WO2020019953A1 - Composition pharmaceutique aérosol renfermant un glycopyrrolate, son procédé de préparation et ses applications - Google Patents

Composition pharmaceutique aérosol renfermant un glycopyrrolate, son procédé de préparation et ses applications Download PDF

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Publication number
WO2020019953A1
WO2020019953A1 PCT/CN2019/094487 CN2019094487W WO2020019953A1 WO 2020019953 A1 WO2020019953 A1 WO 2020019953A1 CN 2019094487 W CN2019094487 W CN 2019094487W WO 2020019953 A1 WO2020019953 A1 WO 2020019953A1
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Prior art keywords
pharmaceutical composition
acid
composition according
aerosol
glycopyrrolate
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PCT/CN2019/094487
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English (en)
Chinese (zh)
Inventor
张春雨
秦践
李麒麟
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四川海思科制药有限公司
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Application filed by 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN202310253443.0A priority Critical patent/CN116196298A/zh
Priority to CN201980023568.6A priority patent/CN111971034A/zh
Publication of WO2020019953A1 publication Critical patent/WO2020019953A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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

Definitions

  • the invention relates to an aerosol pharmaceutical composition, in particular to an aerosol pharmaceutical composition containing a glycopyrrolium salt and a preparation method thereof, and belongs to the field of pharmaceutical preparations.
  • Chronic obstructive pulmonary disease (Chronic, Obstructive, Disease, COPD), referred to as chronic obstructive pulmonary disease, is a feature of continuous airflow limitation, which develops progressively, and chronic inflammation caused by harmful gases and particles in the airway and lung tissue. Sexual response related to chronic respiratory diseases.
  • the morbidity and mortality of COPD are relatively high globally, and they are increasingly valued by various countries and organizations.
  • COPD ranks fourth in the world as the cause of death. According to the prediction of the World Health Organization (WHO), by 2020, the disease will become the third leading cause of human death worldwide.
  • WHO World Health Organization
  • the prevention and treatment of COPD is also very serious, and the morbidity and mortality have increased year by year with various factors such as aging, smoking population, and the environment.
  • bronchodilators are the core drugs for the management of COPD symptoms. They are applicable to the treatment of COPD at various stages. By adjusting the tension of airway smooth muscles, they relax the bronchi and improve the degree of airflow restriction. They play an important role in the medical treatment of COPD.
  • bronchodilators include three categories: anticholinergics, theophyllines, and ⁇ 2 receptor agonists.
  • Theophylline is generally not recommended for the treatment of COPD because of its low efficacy and high side effects.
  • Long-acting anticholinergic drugs (LAMA) and long-acting ⁇ 2 receptor agonists (LABA) are recommended as treatment by GOLD.
  • Glycommonium (glycopyrrolate) is a long-acting quaternary ammonium anticholinergic drug, which has a long-acting scopolamine receptor antagonist effect, usually in the form of its bromide salt (The structural formula is shown in the figure below) It is used in clinical development and successfully developed by Novartis, Switzerland. It is administered by Breezhaler dry powder inhaler once a day for long-term relief of symptoms in adult patients with COPD.
  • the existing glycopyrrolium bromide dry powder inhalation preparations are mainly supplemented with lactose and magnesium stearate.
  • lactose and magnesium stearate may be inhaled into the lungs, and they are used as foreign bodies. There is a risk of adverse reactions when inhaled.
  • the present invention provides a glycopyrrolate aerosol pharmaceutical composition without a propellant and a preparation method thereof.
  • the pharmaceutical composition provided by the present invention contains one or more glycopyrrolium salts as an active substance. Based on the glycopyrrolium, the concentration is between 0.045 ⁇ 0.001 g per 100 ml of the preparation and 0.090 ⁇ 0.001 g per 100 ml of the preparation. Wherein one or more glycopyrrolium salts in the pharmaceutical preparation are present in a completely dissolved form;
  • Chlorobenzyl ammonium as a pharmacologically acceptable preservative
  • the glycopyrrolium salt is formed by glycopyrrolium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid.
  • hydrobromic acid hydrochloric acid
  • hydroiodic acid monomethyl sulfate
  • methanesulfonic acid or p-toluenesulfonic acid.
  • the above pharmaceutical composition according to the present invention preferably does not contain any other excipients other than water, glycopyrrolium ammonium, chlorobenzyl ammonium, disodium ethylenediamine tetraacetate, hydrochloric acid, and optionally sodium chloride. Agents and additives.
  • the present invention relates to liquid active substance preparation pharmaceutical compositions of these compounds which are generally administered by inhalation, wherein the liquid preparation pharmaceutical composition according to the present invention meets high quality standards.
  • a propellant-free liquid formulation pharmaceutical composition is administered using a suitable inhaler.
  • a particularly suitable inhaler is an aerosol pharmaceutical composition capable of nebulizing a small amount of a liquid preparation having a dose required for therapeutic purposes in a few seconds to form a therapeutic inhalation.
  • a preferred sprayer is an active substance liquid mist that is preferably capable of spraying in one or two shots, less than 100 microliters, preferably less than 50 microliters, and most preferably less than 20 microliters.
  • an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, such that the inhalable portion of the aerosol corresponds to a therapeutically effective amount.
  • any pharmaceutically acceptable glycopyrrolium salt can be used as a formulation.
  • glycopyrrolium is used within the scope of the present invention, it is used as a reference for glycopyrrolates.
  • the glycopyrrolate reference corresponds to the free ammonium cation.
  • the glycopyrrolium salt therefore contains an anion as a counterion.
  • glycopyrrolium salt that can be used within the scope of the present invention preferably contains, in addition to glycopyrrolium, as a counter ion (anion), chloride ion, bromide ion, iodide ion, methanesulfonate ion, p-toluenesulfonate ion and / Or methyl sulfate ion compounds.
  • the formulation pharmaceutical composition of the present invention is preferably an active substance that does not contain any other glycopyrronium-free active substance or a pharmaceutically acceptable salt thereof.
  • One or more glycopyrrolium salts in the pharmaceutical composition of the formulation according to the invention are dissolved in water. No other solvents are used. In particular, this formulation has no propellant gas.
  • the pharmaceutical composition of the formulation according to the present invention preferably contains only a single glycopyrrolate salt, preferably glycopyrrolate.
  • the pharmaceutical composition of such a formulation may also contain a mixture of different glycopyrrolium salts and solvates.
  • glycopyrrolium salt concentration of glycopyrrolium salt depends on the therapeutic effect to be achieved. For most conditions that are responsive to glycopyrrolate, glycopyrrolate concentrations range between 0.03 grams per 100 grams of preparation and 0.10 grams per 100 grams of preparation. Since the density of the formulation is 1 g / cm 3 , a 100 gram formulation corresponds to a volume of 100 ml. Within the scope of this specification, the expression “per 100 mL” or “/ 100 mL” is, unless stated differently, a preparation per 100 ml in each case.
  • An amount of 0.035 g / 100 mL to 0.095 g / 100 mL is preferable, and an amount of 0.04 g / 100 mL to 0.09 g / 100 mL is more preferable.
  • the optimal amount is 0.045 ⁇ 0.001 g per 100 ml of preparation to 0.090 ⁇ 0.001 g per 100 ml of preparation.
  • the aerosol pharmaceutical composition of the present invention has a pH between 2.7 and 3.1, preferably between 2.8 and 3.05, more preferably between 2.80 and 3.0, and most preferably 2.9.
  • the pH is adjusted by adding a pharmacologically acceptable acid.
  • Examples of preferred inorganic acids for this purpose also include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid, and the like.
  • Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substances.
  • ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is most preferred.
  • mixtures of the aforementioned acids can also be used, especially in the case of acids having other properties in addition to acidifying properties, such as acids used as flavoring agents or antioxidants, such as citric acid and ascorbic acid.
  • hydrochloric acid and citric acid are particularly preferred.
  • pharmacologically acceptable bases can be used to accurately titrate the pH.
  • Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates.
  • a preferred alkali metal ion is sodium. If such a base is used, care must be taken to ensure that the final salt contained in the final pharmaceutical formulation is pharmacologically compatible with the aforementioned acids.
  • the aerosol pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediaminetetraacetate or disodium ethylenediaminetetraacetate dihydrate, as Stabilizer or complex forming agent.
  • EDTA ethylenediaminetetraacetic acid
  • the use of disodium ethylenediamine tetraacetate is preferred.
  • disodium ethylenediamine tetraacetate it is between 5 mg per 100 ml of the preparation and 20 mg per 100 ml of the preparation, preferably between 5 mg per 100 ml of the preparation and 15 mg per 100 ml of the preparation, more It is preferably between 8 mg per 100 ml of the preparation and 12 mg per 100 ml of the preparation, and most preferably 10 mg per 100 ml of the preparation.
  • disodium ethylenediaminetetraacetate can be used similarly.
  • Other additives although not preferred compared to ethylenediaminetetraacetic acid or its salts, have complexing properties and can be used instead, such as nitrogen Acetic acid and its salts.
  • the complexing agent preferably refers to a molecule capable of entering a coordination bond.
  • the cations are complexed by metal cations.
  • the aerosol pharmaceutical composition may also be added with other pharmacologically acceptable auxiliaries.
  • auxiliaries and additives refer to any pharmacologically acceptable and therapeutically useful substance, which is not an active substance, but can be formulated with the active substance in a pharmacologically suitable solvent to improve the preparation of the active substance. quality. Preferably, these substances have no pharmacological effect or do not have a comparable or at least no pharmacological effect in the desired therapeutic condition.
  • auxiliaries and additives include, for example, other stabilizers, complexing agents, antioxidants, and / or preservatives, flavoring agents, vitamins, and / or other additives known in the art that can extend the shelf life of the final pharmaceutical formulation. This additive also contains pharmaceutically acceptable salts, such as sodium chloride.
  • Preferred auxiliaries include antioxidants, such as ascorbic acid, provided that they are not used to adjust pH, vitamin A, vitamin E, tocopherols and similar vitamins or vitamin precursors present in the human body.
  • Preservatives can be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known in the art, in particular ammonium chlorobenzyl, or benzoic acid, or a benzoate, such as sodium benzoate, at concentrations known in the art.
  • the benzalkonium chloride is mixed in the preparation.
  • the amount of chlorobenzyl ammonium is between 5 mg per 100 ml of the preparation and 20 mg per 100 ml of the preparation, preferably between 5 mg per 100 ml of the preparation and 15 mg per 100 ml of the preparation, more preferably between Between 8 mg per 100 ml of preparation and 12 mg per 100 ml of preparation, most preferably 10 mg per 100 ml of preparation.
  • the preferred formulation in addition to the water solvent and the glycopyrrolium salt, contains only ammonium chlorobenzyl alkane, disodium ethylenediamine tetraacetate and the acid required to adjust the pH, preferably hydrochloric acid.
  • glycopyrrolate aerosol pharmaceutical composition of the present invention can be prepared by mixing the individual components.
  • glycopyrrolate aerosol pharmaceutical composition of the present invention can be used with the Respimat aerosol inhalation device, and can also be used with the aerosol inhalation device shown in FIG. 1 or 2.
  • the aerosol inhalation device shown in FIG. 1 is a piezoelectrically actuated droplet delivery device for delivering a medicinal solution as a jet of droplets to a patient's lung system.
  • the device includes:
  • a liquid storage tank which is arranged in the housing or communicates with a liquid passage in the housing, and is used for storing a certain volume of medicinal liquid
  • the ejection mechanism which is in communication with the liquid in the liquid storage tank includes a piezoelectric actuator and an orifice plate, the orifice plate has a plurality of openings, and the piezoelectric actuator can oscillate the orifice plate with a certain frequency to generate ejected liquid droplets. flow;
  • At least one pressure difference sensor disposed in the housing
  • the differential pressure sensor activates the ejection mechanism when it senses a predetermined pressure change in the housing, thereby generating a stream of ejected droplets
  • the spraying mechanism can generate a sprayed droplet flow, wherein at least about 70% of the droplets have an average sprayed droplet diameter of less than about 5 micrometers, so that at least about 70% of the sprayed droplet flow is delivered to the lungs of the patient.
  • Figure 1 provides a detailed view of an exemplary injector closing mechanism. Removing the housing top cover 152 exposes the ejector closing actuation mechanism 506, which includes a closing guide 508, a sliding seal plate 510, and a motor mechanism 512. When the motor mechanism 512 is activated, the motor mechanism 512 can open and close the sliding seal plate 510 . Any suitable micromotor mechanism can be used.
  • the aerosol inhalation device shown in FIG. 2 includes a base unit 100, an interface tube 200, a spray head 300, and a screw cap 304.
  • the base unit includes an air inlet 101, an air outlet 102, a groove 103 for receiving an interface pipe, and a key lock member 104;
  • the interface pipe includes a first section 200a and a second section 200b, and the first section 200a includes an air inlet 201 and a side opening 202 for accommodating the spray generator, the first segment can be inserted into the groove of the base unit, and the second segment 200b includes a spray outlet 203;
  • the spray head includes a spray generator 301, a liquid container 302, and a base unit
  • the key lock member 303 is complementary to the key lock member 303; the base unit, the interface pipe, and the spray head can be connected to each other, so that when the key lock member is joined with the complementary member, the spray generator is inserted into the side opening of the interface pipe.
  • the glycopyrrolate aerosol pharmaceutical composition containing no propellant provided by the present invention not only solves the problem that the existing glycopyrrolate powder adjuvant is inhaled into the lungs, but also solves the problem of glycopyrrolate powder
  • the problem that the active ingredients of the aerosol can reach the lungs is too small, which can reduce the product specifications, reduce the amount of glycopyrrolium raw materials, reduce the cost of medicines, and reduce the burden on patients; at the same time, due to the existing treatment of chronic obstructive lungs
  • Most aerosols for diseases contain a propellant.
  • the propellant destroys the ozone layer in the atmosphere and is not good for environmental protection.
  • the aerosol has a short fogging time, which reduces the efficiency of the drug.
  • the provided glycopyrrolium aerosol does not contain a propellant, and there is no problem that has an impact on environmental protection. At the same time, because it is used for a long time, it has greatly improved the efficiency of the drug.
  • the present invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition and an aerosolized inhalation device for treating COPD, the aerosol pharmaceutical composition is selected from the aerosol formulations containing the glycopyrrolium salt described above , Or one or more selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, odaterol hydrochloride, adibromide, and humidinium bromide Aerosol preparation.
  • the drug combination system processes the aerosol pharmaceutical composition through the atomizing inhalation device to make it atomize, and the unit dose volume processed by the atomizing inhalation device is 10 to 50 microliters .
  • the aerosol inhalation device in the drug combination system is shown in FIG. 1 or shown in FIG. 2.
  • Figure 1 is a schematic diagram of aerosol inhalation devices related to patents such as WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109475709A and other patents.
  • Figure 2 is a schematic diagram of an aerosol inhalation device involved in patents such as CN103785086A, CN104010685A, CN104271187A, CN107929894A and the like.
  • Each 100 milliliters of a glycopyrrolate aerosol pharmaceutical composition contains:
  • the remaining components are purified water, or water for injection at a temperature of 15-31 ° C and a density of 1.00g / cm 3 , which are prepared by mixing individual components. After filtering and sterilizing, they are canned in a pill box of an atomizing device. .
  • the lung deposition rate (FPF value) of the product of the present invention and the commercially available glycopyrrolate powder was measured by a new generation impactor (NGI), and the results are as follows:
  • the above FPF value is the FPF value of the active ingredient glycopyrronium bromide in the powder or aerosol generated after passing through the corresponding inhalation device of the inhalation preparation product, all measured by the new generation impactor (NGI), Novartis glycopyrrolate inhalation powder
  • NKI new generation impactor
  • the inhalation device corresponding to the aerosol is Breezhaler (that is, a commercially available device of the product).
  • the inhalation device used for the product of Example 1 of the present invention is the inhalation device shown in FIG. 1, and the inhalation device used for the product of Example 6 of the present invention is shown in FIG. 2. Shows the inhalation device.
  • the lung deposition rate of the glycopyrrolate bromide of the present invention is much higher than that of the glycopyrrolate bromide inhalation powder marketed by Novartis, which significantly improves the usage efficiency.

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  • Otolaryngology (AREA)
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Abstract

Composition pharmaceutique aérosol renfermant un glycopyrrolate, chaque 100 ml de ladite composition pharmaceutique contenant entre 0,045 +/- 0,001 g et 0,090 +/- 0,001 g de glyopyrrolate. Ladite composition pharmaceutique se prête particulièrement à la conversion d'une substance active en un aérosol par atomisation de manière à administrer un surfactant par inhalaison en cas d'asthme et de BPCO.
PCT/CN2019/094487 2018-07-26 2019-07-03 Composition pharmaceutique aérosol renfermant un glycopyrrolate, son procédé de préparation et ses applications WO2020019953A1 (fr)

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Application Number Priority Date Filing Date Title
CN202310253443.0A CN116196298A (zh) 2018-07-26 2019-07-03 一种含格隆铵盐的气雾剂药物组合物及其制备方法与应用
CN201980023568.6A CN111971034A (zh) 2018-07-26 2019-07-03 一种含格隆铵盐的气雾剂药物组合物及其制备方法与应用

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CN201810823630.7 2018-07-26
CN201810823630 2018-07-26

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WO2021143785A1 (fr) * 2020-01-15 2021-07-22 四川海思科制药有限公司 Composition pharmaceutique de produit à inhaler pour aérosol contenant de l'indacatérol et procédé de préparation de celle-ci

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CN1473044A (zh) * 2000-10-31 2004-02-04 ���ָ��Ӣ��ķ�������Ϲ�˾ 含提欧川平盐的溶液的可吸入制剂
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
CN105412049A (zh) * 2014-09-16 2016-03-23 四川海思科制药有限公司 一种干粉吸入剂用药物组合物及其制备方法
WO2017192767A1 (fr) * 2016-05-03 2017-11-09 Pneuma Respiratory, Inc. Dispositif d'administration de gouttelettes pour l'administration de fluides au système pulmonaire et méthodes d'utilisation

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DE10056104A1 (de) * 2000-11-13 2002-05-23 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Tiotropiumsalzen und Salzen des Salmeterols
PT2724741T (pt) * 2012-10-26 2017-08-02 Vectura Gmbh Dispositivo de inalação para uso em terapia por aerossol

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
CN1473044A (zh) * 2000-10-31 2004-02-04 ���ָ��Ӣ��ķ�������Ϲ�˾ 含提欧川平盐的溶液的可吸入制剂
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
CN105412049A (zh) * 2014-09-16 2016-03-23 四川海思科制药有限公司 一种干粉吸入剂用药物组合物及其制备方法
WO2017192767A1 (fr) * 2016-05-03 2017-11-09 Pneuma Respiratory, Inc. Dispositif d'administration de gouttelettes pour l'administration de fluides au système pulmonaire et méthodes d'utilisation

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