CN116194087A - Indanterol-containing inhalation aerosol pharmaceutical composition and preparation method thereof - Google Patents

Indanterol-containing inhalation aerosol pharmaceutical composition and preparation method thereof Download PDF

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Publication number
CN116194087A
CN116194087A CN202180005956.9A CN202180005956A CN116194087A CN 116194087 A CN116194087 A CN 116194087A CN 202180005956 A CN202180005956 A CN 202180005956A CN 116194087 A CN116194087 A CN 116194087A
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micronized
indacaterol
magnesium stearate
pharmaceutical composition
propellant
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张轩邈
毛华
周洋
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • 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
    • 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
    • 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

Abstract

An aerosol pharmaceutical composition and a preparation method thereof, wherein the composition comprises indacaterol or salt thereof, magnesium stearate and a propellant, and is prepared by uniformly mixing the components and filling the components into an aluminum pot. The aerosol product solves the problems that the indacaterol suspension aerosol is prepared into engineering particle particles with auxiliary materials in advance, the preparation process is complex and the controllability is poor, and better meets the clinical needs.

Description

Indanterol-containing inhalation aerosol pharmaceutical composition and preparation method thereof Technical Field
The invention relates to an inhalation aerosol pharmaceutical composition and a preparation method thereof, in particular to an inhalation aerosol pharmaceutical composition containing indacaterol and a preparation method thereof, belonging to the technical field of inhalation aerosols.
Background
There are approximately 4200 ten thousand asthmatics and 2800 ten thousand chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) patients worldwide. Over the last decade, with global air pollution and environmental deterioration, the incidence and mortality of asthma is on the rise, with over 18 tens of thousands of deaths annually from asthma. Another analysis shows that COPD will climb from the sixth to the third of the current global causes of death by 2020. Bronchodilators improve airflow limitation and are the main means for treating COPD. Global initiative for COPD (GOLD) in 2019 indicated that COPD comprehensively evaluates patients of class B, and initial treatment recommended the selection of one long-acting bronchodilator alone. Currently long-acting β2-receptor agonists (LABA) or long-acting anticholinergic drugs remain the treatment of choice for improving their symptoms and reducing acute exacerbations.
Indamterol is a new generation of long-acting LABA, inhaled 1 time a day, and the effect of expanding bronchi can last for 24 hours. Indantrole is a partial agonist of the beta 2 receptor, close to a full agonist, and has the receptor affinity equivalent to that of formoterol, and the intrinsic activity higher than that of salmeterol, so that the indacaterol takes effect more rapidly within 5 minutes after the first dose. Indamterol catalyzes ATP to be converted into cAMP by activating intracellular adenylate cyclase, so that free calcium ion release is reduced to cause airway smooth muscle relaxation; indamatrox inhibits the release of various inflammatory mediators such as histamine, leukotriene and prostaglandin by mast cells, and exerts an anti-inflammatory effect by inhibiting neutrophil infiltration and reducing vascular permeability. Indamterol can improve dyspnea symptoms and life quality of COPD patients, and reduce acute exacerbation times. Indanterol can improve pulmonary function and dyspnea symptoms of patients in stable phase, and has the curative effects of improving life quality and reducing acute exacerbation of COPD equivalent to salmeterol and formoterol.
The existing commercially available indacaterol single or compound preparation containing indacaterol is mainly administered by dry powder inhalation, comprising
Figure PCTCN2021071893-APPB-000001
Administration by dry powder inhalation requires that patients learn the inhalation method, and for some severe COPD patients may not reach inhalation capacity, the drug may not be effectively delivered to the lungs or the delivered dose may be reduced, resulting in reduced efficacy of the drug. There is thus a need to develop other inhalation formulation dosage forms, wherein aerosols are a new choice.
CN103874483B discloses a pharmaceutical composition of inhaled aerosol containing indacaterol, wherein indacaterol is required to be prepared into spherical engineering particles with a carrier through special processes such as spray drying and the like, and then prepared into aerosol, the preparation method is complex, the controllability is poor, and the production cost is high.
In summary, the preparation method of the suspension indacaterol aerosol preparation reported at present is complex and has poor controllability. There is therefore a need to develop new indacaterol aerosols.
Disclosure of Invention
The present invention provides an inhalation aerosol pharmaceutical composition comprising the active ingredient indacaterol or a pharmaceutically acceptable salt thereof, magnesium stearate and a propellant, optionally in micronized form.
Further, the pharmaceutically acceptable salt of the active ingredient indacaterol is indacaterol maleate or a micronized form thereof, or indacaterol acetate or a micronized form thereof, the propellant is at least one selected from trichloro-monofluoromethane, dichloro-difluoromethane, dichloro-tetrafluoroethane, 1,2, 3-heptafluoropropane.
Further, the composition comprises the following components in percentage by weight: the active component indacaterol or pharmaceutically acceptable salt thereof is 0.0012-3%, magnesium stearate is 0.0005-0.162%, and the balance is propellant. Alternatively, indacaterol or a pharmaceutically acceptable salt thereof is in its micronized form.
In some embodiments, the composition further comprises at least one of the active ingredients glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, beclomethasone dipropionate, each in an amount of 0.0006% to 1.5% by weight of the composition. Optionally, the active ingredients glycopyrrolate, mometasone furoate, fluticasone propionate, budesonide, beclomethasone propionate are in their micronized form.
In some embodiments, the composition comprises the following components in weight percent: indanterol maleate 0.06-1.2%, glycopyrronium bromide 0.0006-1.5%, mometasone furoate 0.005-1.5%, magnesium stearate 0.0045-0.081%, and the balance being propellant. Alternatively, indacaterol maleate, glycopyrrolate, mometasone furoate are in their micronized form. Optionally, the magnesium stearate is in its micronized form.
In one embodiment, the composition contains per 10000 g: indanterol maleate 36.0g, glycopyrrolate 19.5g, magnesium stearate 2.9g, and the balance 1, 2-tetrafluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or magnesium stearate are in their micronized form.
In one embodiment, the composition contains per 10000 g: indanterol maleate 30.0g, glycopyrrolate 16.0g, mometasone furoate 30.0g, magnesium stearate 2.0g, and the balance 1, 2-tetrafluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or mometasone furoate and/or magnesium stearate are in their micronized form.
In one embodiment, the composition contains per 10000 g: indanterol maleate 6.00g, glycopyrrolate 3.00g, mometasone furoate 12.00g, magnesium stearate 1.05g and the balance 1, 2-tetrafluoroethane. Optionally, indacaterol maleate and/or glycopyrrolate and/or mometasone furoate and/or magnesium stearate are in their micronized form.
In some embodiments, the composition further comprises additional specific adjuvants selected from at least one of oleic acid, phospholipids, tween-80, polyvinylpyrrolidone, and polyethylene glycol.
Further, the weight percentage of the other specific auxiliary materials in the composition is 0.0020-5%.
In one embodiment, the composition contains per 10000 g: micronized indacaterol maleate 36.0g, micronized glycopyrrolate 19.5g, magnesium stearate 2.9g, polyvinylpyrrolidone-K25 or tween-801.0 g, or oleic acid 0.51g, the balance 1, 2-tetrafluoroethane; optionally, the magnesium stearate is in micronized form.
Further, the particle size distribution of each micronization component is D 90 Less than or equal to 20 mu m, preferably D 90 Less than or equal to 10 mu m, more preferably D 90 ≤5μm。
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
(1) Uniformly mixing the active ingredient and magnesium stearate to obtain a mixture;
(2) Adding the propellant with the prescribed amount into the mixture prepared in the step (1), uniformly mixing to obtain a liquid medicine, and adding the propellant which is volatilized and lost in an equivalent way if necessary;
(3) Filling the liquid medicine prepared in the step (2) into an aluminum pot, and pressing a quantitative valve.
In some embodiments, at least one of oleic acid, phospholipids, tween-80, polyvinylpyrrolidone, and polyethylene glycol is further added in step (2).
In some embodiments, the active ingredient comprises indacaterol, indacaterol maleate, or indacaterol acetate; preferably, the active ingredient further comprises at least one of glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, beclomethasone propionate.
In some embodiments, the present invention also provides a method of preparing the above pharmaceutical composition, comprising the steps of:
(1) The preparation method comprises the steps of adopting an air flow pulverizer to micronize or co-micronize each active ingredient, and then uniformly mixing the active ingredients with magnesium stearate to obtain a mixture; or mixing each active ingredient and magnesium stearate uniformly, and then performing co-micronization by adopting an air flow pulverizer to obtain a mixture;
(2) Adding the propellant with the prescribed amount into the mixture prepared in the step (1), uniformly mixing to obtain a liquid medicine, and adding the propellant which is volatilized and lost in an equivalent way if necessary;
(3) Filling the liquid medicine prepared in the step (2) into an aluminum pot, and pressing a quantitative valve.
In some embodiments, at least one of oleic acid, phospholipids, absolute ethanol, tween-80, polyvinylpyrrolidone, and polyethylene glycol is further added in step (2).
The invention has the advantages and beneficial effects that:
the preparation process of the indacaterol-containing inhalation aerosol pharmaceutical composition provided by the invention is simple and controllable, the problems that the existing indacaterol-containing inhalation aerosol needs to be prepared into engineering particle particles with auxiliary materials, the preparation process is complex and the controllability is poor are solved, the preparation of the indacaterol aerosol preparation is smoothly realized, and the indacaterol aerosol preparation better meets clinical requirements.
The product of the invention has excellent in-vitro particle distribution performance of the medicine, can reach higher FPF value (fine particle fraction percent, FPF percent) and has higher inhalable component percentage.
The corresponding relation between the propellant English code and the chemical name in the invention is as follows:
propellant English code Chemical name of propellant
CFC11 Trichlorofluoromethane
CFC12 Dichloro difluoromethane
CFC114 Dichloro tetrafluoroethane
HFA-134a 1, 2-tetrafluoroethane
HFA-227 1,2, 3-heptafluoropropane
The FPF values of the samples according to the invention were all determined using a Next Generation Impactor (NGI) pharmaceutical impactor from UK Copley Scientific.
Detailed Description
The foregoing summary of the invention is described in further detail below in conjunction with the detailed description. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. Various substitutions and alterations are made by those skilled in the art without departing from the spirit and scope of the invention.
Examples 1 to 5
Prescription:
Figure PCTCN2021071893-APPB-000002
the preparation method comprises the following steps:
(1) Pulverizing Indamterol maleate raw material medicine by using an airflow pulverizer to ensure that the granularity D of the raw material medicine 90 Less than 5 μm.
(2) The amounts of indacaterol maleate and adjuvants such as magnesium stearate, polyvinylpyrrolidone and polyethylene glycol in the respective examples were weighed and put into a mixing tank. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box and examined for changes in FPF values after 6 months. The measuring method comprises the following steps: testing was performed using an NGI drug impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000003
the results show that: in example 5, which does not contain magnesium stearate, the FPF value of indacaterol maleate drops significantly in the stability study.
Examples 6 to 8
Prescription:
Figure PCTCN2021071893-APPB-000004
the preparation method comprises the following steps:
(1) Respectively crushing the raw materials of indacaterol maleate, glycopyrrolate and mometasone furoate by using an airflow crusher to ensure the granularity D of the raw materials 90 Less than 5 μm.
(2) The method comprises the steps of weighing the raw material medicines of indacaterol maleate, glycopyrronium bromide and mometasone furoate and the auxiliary material magnesium stearate according to the prescription amount, and putting the raw material medicines into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
Examples 9 to 11
Prescription:
Figure PCTCN2021071893-APPB-000005
Figure PCTCN2021071893-APPB-000006
the preparation method comprises the following steps:
(1) Respectively crushing indacaterol maleate, glycopyrrolate and fluticasone propionate raw materials by using an airflow crusher to ensure that the granularity D of each raw material is equal to that of the raw material 90 Are smaller than 5 mu m.
(2) Weighing the prescription amount of indacaterol, glycopyrrolate, fluticasone propionate bulk drug and auxiliary magnesium stearate, and putting the bulk drug and the auxiliary magnesium stearate into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
Samples of examples 6 to 11 were placed in a 40℃RH 75% stability sample box and examined for changes in FPF values after 6 months. The measuring method comprises the following steps: testing was performed using an NGI drug impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000007
the results show that: in the stability studies of examples 6 to 11, the decrease in the FPF value of each active ingredient was small after 6 months of standing, and the FPF value was stable.
Examples 12 to 21
Prescription:
Figure PCTCN2021071893-APPB-000008
Figure PCTCN2021071893-APPB-000009
the preparation method comprises the following steps:
(1) Pulverizing Indamterol maleate raw material medicine by using an airflow pulverizer to ensure that the granularity D of the raw material medicine 90 Less than 5 μm.
(2) The method comprises the steps of weighing the prescription amount of indacaterol maleate raw material medicine and auxiliary material magnesium stearate, and putting the raw material medicine and the auxiliary material magnesium stearate into a mixing barrel. HFA-134a, CFC-12, HFA-227 were added in the prescribed amounts as described in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of examples 12, 13, 15, 20 were measured using an NGI pharmacia impactor at a flow rate of 15L/min. Meanwhile, the sample of the preferred embodiment is placed in a stability retention box at 40 ℃ and RH 75%, and the change condition of the FPF value after 3 months is examined.
Detection result:
Figure PCTCN2021071893-APPB-000010
the test results show that when the prescription does not contain magnesium stearate, the FPF value of the indacaterol maleate is obviously reduced when the sample is subjected to an accelerated stability test, but when the prescription contains magnesium stearate, the FPF value of the indacaterol maleate is tested when the sample is accelerated for 6 months, and the result is basically kept stable.
Examples 22 to 33
Prescription:
Figure PCTCN2021071893-APPB-000011
Figure PCTCN2021071893-APPB-000012
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on the indacaterol maleate and glycopyrrolate bulk drugs by using a jet mill to ensure that the granularity D of each bulk drug is 90 Less than 5 μm.
(2) The method comprises the steps of weighing the raw material medicines of the indacaterol maleate and the glycopyrrolate and the auxiliary material magnesium stearate, and putting the raw material medicines into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000013
the test result shows that the FPF value of the indacaterol maleate is not obviously changed by introducing the glycopyrronium bromide into a binary system of the indacaterol maleate and the magnesium stearate, and meanwhile, the FPF value of the glycopyrronium bromide is higher in a system containing the magnesium stearate.
Examples 34 to 45
Prescription:
Figure PCTCN2021071893-APPB-000014
Figure PCTCN2021071893-APPB-000015
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on indacaterol and glycopyrrolate bulk drugs by using a jet mill to ensure that the granularity D of each bulk drug is 90 Less than 5 μm.
(2) Weighing the raw materials of indacaterol and glycopyrrolate with the prescription amount and auxiliary magnesium stearate, and putting the raw materials into a mixing barrel. Oleic acid, phospholipids, absolute ethanol, tween 80, polyethylene glycol, polyvinylpyrrolidone, HFA-134a were added in the prescribed amounts as described in the above examples. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values for the samples of examples 34-45 were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000016
test results show that the FPF value of the prepared sample is not affected by adding other auxiliary materials into a ternary system containing indacaterol, glycopyrrolate and magnesium stearate.
The samples of the above examples were placed in a 40 ℃ and 75% RH stability sample box to examine the impurity changes of the products after 6 months.
Impurity HPLC content (%) detection result:
Figure PCTCN2021071893-APPB-000017
the test result shows that in a ternary system containing indacaterol, glycopyrrolate and magnesium stearate, the auxiliary materials of phospholipid, oleic acid, polyethylene glycol, polyvinylpyrrolidone and tween 80 have small influence on the chemical stability of the product.
The structural formula of glycopyrronium bromide impurity I and impurity J in the above table is:
Figure PCTCN2021071893-APPB-000018
examples 46 to 50
Prescription:
Figure PCTCN2021071893-APPB-000019
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on the indacaterol maleate and glycopyrrolate bulk drugs by using a jet mill to ensure that the granularity D of each bulk drug is 90 Less than 5 μm.
(2) The method comprises the steps of weighing the raw material medicines of the indacaterol maleate and the glycopyrrolate and the auxiliary material magnesium stearate, and putting the raw material medicines into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000020
the test result shows that in the ternary system product containing indacaterol maleate, glycopyrrolate and magnesium stearate, the FPF value of indacaterol maleate can be maintained at a higher level along with the increase of the dosage of magnesium stearate, and the FPF value of glycopyrrolate is obviously improved.
Examples 51 to 63
Prescription:
Figure PCTCN2021071893-APPB-000021
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on the indacaterol maleate, glycopyrrolate, mometasone furoate and magnesium stearate by using a jet mill to ensure that the granularity D of each raw material and auxiliary material is 90 Less than 5 μm.
(2) The method comprises the steps of weighing the raw material medicines of indacaterol maleate, glycopyrronium bromide and mometasone furoate and the auxiliary material magnesium stearate according to the prescription amount, and putting the raw material medicines into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000022
Figure PCTCN2021071893-APPB-000023
the test result shows that in the system of indacaterol maleate, glycopyrrolate and magnesium stearate, the quaternary system product formed by adding mometasone furoate has higher FPF value of each raw material medicine and smaller difference between the examples.
Examples 64 to 67
Prescription:
Figure PCTCN2021071893-APPB-000024
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on indacaterol, glycopyrrolate and fluticasone propionate bulk drugs by using a jet mill to ensure that the granularity D of each bulk drug is equal to that of each bulk drug 90 Less than 5 μm.
(2) Weighing the prescription amount of indacaterol, glycopyrrolate, fluticasone propionate bulk drug and auxiliary magnesium stearate, and putting the bulk drug and the auxiliary magnesium stearate into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000025
the test results show that in quaternary system products consisting of indacaterol, glycopyrrolate, fluticasone propionate and magnesium stearate, the FPF values of the raw materials are higher, and the difference between the examples is smaller.
Examples 68 to 70
Prescription:
Figure PCTCN2021071893-APPB-000026
the preparation method comprises the following steps:
(1) Respectively carrying out jet milling on the indacaterol acetate, the glycopyrrolate, the fluticasone propionate bulk drug and the magnesium stearate by using a jet mill to ensure that the granularity D of each bulk drug and auxiliary materials 90 Are smaller than 5 mu m.
(2) The micronized indacaterol acetate, glycopyrrolate, fluticasone propionate bulk drug and micronized auxiliary magnesium stearate with the prescription amounts are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000027
the test results show that in quaternary system products composed of indacaterol acetate, glycopyrrolate, fluticasone propionate and magnesium stearate, the FPF values of the raw materials are higher, and the difference between the examples is smaller.
Examples 71 to 74
Prescription:
Figure PCTCN2021071893-APPB-000028
the preparation method comprises the following steps:
(1) Placing indacaterol maleate, glycopyrrolate bulk drug and magnesium stearate in a three-dimensional mixer to perform three-dimensional mixing for 30 minutes, and performing jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) The micronized raw and auxiliary materials are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000029
the test results show that: different propellants have no obvious effect on the FPF value of the product, and the FPF value of each propellant preparation sample is close.
Examples 75 to 78
Prescription:
Figure PCTCN2021071893-APPB-000030
the preparation method comprises the following steps:
(1) Examples 75 and 76 were prepared by jet milling Indamterol maleate and glycopyrrolate to give a particle size D 90 Less than 5 μm. Examples 77, 78, horsesPlacing indacaterol maleate, glycopyrrolate bulk drug and magnesium stearate in a three-dimensional mixer to perform three-dimensional mixing for 30 minutes, and then performing jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) Examples 75 and 76 weighed micronized prescription amounts of drug substance and magnesium stearate, examples 77 and 78 weighed micronized prescription amounts of the mixture of raw and auxiliary materials, and put them into a mixing tank. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
Detection result:
Figure PCTCN2021071893-APPB-000031
the test results show that: after the glycopyrrolate is crushed together with indacaterol and magnesium stearate, the FPF value of the glycopyrrolate is higher than that of a sample prepared by crushing the raw materials independently.
Examples 79 to 85
Prescription:
Figure PCTCN2021071893-APPB-000032
(1) Placing indacaterol maleate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) The micronized raw and auxiliary materials are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box to examine the change in FPF values of the respective products after 6 months.
Detection result:
Figure PCTCN2021071893-APPB-000033
Figure PCTCN2021071893-APPB-000034
the test results show that: the product prepared by co-micronizing the bulk drug and the magnesium stearate is placed under an acceleration condition, the FPF value of the product is little in change, and the physical stability of the product is good.
Examples 86 to 90
Prescription:
Figure PCTCN2021071893-APPB-000035
(1) Placing indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) The micronized raw and auxiliary materials are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box to examine the change in FPF values of the respective products after 6 months.
Detection result:
Figure PCTCN2021071893-APPB-000036
the test results show that: after the mixture of the indacaterol maleate, the glycopyrrolate and the magnesium stearate is micronized, the prepared sample is placed for 6 months under the acceleration condition, the FPF value is not changed obviously, and the physical stability of the indacaterol maleate and the glycopyrrolate is good. It was also found that after the glycopyrrolate was crushed together with indacaterol and magnesium stearate, the FPF value of glycopyrrolate was higher than that of the samples prepared by crushing the bulk drugs individually.
Examples 91 to 94
Prescription:
Figure PCTCN2021071893-APPB-000037
(1) Placing indacaterol acetate or indacaterol and glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) The micronized raw and auxiliary materials are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box to examine the change in FPF values of the respective products after 6 months.
Detection result:
Figure PCTCN2021071893-APPB-000038
the test results show that: indanterol acetate or indacaterol and glycopyrrolate and magnesium stearate are mixed together for co-micronization, and the prepared product has no obvious change of FPF value in the placing process and good physical stability.
Examples 95 to 103
Prescription:
Figure PCTCN2021071893-APPB-000039
Figure PCTCN2021071893-APPB-000040
(1) Placing indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) The micronized raw and auxiliary materials are weighed and put into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box to examine the change in FPF values of the respective products after 6 months.
FPF (%) detection result:
Figure PCTCN2021071893-APPB-000041
the detection result shows that: the ratio of the raw materials to magnesium stearate in the prescription is increased, the prescription is placed for 6 months under the acceleration condition, the FPF value of the sample does not change obviously, and the physical stability of the product is good.
Examples 104 to 115
Prescription:
Figure PCTCN2021071893-APPB-000042
Figure PCTCN2021071893-APPB-000043
(1) Placing indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm; respectively carrying out jet milling on the raw materials of the glucocorticoids to ensure that the granularity reaches D 90 Less than 5 μm.
(2) Weighing the micronized raw and auxiliary materials with the prescription amount and the micronized glucocorticoid raw material medicines with the corresponding prescription amount, and putting the raw and auxiliary materials into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40℃and RH 75% stability sample box to examine the change in FPF values of the respective products after 6 months.
FPF (%) detection result:
Figure PCTCN2021071893-APPB-000044
Figure PCTCN2021071893-APPB-000045
the test results show that: after being co-micronized, indacaterol maleate, glycopyrrolate and magnesium stearate are additionally added with a glucocorticoid bulk drug, the prepared product is placed for 6 months under an acceleration condition, the FPF values of three active ingredients are not changed remarkably, and the physical stability is good.
Examples 116 to 121
Prescription:
Figure PCTCN2021071893-APPB-000046
(1) Placing indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm; respectively carrying out jet milling on the raw materials of the glucocorticoids to ensure that the granularity reaches D 90 Less than 5 μm.
(2) Weighing the micronized raw and auxiliary materials with the prescription amount and the micronized glucocorticoid raw material medicines with the corresponding prescription amount, and putting the raw and auxiliary materials into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The FPF values of the samples of the various examples were determined using an NGI pharmaceutical impactor at a flow rate of 15L/min.
FPF (%) detection result:
examples Indantrole maleate Glycopyrronium bromide Fluticasone propionate
116 50.42 47.99 48.59
117 50.89 48.37 44.62
Indantrole maleate Glycopyrronium bromide Budesonide
118 49.12 48.28 46.52
119 51.34 49.49 44.08
Indantrole maleate Glycopyrronium bromide Beclomethasone dipropionate
120 52.01 48.98 47.09
121 50.39 47.49 44.54
The test results show that: the glucocorticoid bulk drugs with different prescription amounts have no obvious influence on the FPF values of the indacaterol maleate and the glycopyrrolate, and the FPF values of the indacaterol maleate and the glycopyrrolate are higher by adopting the three compound aerosols prepared after the indacaterol maleate, the glycopyrrolate and the magnesium stearate are co-micronized.
Examples 122 to 133
Prescription:
Figure PCTCN2021071893-APPB-000047
(1) Placing indacaterol maleate, glycopyrrolate and magnesium stearate in a three-dimensional mixer for three-dimensional mixing for 30 minutes, and then carrying out jet milling on the mixture to obtain the particle size D of the milled mixture 90 Less than 5 μm.
(2) Weighing the micronized raw and auxiliary materials with the prescription amount and auxiliary materials with the corresponding prescription amount, and putting the raw and auxiliary materials into a mixing barrel. HFA-134a was dosed as specified in the examples above. The mixing drum was started to stir (stirring speed 30 rpm) for 30 minutes. If the liquid medicine is volatilized, the propellant is used for supplementing the liquid medicine to the original weight before filling. Filling, namely filling the mixed liquid medicine into an aluminum pot by Pamasol Suspension filler, and pressing a quantitative valve.
The samples of the above examples were placed in a 40 ℃ and RH 75% stability sample box and examined for FPF values and impurity changes of the respective products after 6 months.
Detection result:
Figure PCTCN2021071893-APPB-000048
Figure PCTCN2021071893-APPB-000049
the test results show that: when one of polyvinylpyrrolidone, tween 80 and oleic acid is contained in the prescription, the FPF values of the indacaterol maleate and the glycopyrrolate are improved to a certain extent. All example products were left under accelerated conditions for 6 months without significant changes in FPF values.
Impurity HPLC content (%) check:
Figure PCTCN2021071893-APPB-000050
the test results show that: examples 122 to 133 were left under accelerated conditions for 6 months, and the product impurities were slowly increased and had good chemical stability.

Claims (15)

  1. An inhalation aerosol pharmaceutical composition comprising micronized indacaterol or a pharmaceutically acceptable salt thereof, magnesium stearate and a propellant, optionally the magnesium stearate being in micronized form.
  2. The pharmaceutical composition of claim 1, wherein the micronized indacaterol pharmaceutically acceptable salt is micronized indacaterol maleate or micronized indacaterol acetate, the propellant is at least one selected from trichloro-monofluoromethane, dichloro-difluoromethane, dichloro-tetrafluoroethane, 1,2, 3-heptafluoropropane.
  3. The pharmaceutical composition according to claim 1 or 2, wherein the composition comprises the following components in percentage by weight: 0.0012 to 3 percent of micronized indacaterol or pharmaceutically acceptable salt thereof, 0.0005 to 0.162 percent of magnesium stearate and the balance of propellant.
  4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the composition further comprises at least one of micronized glycopyrrolate, micronized mometasone furoate, micronized fluticasone propionate, micronized budesonide, micronized beclomethasone propionate, each in an amount of 0.0006% to 1.5% by weight of the composition.
  5. The pharmaceutical composition of claim 4, wherein the composition comprises the following components in percentage by weight: 0.06 to 1.2 percent of micronized indacaterol maleate, 0.0006 to 1.5 percent of micronized glycopyrronium bromide, 0.005 to 1.5 percent of micronized mometasone furoate, 0.0045 to 0.081 percent of magnesium stearate and the balance of propellant.
  6. The pharmaceutical composition of claim 4, wherein the composition comprises per 10000 g: micronized indacaterol maleate 36.0g, micronized glycopyrrolate 19.5g, magnesium stearate 2.9g, balance 1, 2-tetrafluoroethane.
  7. The pharmaceutical composition of claim 4, wherein the composition comprises per 10000 g: 6.00g of micronized indacaterol maleate, 3.00g of micronized glycopyrronium bromide, 12.00g of micronized mometasone furoate, 1.05g of magnesium stearate and the balance of 1, 2-tetrafluoroethane.
  8. The pharmaceutical composition of claim 4, wherein the composition comprises per 10000 g: 30.0g of micronized indacaterol maleate, 16.0g of micronized glycopyrronium bromide, 30.0g of micronized mometasone furoate, 2.0g of magnesium stearate and the balance of 1, 2-tetrafluoroethane.
  9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising other specific excipients selected from at least one of oleic acid, phospholipids, tween-80, polyvinylpyrrolidone and polyethylene glycol.
  10. The pharmaceutical composition according to claim 9, wherein the other specific excipients are present in the composition in a weight percentage of 0.0020% to 5%.
  11. The pharmaceutical composition of claim 6, further comprising per 10000g of polyvinylpyrrolidone-K25 or tween-801.0 g, or oleic acid 0.51g.
  12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the particle size distribution of each micronised component is D 90 Less than or equal to 20 mu m, preferably D 90 Less than or equal to 10 mu m, more preferably D 90 ≤5μm。
  13. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 12, comprising the steps of:
    (1) The preparation method comprises the steps of adopting an air flow pulverizer to micronize or co-micronize each active ingredient, and then uniformly mixing the active ingredients with magnesium stearate to obtain a mixture; or mixing each active ingredient and magnesium stearate uniformly, and then performing co-micronization by adopting an air flow pulverizer to obtain a mixture;
    (2) Adding the propellant with the prescribed amount into the mixture prepared in the step (1), uniformly mixing to obtain a liquid medicine, and adding the propellant which is volatilized and lost in an equivalent way if necessary;
    (3) Filling the liquid medicine prepared in the step (2) into an aluminum pot, and pressing a quantitative valve.
  14. The method of claim 13, wherein at least one of oleic acid, phospholipid, tween-80, polyvinylpyrrolidone and polyethylene glycol is further added in step (2).
  15. The method of preparation of claim 13 or 14, wherein the active ingredient comprises indacaterol, indacaterol maleate, or indacaterol acetate; preferably, the active ingredient further comprises at least one of glycopyrronium bromide, mometasone furoate, fluticasone propionate, budesonide, beclomethasone propionate.
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