[go: up one dir, main page]

CN109200034A - A kind of composition and preparation method thereof of inhalable dry powder form - Google Patents

A kind of composition and preparation method thereof of inhalable dry powder form Download PDF

Info

Publication number
CN109200034A
CN109200034A CN201710523660.1A CN201710523660A CN109200034A CN 109200034 A CN109200034 A CN 109200034A CN 201710523660 A CN201710523660 A CN 201710523660A CN 109200034 A CN109200034 A CN 109200034A
Authority
CN
China
Prior art keywords
lactose
magnesium stearate
composite particles
composition
milling
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.)
Pending
Application number
CN201710523660.1A
Other languages
Chinese (zh)
Inventor
孙中英
周山
王华美
张克茹
王小宁
郑亚真
董平
江金凤
刘飞
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.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group 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 Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN201710523660.1A priority Critical patent/CN109200034A/en
Publication of CN109200034A publication Critical patent/CN109200034A/en
Pending 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
    • A61K31/33—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种可吸入干粉形式的组合物及其制备方法，特别是涉及一种含有格隆溴铵的干粉吸入剂及其制备方法。本发明组合物中的抗粘附剂和复合颗粒能够保证格隆溴铵在制剂加工过程中和存储时的雾粒分布的稳定性，可保持或略微提高其雾粒分布值，组合物中的格隆溴铵的具有优良的雾粒分布数据。The invention relates to a composition in the form of inhalable dry powder and a preparation method thereof, in particular to a dry powder inhalant containing glycopyrronium bromide and a preparation method thereof. The anti-adhesion agent and the composite particles in the composition of the present invention can ensure the stability of the fog particle distribution of glycopyrronium bromide during preparation processing and storage, and can maintain or slightly increase its fog particle distribution value. Glycopyrrolate has excellent haze distribution data.

Description

A kind of composition and preparation method thereof of inhalable dry powder form
Technical field
The present invention relates to a kind of compositions and preparation method thereof of inhalable dry powder form, contain lattice more particularly to one kind The Foradil Aerolizer formoterol fumarate and preparation method thereof of grand bromine ammonium.
Background technique
Foradil Aerolizer formoterol fumarate (DPI) is to integrate the knowledge of powder technology on the basis of metered dose inhalation aerosol and developed The novel form come, it is after individually or with carrier mixing micronized medicine, through special drug delivery device, to pass through the master of patient Dynamic air-breathing, it is medicinal atomized at respiratory tract is entered after aerosol, play a kind of drug delivery system locally or systemically acted on.The life of lung Reason structure determines that the drug particle size size into lung needs strict control.According to right in " Chinese Pharmacopoeia " two annex I L Powder spray requirement " the drug particle size size in inhalation powder spray should control at 10 μm hereinafter, wherein it is most of should 5 μm with Under ".It is generally acknowledged that being 1~5 μm for the suitable drug particle size size of pulmonary administration.
Glycopyrronium bromide is a kind of muscarine antagonist, can be combined individually or with other drugs and is used in the form of Foradil Aerolizer formoterol fumarate The treatment of chronic obstructive pulmonary disease.Its structural formula is as follows:
CN101484134A is according to the report, there is glycopyrronium bromide to tend to reunite during storage, this problem influences The physics and chemical stability of drug and its performance in the formulation.Glycopyrronium salt is mixed with antitack agent, then with carrier Particle mixing is advantageous, and this method can reduce the reunion tendency of gained drug, and therefore improve the stability of gained drug.
Summary of the invention
The present invention provides following technical schemes:
On the one hand, the present invention provides a kind of composition of inhalable dry powder form containing glycopyrronium bromide, preparations Method the following steps are included:
(a) lactose and magnesium stearate are mixed and obtained composite particles of milling；
(b) composite particles and lactose of mixing step (a)；
(c): glycopyrronium bromide is micronized together with magnesium stearate, and the mixture of micronization and step (b) are mixed, with Prepare the composition of dry powder form.
Wherein mill in (a) composite particles mode include but is not limited to mechanical fusion, ultracentrifugation mill, jet grinding, High pressure homogenization, ball milling, agitating type sanding, air jet mill, needle mill, sledge mill or chopping, it is preferred that the lapping mode is ball Mill.In some embodiments of the application, magnesium stearate is applied on lactose carrier particles surface；In some of the application In embodiment, magnesium stearate is discontinuously applied on lactose carrier particles surface.
In some embodiments of the application, the partial size X of the composite particles of (a)50It is 10 μm of <, of the invention some In embodiment, the partial size X of composite particles50It is 3-5 μm.
In some embodiments, the partial size X of the composite particles of (a)90It is 15-35 μm, in some embodiment party of the invention In case, the partial size X of composite particles90It is 20-25 μm.
In some specific embodiments of the invention, wherein the size distribution of the composite particles in (a) component is as follows: X10 It is 0.5-0.7 μm, X50It is 3-4.5 μm, X90It is 22-25 μm；In some specific embodiments, the size distribution of composite particles It is as follows: X10It is 0.5-0.7 μm, X50It is 4-4.2 μm, X90It is 22-25 μm.
In some embodiments, wherein lactose is in coarse granule shape before milling in (a), can sufficiently subtract during milling It is small.
In some embodiments, in the composite particles of (a), the weight of magnesium stearate is the 0.2-3% of composite particles, excellent It is selected as 0.4-2%, more preferably 0.6-1.5%, is 1% in a specific embodiment.
In some embodiments, lactose (b) is commercially available acquisition；In some embodiments, lactose is selected from α- Lactose or beta lactose or its solvate；It in some embodiments, is alpha-lactose or its monohydrate；In some embodiments In, for the alpha-lactose of grinding or its hydrate；It in some embodiments, is the alpha-lactose monohydrate of grinding.
In some embodiments, in step (b) lactose partial size X50It is 5-500 μm, preferably 10-300 μm, more preferably It is 20-150 μm, in some embodiments of the present invention, the partial size X of lactose50It is 30-70 μm.
In some embodiments, the partial size X of lactose (b)90It is 10-800 μm, preferably 20-500 μm, more preferably 40-300 μm, in some embodiments of the present invention, the partial size X of lactose90It is 70-200 μm.
In some specific embodiments of the invention, wherein the lactose in step (b) isML001。
In some embodiments, the composite particles of step (a) and the ratio (by weight) of the lactose in (b) component are 1:50-1:5, preferably 1:40-1:7, more preferable 1:30-1:10.
In some specific embodiments of the invention, wherein the ratio of the lactose of the composite particles of (a) and (b) is (with weight Meter) it is about 1:33,1:20 and 1:14.
In some embodiments, in the mixture that glycopyrronium bromide and magnesium stearate are micronized altogether in step (c), lattice Grand bromine ammonium particle surface is enclosed with magnesium stearate, the partial size X of gained mixture50≤ 5 μm, preferably 1.20-2.90 μm, more preferably It is 1.30-2.25 μm；In some specific embodiments, the partial size X of gained mixture50It is about 1.67-1.74 μm.
Wherein in (c) component, by weight, magnesium stearate is the 15-70%, preferably 25-50% of glycopyrronium bromide weight； In some specific embodiments, magnesium stearate is 9-11%, 16-17% and 42%-43% of glycopyrronium bromide weight.
It wherein can also include the other active components in addition to glycopyrronium bromide in composition of the invention.Other described work Property ingredient includes β 2 receptor agonist or corticosteroid.
Wherein β 2 receptor agonist include Terbutaline, Vilantro, Reproterol, salbutamol, salmeterol, good fortune not Special sieve, carmoterol, Mivitro, datro, Ao Dateluo, fenoterol, clenbuterol, bambuterol, Broxaterol, Adrenaline, isoprel or Hexoprenaline or their salt and/or solvate forms.
In some specific embodiments of the invention, β 2 receptor agonist is maleic acid datro.
In some embodiments, corticosteroid includes rofleponide, flunisolide, budesonide, ciclesonide, chaff Sour Mometasone, fluticasone furoate, fluticasone propionate, beclomeasone propionate, Loteprednol or Triamcinolone acetonide or their salt And/or solvate forms.
In some embodiments, the other active components are through being micronized, in some embodiments, through what is be micronized The partial size X of other active components50≤ 5 μm, preferably 1.20-2.90 μm, more preferably 1.30-2.25 μm.
In some specific embodiments of the invention, other active components are maleic acid datro, and partial size is about 1.86μm。
Wherein, when also containing other active components in the composition being produced, other active components can be existed Be micronized together with glycopyrronium bromide and magnesium stearate in step (c), after other active components can also being first micronized again with it is micro- The glycopyrronium bromide magnesium stearate of dusting and the mixture of step (b) are mixed together；In some embodiments, maleic acid indenes reaches spy Luo Xianjing is crushed, then is mixed together with the mixture of the glycopyrronium bromide magnesium stearate of micronization and step (b)；In some embodiment party In case, maleic acid datro first after being micronized again with the glycopyrronium bromide magnesium stearate of micronization and the mixture of step (b) It is mixed together.
In some embodiments, by weight, the weight for the mixture that maleic acid datro and step (c) obtain it With and composition gross weight ratio less than 5%, preferably less than 3%, more preferably less than 1.5%.
On the other hand, the preparation side of the composition of the present invention provides a kind of inhalable dry powder form containing glycopyrronium bromide Method, comprising the following steps:
(i), lactose and magnesium stearate are mixed and is ground to prepare composite particles；
(ii), composite particles obtained in step (i) are mixed with lactose；
(iii), glycopyrronium bromide and magnesium stearate are mixed and is micronized；
(iv), the mixture that the mixture and step (iii) for taking step (ii) to obtain obtain is mixed to prepare dry powder form Composition.
Wherein, when also containing other active components in the composition being produced, other active components can be existed (iii) it is micronized, the other active components through being micronized can also be existed together with glycopyrronium bromide and magnesium stearate in step (iv) it is mixed together in step with the obtained mixture of (ii) and (iii) step.
Wherein in step (i), the present invention in lactose granule by adding magnesium stearate and carrying out grinding for some strength Mill is prepared for a kind of opposite composite particles for grinding preceding lactose granule and reducing of partial size.
Wherein the dosage (by weight) of the magnesium stearate in step (i) is the 0.2-3% of composite particles weight, preferably For 0.4-2%, more preferably 0.6-1.5%.Magnesium stearate in some specific embodiments of the invention, in composite particles Dosage (by weight) be composite particles 1%.
Wherein in step (i) lactose used partial size X50It is 5-500 μm, preferably 10-300 μm, more preferably 20- 150 μm, in some embodiments of the present invention, the partial size X of lactose used50It is 30-70 μm.
Wherein in step (i) lactose used partial size X90It is 10-800 μm, preferably 20-500 μm, more preferably 40- 300 μm, in some embodiments of the present invention, the partial size X of lactose used90It is 70-200 μm.
In some specific embodiments of the invention, lactose used is in step (i)ML001。
Wherein lactose used is selected from alpha-lactose or beta lactose or its solvate, the α-preferably ground in step (i) Lactose or its solvate, the alpha-lactose monohydrate more preferably ground.
Wherein in step (i) magnesium stearate used partial size X50It is 0.5-50 μm, preferably 1-20 μm, more preferably 2- 10 μm, in some embodiments of the present invention, the partial size X of magnesium stearate used50It is 5-8 μm.
Wherein in step (i) magnesium stearate used partial size X90It is 1-100 μm, preferably 5-50 μm, more preferably 10- 20 μm, in some embodiments of the present invention, the partial size X of magnesium stearate used90It is 13-16 μm.
In some specific embodiments of the invention, wherein the size distribution of magnesium stearate used is such as in step (i) Under: X10It is 1-2 μm, X50It is 6-7 μm, X90It is 14-15 μm.
Wherein the composite particles in step (i) after grinding are compared with the lactose granule before grinding, partial size X50It is reduced at least 60%, it is preferably reduced to few 70%, is more preferably reduced at least 80%.
In some specific embodiments of the invention, before the composite particles and grinding in the step (i) after grinding Lactose granule is compared, partial size X50It is reduced at least 85%.
Wherein lapping mode described in preparation composite particles of the present invention includes but is not limited to mechanical fusion, surpasses in step (i) Fast centrifugal mill, jet grinding, high pressure homogenization, ball milling, agitating type sanding, air jet mill, needle mill, sledge mill or chopping.Grinding step Cause magnesium stearate to be applied in carrier particle surface suddenly.Preferably, the lapping mode is ball milling, wherein ball mill The rotation revolving speed of container is 120-600rpm, preferably 240-550rpm, more preferably 360-500rpm.
In some specific embodiments of the invention, wherein lapping mode is ball milling, the container of ball mill in step (i) Rotation revolving speed be 480rpm.
Wherein ball mill can according to need the suitable abrasive media of selection, the material of the abrasive media in step (i) It is preferably nonmetallic including metal and nonmetallic.
Wherein in step (i) abrasive media can select as needed it is suitably sized, such as when abrasive media is spherical, The diameter of abrasive media is not more than 5cm, preferably no greater than 2cm, more preferably no more than 1cm.
Wherein ball mill is planetary ball mill in step (i), and the rotation revolving speed of the container of planetary ball mill is 120- 600rpm, preferably 240-550rpm, more preferably 360-500rpm.The revolution revolving speed of the container of planetary ball mill is 60- 300rpm, preferably 120-275rpm, more preferably 180-250rpm.
In some specific embodiments of the invention, wherein the container of planetary ball mill is walked around certainly in step (i) Speed is 480rpm, and revolution revolving speed is 240rpm.
Wherein the ball milling mixing time is 5-120 minutes, preferably 10-60 minutes, most preferably 12-18 points in step (i) Clock.Wherein the operation of ball milling repeats 1-4 times, preferably 2-3 times.
In some specific embodiments of the invention, wherein the ball milling mixing time is 15 minutes in step (i), ball milling Operation is repeated 2 times.
Wherein the weight ratio of lactose is 1:50-1:5, preferably 1:40-1:7 in the composite particles of step (i) and step (ii), More preferable 1:30-1:10.
In some specific embodiments of the invention, the weight of lactose in the composite particles and step (ii) of step (i) Than for about 1:33,1:20 and 1:14.
Wherein in step (iii) magnesium stearate dosage (by weight) be glycopyrronium bromide weight 15-70%, preferably 25-50%, more preferably 30-45%.
In some specific embodiments of the invention, the dosage (by weight) of the magnesium stearate in step (iii) is 9-11%, 16-17%, 42%-43% of glycopyrronium bromide weight.
Wherein the hybrid mode of step (ii) be those skilled in the art well known to, such as sieving mixing.
Wherein the micronization equipment of step (iii) is well known to those skilled in the art, including various grindings and crushing Machinery, such as pressure mill formula pulverizer such as mechanical fusion are ground, impact grinder such as ball mill, homogenizer, microfluidization device and gas Flow pulverizer.
In some specific embodiments of the invention, the micronization equipment of step (c) is airslide disintegrating mill.
The hybrid mode that wherein hybrid mode of step (iv) is is well known to those skilled in the art, and purpose includes mixed It closes uniformly, such as sieving mixing.
Wherein in step (ii) lactose partial size X50It is 5-500 μm, preferably 10-200 μm, more preferably 20-100 μm, In some embodiments of the present invention, the partial size X of lactose50It is 30-70 μm.
Wherein in step (ii) lactose partial size X90It is 10-800 μm, preferably 20-500 μm, more preferably 40-300 μm, In some embodiments of the present invention, the partial size X of lactose90It is 70-200 μm.
In some specific embodiments of the invention, the size distribution of lactose is as follows in step (ii): X10It is 3-7 μm, X50It is 37-61 μm, X90It is 90-194 μm.
Wherein lactose is selected from alpha-lactose or beta lactose or its solvate in step (ii), the alpha-lactose preferably ground or Its solvate, the alpha-lactose monohydrate more preferably ground.
Composition prepared by the present invention can guarantee droplet distribution of the glycopyrronium bromide in formulation process and when storage Stability, can keep or slightly improve its droplet Distribution Value, the glycopyrronium bromide in composition is distributed with excellent droplet The fine grained data of data, especially the 4th grade-the 6 grade.
Definition:
Term " ball mill " refers to the device with abrasive media and rotatable container, including but not limited to planetary ball Abrasive media and carrier are collectively disposed among container by grinding machine before ball mill operation, and when container rotation, abrasive media is in container In carrier collided and is ground and be sufficiently mixed carrier." abrasive media " as described herein refers in a reservoir to load Body is collided and is ground and makes the well-mixed energy carrier of carrier, separable with container, the abrasive media typical shape Including spherical, spherical (such as oval) but it is also possible to be other shapes (such as rodlike, rotary table, column ball, short pole), institute The material for stating abrasive media includes metal (such as steel, iron, alloy etc.) and nonmetallic (such as glass, plastics, agate, zircon, rock Stone, ceramics etc.), the example of abrasive media has glass marble, plastic bead, steel ball, agate ball, zirconium oxide bead, zirconium silicate pearl etc.；It can turn The material of dynamic container include metal (such as stainless steel) and it is nonmetallic (such as agate, ceramics, nylon, polyurethane, polytetrafluoroethylene (PTFE), Zirconium oxide, hard alloy etc.).
Term " planetary ball mill " refer to rotatable disk, rotatable container (such as 2 or 4 containers) and Abrasive media and carrier are collectively disposed among container by the device of abrasive media before ball mill operation, container it is orderly be placed in disk On, when the disk makees revolution motion, container makees spinning motion on its revolution orbit, and container and disk rotate simultaneously, and rotation turns Speed is greater than the revolving speed of revolution, such as the rotating ratio of rotation and revolution is 2:1.
Term " rpm " refers to the unit of revolving speed, and rpm is the abbreviation of revolutions per minute, indicates per minute Revolving speed, such as 480rpm refers to per minute for 480 turns.
Term " pulmonary deposition ratio of active constituent " refers to that sucking preparation can reach the active constituent of the lung depths of patient The percentage of particle.
Term " droplet distribution ", i.e. minuteness particle dosage are the important parameters of the evaluation sucking quality of the pharmaceutical preparations, refer to sucking dust cloud The fine drug particle dose of agent accounts for the percentage of labelled amount, can be measured by device outside and (can refer to that " the Chinese people are total With state's pharmacopeia " version the 4th " 0951 sucking preparation minuteness particle air dynamic behaviour measuring method " was measured 2015 years), Its numerical value can reflect active constituent in the deposition of lung, such as when gas flow reaches 60L/min, and droplet is distributed in 2-7 grades Ratio it is suitable with the pulmonary deposition ratio of active constituent.
In general, by the characteristic equivalent sphere diameter (referred to as volume diameter) of laser diffraction measurement, thus quantitative The granularity of grain, such as measured by laser particle analyzer.
The present invention indicates size distribution (particle size distribution) with volume diameter (VD).
Term " X50" referring to that cumulative particle sizes percentile reaches partial size corresponding when 50%, its physical significance is grain The particle that diameter is greater than it accounts for 50%, and the particle less than it also accounts for 50%.
Term " X10" referring to that cumulative particle sizes percentile reaches partial size corresponding when 10%, its physical significance is grain The particle that diameter is greater than it accounts for 90%, and the particle less than it accounts for 10%.
Term " X90" referring to that cumulative particle sizes percentile reaches partial size corresponding when 90%, its physical significance is grain The particle that diameter is greater than it accounts for 10%, and the particle less than it accounts for 90%.
Specific embodiment
The present invention is further described in detail With reference to embodiment.But this should not be interpreted as to the present invention The range of protection is only limitted to following embodiment.
Embodiment 1 prepares lactose/magnesium stearate composite particles
Lactose: commercially available alpha-lactose monohydrate, model:ML001
Magnesium stearate is plant origin.
Test method:
Take lactose 297g, magnesium stearate 3g and zirconia ball (diameter is not more than 1cm) in right amount, control QM-3SP4 is planetary Ball mill carries out ball milling, and setting speed 480rpm, each ball milling 15min, ball milling 2 times, obtains magnesium stearate content as 1% altogether Lactose Magnesium Stearate composite particles.
Mixed partial size is measured by HELOS OASIS laser particle analyzer, the results are shown in Table 1.
The partial size of 1 composite particles of table
Sample X10/μm X50/μm X90/μm
Composite particles 0.62 4.05 24.30
2 glycopyrronium bromide of embodiment is micronized altogether with magnesium stearate
Test method:
Appropriate glycopyrronium bromide and magnesium stearate are taken, respectively according to mass ratio 10:1, after 6:1,7:3 mixing, using air-flow powder (J20 type airslide disintegrating mill crushes pressure: 0.5~1.0MPa to the mode of broken machine mixing；Blanking pressure: 0.5~1.0MPa) make firmly Fatty acid magnesium is sufficiently wrapped in glycopyrronium bromide surface.
Mixed partial size is measured by HELOS OASIS laser particle analyzer, the results are shown in Table 2.
2 glycopyrronium bromide of table and magnesium stearate are according to the partial size after different proportion co-grinding
The composition of inhalable dry powder form of the preparation of embodiment 3 containing glycopyrronium bromide
The sample of the present embodiment is prepared according to the composition of table 3:
3 composition of table
Lactose: commercially available alpha-lactose monohydrate, model:ML001。
Test method:
1) composite particles made from lactose and embodiment 1, are weighed according to the recipe quantity in table, cross 60 mesh 3 times mixing；
2), smashed maleic acid datro (X is weighed according to the recipe quantity in table10=0.56 μm；X50=1.86 μ m；X90=3.94 μm), the glycopyrronium bromide of each batch made from embodiment 2 and magnesium stearate mixture be (by mixture in table The quality of two kinds of substances is shown respectively), 80 meshes, which are crossed, according to equal increments method with 1) gained mixture mixes 5 times；
The droplet measure of spread of 4 embodiment of embodiment, 3 each batch composition
Test apparatus: pharmaceutical aerosol collector: NGI-170 type (Next Generation Pharmaceutical Impactor)。
Test method: 3 gained each batch powder of embodiment is fitted into No. 3 HPMC capsules with aliquot 25mg, and The droplet distribution of detection gained capsule sample immediately after preparation.Each batch capsule each 1 is taken, is set in suction apparatus, entrance is adjusted For gas flow rate to 60L/min, every suction time is 4s, measures droplet distribution and the transmitting dosage of dry powder in each capsule, counts 2-7 The amount of grade (aerodynamic size range: 0.34~4.46 μm) catch tray is distributed total amount as droplet.It the results are shown in Table 3, table 4:
(ratio of glycopyrronium bromide magnesium stearate not protect 10:1 the distribution of 4 each batch composition droplet of table in specification Interior, embodiment does not change)
5 part batch composition depositions at different levels (two) of table
5 glycopyrronium bromide droplet distributional stability of embodiment is investigated
Test method:
The sample of the A1 and B2 of Example 4, room temperature keep sample 6 weeks, are distributed according to the method results of regular determination droplet of embodiment 4 Variation, the results are shown in Table 5:
The droplet changes in distribution of table 5A1 sample
Table 6B2 sample droplet changes in distribution
The foregoing is merely a specific embodiment of the invention, the range that is not intended to limit the invention.Any this field Technical staff, the equivalent variations made under the premise of not departing from design and the principle of the present invention, modification and combination should all belong to In the scope of protection of the invention.

Claims (10)

1.一种的含有格隆溴铵的可吸入干粉形式的组合物，其制备方法包括以下步骤：1. the composition containing the respirable dry powder form of glycopyrronium bromide, its preparation method may further comprise the steps: (a)、乳糖和硬脂酸镁混合并碾磨得到粒径X50为＜10μm的复合颗粒，其制备方式包括机械融合、超速离心磨、喷射研磨、高压均化、球磨、搅拌式砂磨、空气喷射磨、针磨、锤磨或切碎；(a), lactose and magnesium stearate are mixed and milled to obtain composite particles with a particle size X 50 of <10 μm, and the preparation methods include mechanical fusion, ultracentrifugal milling, jet milling, high pressure homogenization, ball milling, stirring sand milling , air jet mill, pin mill, hammer mill or chopped; (b)、混合步骤(a)的复合颗粒和乳糖，所述乳糖的粒径为5-500μm；(b), the composite particle of mixing step (a) and lactose, the particle diameter of described lactose is 5-500 μm; (c)、格隆溴铵与硬脂酸镁一起进行微粉化至粒径X50≤5μm，将微粉化的混合物和步骤(b)混合，以制备干粉形式的组合物；(c), glycopyrronium bromide and magnesium stearate are micronized to particle diameter X 50 ≤ 5 μm, and the micronized mixture is mixed with step (b) to prepare a composition in the form of dry powder; 其中，(a)组分中的复合颗粒与(b)组分中的乳糖的比例以重量计为1:50-1:5。Wherein, the ratio of the composite particles in the (a) component to the lactose in the (b) component is 1:50-1:5 by weight. 2.权利要求1所述的可吸入干粉形式的组合物，其中(a)组分中的复合颗粒中的硬脂酸镁的重量为复合颗粒的0.2-3％。2. The composition in the form of respirable dry powder according to claim 1, wherein the weight of magnesium stearate in the composite particles in the component (a) is 0.2-3% of the composite particles. 3.权利要求1所述的可吸入干粉形式的组合物，其中(b)组分中的乳糖选自α-乳糖或β-乳糖或其溶剂化物。3. The composition in the form of an inhalable dry powder of claim 1, wherein the lactose in component (b) is selected from alpha-lactose or beta-lactose or solvates thereof. 4.权利要求1所述的可吸入干粉形式的组合物，其中(c)组分中的硬脂酸镁的占比以重量计为格隆溴铵重量的15-70％。4. The composition in the form of an inhalable dry powder according to claim 1, wherein the proportion of magnesium stearate in component (c) is 15-70% by weight of the weight of glycopyrronium bromide. 5.权利要求1所述可吸入干粉形式的组合物，其中：5. The composition in the form of a respirable dry powder of claim 1, wherein: 步骤(a)制得的复合颗粒的粒径X50为3-5μm，其制备方式为球磨，其中硬脂酸镁的重量为复合颗粒的0.6-1.5％；The particle diameter X 50 of the composite particles prepared in step (a) is 3-5 μm, and the preparation method is ball milling, wherein the weight of magnesium stearate is 0.6-1.5% of the composite particles; 步骤(b)所用乳糖的粒径X50为30-70μm，所述乳糖为研磨型α-乳糖的一水合物；The particle size X 50 of the lactose used in step (b) is 30-70 μm, and the lactose is the monohydrate of ground α-lactose; 步骤(c)格隆溴铵与硬脂酸镁共微粉化得到的混合物的粒径X50为1.30-2.25μm，其中硬脂酸镁为格隆溴铵重量的30-45％；The particle size X 50 of the mixture obtained by step (c) co-micronization of glycopyrronium bromide and magnesium stearate is 1.30-2.25 μm, wherein magnesium stearate is 30-45% of the weight of glycopyrronium bromide; 且(a)组分中的复合颗粒与(b)组分中的乳糖的比例以重量计为1:30-1:10。And the ratio of the composite particles in the (a) component to the lactose in the (b) component is 1:30-1:10 by weight. 6.权利要求5所述的可吸入干粉形式的组合物，还包括经微粉化的第二、三或者多种其他活性成分，所述经微粉化的其他活性成分选自β2受体激动剂或皮质类固醇，其他活性成分在步骤(c)中与格隆溴铵和硬脂酸镁一起微粉化至X50≤5μm，或是将其他活性成分先微粉化至X50≤5μm后再与微粉化的格隆溴铵硬脂酸镁和步骤(b)的混合物一起混合。6. The composition in the form of an inhalable dry powder of claim 5, further comprising a micronized second, third or more other active ingredients selected from the group consisting of a beta2 receptor agonist or Corticosteroids, other active ingredients are micronized to X 50 ≤ 5 μm together with glycopyrronium bromide and magnesium stearate in step (c), or other active ingredients are first micronized to X 50 ≤ 5 μm and then micronized with The glycopyrrolate magnesium stearate is mixed with the mixture of step (b). 7.权利要求6所述的可吸入干粉形式的组合物，其中所述其他活性成分为马来酸茚达特罗，所述马来酸茚达特罗在步骤(c)中与格隆溴铵和硬脂酸镁一起微粉化至X50为1.30-2.25μm，或是将马来酸茚达特罗先微粉化至X5为1.30-2.25μm后再与微粉化的格隆溴铵硬脂酸镁和步骤(b)的混合物一起混合。7. The composition in the form of a respirable dry powder of claim 6, wherein the other active ingredient is indacaterol maleate, which in step (c) is combined with glycopyrronium bromide Ammonium and magnesium stearate are micronized together to a X 50 of 1.30-2.25 μm, or indacaterol maleate is first micronized to an X 5 of 1.30-2.25 μm and then mixed with micronized glycopyrronium bromide. Magnesium fatty acid and the mixture of step (b) are mixed together. 8.权利要求1-7所述任意一种可吸入干粉形式的组合物的制备方法，包括：8. the preparation method of the composition of any one of the described inhalable dry powder forms of claim 1-7, comprising: (i)、将乳糖和硬脂酸镁混合并研磨以制备复合颗粒，其制备方式包括机械融合、超速离心磨、喷射研磨、高压均化、球磨、搅拌式砂磨、空气喷射磨、针磨、锤磨或切碎，所述研磨导致复合颗粒相对于研磨前乳糖的粒径减小；(i), mixing and grinding lactose and magnesium stearate to prepare composite particles, the preparation methods of which include mechanical fusion, ultracentrifugal milling, jet milling, high pressure homogenization, ball milling, agitated sand milling, air jet milling, needle milling , hammer milling or chopping which results in a reduction in the particle size of the composite particles relative to the lactose before milling; (ii)、将步骤(i)中制得的复合颗粒与乳糖混合；(ii), mixing the composite particles obtained in step (i) with lactose; (iii)、将格隆溴铵和硬脂酸镁混合并微粉化；(iii), mixing glycopyrronium bromide and magnesium stearate and micronizing; (iv)、取步骤(ii)得到的混合物和步骤(iii)得到的混合物进行混合；(iv), take the mixture that step (ii) obtains and the mixture that step (iii) obtains and mix; 其中，当所述制备方法中涉及加入其它活性成分时，可以在步骤(iii)中加入其它活性成分共同微粉化，或者将其他经微粉化的活性成分在(iv)步骤中与所述(ii)和(iii)步骤得到的混合物一起混合。Wherein, when the preparation method involves adding other active ingredients, other active ingredients may be added in step (iii) for co-micronization, or other micronized active ingredients may be mixed with said (ii) in step (iv). ) and the mixture obtained in steps (iii) are mixed together. 9.权利要求8所述的制备方法，其中步骤(i)中的制备方式为球磨，球磨机的容器的自转转速为120-600rpm，研磨介质为直径不大于5cm的球形，球磨混合时间为5-120分钟。9. the described preparation method of claim 8, wherein the preparation method in the step (i) is ball milling, the rotation speed of the container of the ball mill is 120-600rpm, and the grinding medium is a spherical shape with a diameter not greater than 5cm, and the ball milling mixing time is 5- 120 minutes. 10.权利要求8所述的制备方法，其中步骤(i)所用乳糖的粒径X50为5-500μm；所用硬脂酸镁的粒径X50为0.5-50μm。10. The preparation method of claim 8, wherein the particle size X 50 of the lactose used in step (i) is 5-500 μm; the particle size X 50 of the used magnesium stearate is 0.5-50 μm.
CN201710523660.1A 2017-06-30 2017-06-30 A kind of composition and preparation method thereof of inhalable dry powder form Pending CN109200034A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710523660.1A CN109200034A (en) 2017-06-30 2017-06-30 A kind of composition and preparation method thereof of inhalable dry powder form

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710523660.1A CN109200034A (en) 2017-06-30 2017-06-30 A kind of composition and preparation method thereof of inhalable dry powder form

Publications (1)

Publication Number Publication Date
CN109200034A true CN109200034A (en) 2019-01-15

Family

ID=64977054

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710523660.1A Pending CN109200034A (en) 2017-06-30 2017-06-30 A kind of composition and preparation method thereof of inhalable dry powder form

Country Status (1)

Country Link
CN (1) CN109200034A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109745565A (en) * 2019-01-28 2019-05-14 上海方予健康医药科技有限公司 A kind of dry powder composite and preparation method thereof for sucking
WO2020259244A1 (en) * 2019-06-26 2020-12-30 长风药业股份有限公司 Pharmaceutical inhalation aerosol and preparation method therefor
WO2021143785A1 (en) * 2020-01-15 2021-07-22 四川海思科制药有限公司 Pharmaceutical composition of aerosol inhalant containing indacaterol and preparation method thereof
CN117064869A (en) * 2023-09-27 2023-11-17 山东京卫制药有限公司 Capsule type inhalation powder spray and preparation method thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1942172A (en) * 2004-03-17 2007-04-04 奇斯药制品公司 Pharmaceutical formulations for dry powder inhalers comprising a low-dosage strength active ingredient
CN101325945A (en) * 2005-12-12 2008-12-17 雅戈泰克股份公司 Powder composition for inhalation
CN101422457A (en) * 2007-10-31 2009-05-06 江苏正大天晴药业股份有限公司 Tiotropium bromide respirable dry powder composition
CN101484134A (en) * 2006-06-30 2009-07-15 诺瓦提斯公司 Compositions of glycopyrronium salt for inhalation
CN102858326A (en) * 2010-04-01 2013-01-02 奇斯药制品公司 Process for the preparation of carrier particles for respirable dry powders
AU2013100008A4 (en) * 2013-01-04 2013-01-31 Novartis Ag Inhalable formulations of glycopyrronium bromide
CN104146960A (en) * 2004-11-23 2014-11-19 维克特拉有限公司 Dry powder inhaler formulations comprising surface-modified particles with anti- adherent additives
CN105338960A (en) * 2013-07-11 2016-02-17 奇斯药制品公司 Dry powder formulation comprising anticholinergic, corticosteroid and beta-adrenergic for administration by inhalation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1942172A (en) * 2004-03-17 2007-04-04 奇斯药制品公司 Pharmaceutical formulations for dry powder inhalers comprising a low-dosage strength active ingredient
CN104146960A (en) * 2004-11-23 2014-11-19 维克特拉有限公司 Dry powder inhaler formulations comprising surface-modified particles with anti- adherent additives
CN101325945A (en) * 2005-12-12 2008-12-17 雅戈泰克股份公司 Powder composition for inhalation
CN101484134A (en) * 2006-06-30 2009-07-15 诺瓦提斯公司 Compositions of glycopyrronium salt for inhalation
CN101422457A (en) * 2007-10-31 2009-05-06 江苏正大天晴药业股份有限公司 Tiotropium bromide respirable dry powder composition
CN102858326A (en) * 2010-04-01 2013-01-02 奇斯药制品公司 Process for the preparation of carrier particles for respirable dry powders
AU2013100008A4 (en) * 2013-01-04 2013-01-31 Novartis Ag Inhalable formulations of glycopyrronium bromide
CN105338960A (en) * 2013-07-11 2016-02-17 奇斯药制品公司 Dry powder formulation comprising anticholinergic, corticosteroid and beta-adrenergic for administration by inhalation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109745565A (en) * 2019-01-28 2019-05-14 上海方予健康医药科技有限公司 A kind of dry powder composite and preparation method thereof for sucking
CN109745565B (en) * 2019-01-28 2021-05-18 上海方予健康医药科技有限公司 Dry powder composition for inhalation and preparation method thereof
WO2020259244A1 (en) * 2019-06-26 2020-12-30 长风药业股份有限公司 Pharmaceutical inhalation aerosol and preparation method therefor
WO2021143785A1 (en) * 2020-01-15 2021-07-22 四川海思科制药有限公司 Pharmaceutical composition of aerosol inhalant containing indacaterol and preparation method thereof
CN116194087A (en) * 2020-01-15 2023-05-30 四川海思科制药有限公司 Indanterol-containing inhalation aerosol pharmaceutical composition and preparation method thereof
CN117064869A (en) * 2023-09-27 2023-11-17 山东京卫制药有限公司 Capsule type inhalation powder spray and preparation method thereof

Similar Documents

Publication Publication Date Title
US6780508B1 (en) Powder particles with smooth surface for use in inhalation therapy
EP1007017B1 (en) New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof
CN105338960B (en) Dry powder formulation containing anticholinergic, corticosteroid and beta-adrenergic for inhalation administration
CN105726548B (en) It include the dry composition agent of corticosteroid and BETA- adrenergic for inhalation
JPH10502647A (en) Formulations for inhalation applications
SK14912002A3 (en) Pharmaceutical formulations for dry powder inhalers in the form of hard-pellets
JPS63502895A (en) Novel pharmaceutical composition for inhalation
CN109200034A (en) A kind of composition and preparation method thereof of inhalable dry powder form
HK1206602A1 (en) Dry powder for inhalation formulation comprising salmeterol xinafoate, fluticasone propionate and tiotropium bromide, and method for preparing same
CN109745565A (en) A kind of dry powder composite and preparation method thereof for sucking
AU2013275641B2 (en) Method for producing powder for inhalation
WO2019067708A1 (en) Method for particle size reduction
CN114425049A (en) Method for preparing carrier for pharmaceutical composition in form of inhalable dry powder
CA2926978A1 (en) Process for preparing pharmaceutical formulations for inhalation comprising a high-dosage strength active ingredient
CN109745564A (en) A kind of preparation method sucking dry powder composite
Gilani et al. Influence of formulation variables and inhalation device on the deposition profiles of cromolyn sodium dry powder aerosols
CN108066329B (en) Preparation method of microparticles of fluticasone or derivatives thereof for inhalation
CN112933064A (en) Salmeterol xinafoate particle for inhalation and preparation method thereof
JP6033055B2 (en) Method for producing inhalable powder
JP6116206B2 (en) Method for producing inhalable powder
CN111297837B (en) Preparation method of dry powder inhalant
JP5937498B2 (en) Method for producing inhalable powder
JP6091862B2 (en) Method for producing inhalable powder
CN120815064A (en) A method for preparing a granular composition for inhalation with a bulk density of 0.26-0.28 g/ml
WO2019060797A9 (en) Method for manufacture of inhalation powders

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20190115