in the carrier.
  • the composition can be frozen and filled into vials, and the water can be removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same way, except that the active ingredients are not dissolved in the carrier, but are suspended in the carrier, and sterilization is not accomplished by filtration.
  • the active ingredient can be sterilized by contacting with ethylene oxide and resuspending it in a sterile carrier.
  • a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.
  • a single-taste active preparation or a pharmaceutical composition in a pharmaceutical combination can also be made into a sustained-release preparation according to a conventional method, such as a sustained-release pellet or a controlled-release pellet.
  • the composition may contain from 0.1% to 99% by weight, preferably from 1 to 60% by weight of active substance.
  • the present invention also relates to the addition or synergistic composition of ambroxol and erdosteine, ambroxol and acetylcysteine.
  • synergistic compositions are used for sputum caused by diseases such as chronic bronchitis and bronchial asthma. Viscosity, difficulty in expectoration, and sputum obstruction can also be used to prevent complications such as difficulty in expectoration and pneumonia after surgery.
  • the present invention may also relate to a kit, which is characterized in that it contains ambroxol, erdosteine, acetylcysteine, or a pharmaceutically acceptable salt thereof, wherein the content of ambroxol is 1- 2000mg, Erdosteine content is 1-2000mg.
  • the invention also relates to another kit, the content of ambroxol is 1-2000 mg, and the content of acetylcysteine is 1-2000 mg.
  • the patient uses the drugs in the kit sequentially and / or simultaneously to achieve the purpose of using the composition of the present invention.
  • the following examples are provided to further illustrate the present invention without any limitation. detailed description
  • mice 160 male mice were randomly divided into 15 groups, which were negative control groups, low, medium and high dose groups of ambroxol hydrochloride, low, medium and high dose groups of acetylcysteine, low, medium and high doses of erdosteine High-dose group, ambroxol and acetylcysteine (1: 1) low, medium, and high-dose groups, ambroxol and erdosteine salt (1: 1), low, medium, and high-dose groups, each The oral test sample was taken once a day for 3 consecutive days, with a dose volume of 0.4 ml. The negative control group received the same volume of saline.
  • Magnesium stearate 0.5mg 208mg per tablet After mixing the above raw materials and auxiliary materials uniformly, granulate according to the conventional wet method, dry, and tablet,
  • the granules were respectively crushed with microcrystalline cellulose, ambroxol, and erdosteine through a 100-mesh sieve in advance, weighed according to the prescription of pill 1, and mixed uniformly.
  • a hypromellose aqueous solution was used as a binder to prepare pellets. It is dried at 50 to 60 ° C, and pellets of 20 to 30 mesh are selected and used.
  • the prepared and selected pellets are placed in a fluidized bed, and the bottom spray method is adopted to suspend fluidization with hot air.
  • the inlet air temperature is 55 ° C, and the bed temperature is controlled at 30 ° C.
  • the coating solution is provided at a rate of 5 g per minute, the atomization pressure is 2 bar, and the small The pellets are continuously sprayed. After the spraying is completed, the air volume is reduced, and the pellets are dried at 40 ° C for a while in a microboiling state. After taking out, it was dried in an oven at 40 ° C for 24 hours, and the weight was increased by about 18 ° /. , Determine the content,
  • a clinically used or home-used kit which is configured with two or three medicine tablets, namely ambroxol, whose content is l-2000mg and erdosteine, whose content is l-2000mg, or ambroxol, an amount of l-2000mg acetylcysteine, a level of contents l-2000mg o skilled in the art using well known methods disclosed above may be combined to complete the configuration of the composition of the present invention.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition contenant de l'ambroxol et de l'erdostéine, ou leurs sels pharmaceutiquement acceptables, ainsi qu'une composition contenant de l'ambroxol et de l'acétylcystéine, ou leurs sels pharmaceutiquement acceptables. Ladite invention concerne également des trousses contenant les compositions susmentionnées et l'utilisation de ces produits. Ces compositions peuvent être utilisées pour traiter l'expectoration filante, la difficulté à la stéthocatharsis, causées par la bronchite chronique, l'asthme bronchique, et peuvent aussi être utilisées pour prévenir la difficulté à la stéthocatharsis et la complication en pneumonite après une intervention chirurgicale.
PCT/CN2005/000789 2004-06-18 2005-06-06 Composition medicamenteuse contenant de l'ambroxol et de l'erdosteine ou de l'acetylcysteine WO2005123052A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410048798.3 2004-06-18
CN200410048798 2004-06-18

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Publication Number Publication Date
WO2005123052A1 true WO2005123052A1 (fr) 2005-12-29

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017746A1 (fr) * 1990-05-21 1991-11-28 Norwich Eaton Pharmaceuticals, Inc. Utilisation de phenylpropanolamine comme secretagogue muqueux des voies respiratoires superieures
EP0687464A2 (fr) * 1994-06-15 1995-12-20 Allphamed Pharbil Pharma GmbH Procédé de fabrication de comprimés effervescents et comprimés effervescents
CN1130354A (zh) * 1993-09-07 1996-09-04 普罗克特和廿保尔公司 含有丙酸类非甾体消炎药氨基酸盐和减充血药、祛痰药、抗组胺药和镇咳药中至少一种的组合物
WO1996029061A1 (fr) * 1995-03-21 1996-09-26 Basf Aktiengesellschaft Procede permettant de preparer des compositions de principe actif sous forme de solution solide dudit principe actif dans une matrice polymere et preparations de principe actif obtenues a l'aide dudit procede
JP2002363072A (ja) * 2001-04-03 2002-12-18 Taisho Pharmaceut Co Ltd 鎮咳用組成物
CN1422162A (zh) * 2000-03-30 2003-06-04 先灵公司 用于治疗伴有咳嗽的过敏和炎症状况的组合物和方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017746A1 (fr) * 1990-05-21 1991-11-28 Norwich Eaton Pharmaceuticals, Inc. Utilisation de phenylpropanolamine comme secretagogue muqueux des voies respiratoires superieures
CN1130354A (zh) * 1993-09-07 1996-09-04 普罗克特和廿保尔公司 含有丙酸类非甾体消炎药氨基酸盐和减充血药、祛痰药、抗组胺药和镇咳药中至少一种的组合物
EP0687464A2 (fr) * 1994-06-15 1995-12-20 Allphamed Pharbil Pharma GmbH Procédé de fabrication de comprimés effervescents et comprimés effervescents
WO1996029061A1 (fr) * 1995-03-21 1996-09-26 Basf Aktiengesellschaft Procede permettant de preparer des compositions de principe actif sous forme de solution solide dudit principe actif dans une matrice polymere et preparations de principe actif obtenues a l'aide dudit procede
CN1422162A (zh) * 2000-03-30 2003-06-04 先灵公司 用于治疗伴有咳嗽的过敏和炎症状况的组合物和方法
JP2002363072A (ja) * 2001-04-03 2002-12-18 Taisho Pharmaceut Co Ltd 鎮咳用組成物

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