CN111467498A - Pharmaceutical composition preparation - Google Patents
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- CN111467498A CN111467498A CN202010406769.9A CN202010406769A CN111467498A CN 111467498 A CN111467498 A CN 111467498A CN 202010406769 A CN202010406769 A CN 202010406769A CN 111467498 A CN111467498 A CN 111467498A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- 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
The invention provides a pharmaceutical composition preparation, which comprises an anticholinergic drug tiotropium salt or hydrate thereof, β 2-receptor agonist arformoterol or salt thereof, and inhaled glucocorticoid fluticasone or ester derivatives thereof, wherein tiotropium bromide acts on muscarinic receptors on bronchial smooth muscle, can inhibit the cholinergic action of acetylcholine released from the tail end of parasympathetic nerve and block muscle tension, arformoterol acts on β 2-receptors on cell membranes of airway smooth muscle, reduces the release of mast cells and basophil cells and media, reduces the permeability of microvessels and increases the swinging of airway epithelial cilia, and the fluticasone is an effective anti-inflammatory drug, and three mechanisms jointly play the roles of relaxing the bronchus and anti-inflammatory effects when the three drugs are used together, so that the pharmaceutical composition preparation has a wider application range on important clinical indexes such as reducing acute exacerbation, reducing the all-cause death rate, improving the pulmonary function and improving the quality of life of patients with chronic obstructive pulmonary diseases, and the use of a triple therapy is wider.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition preparation.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a Chronic bronchitis and/or emphysema characterized by airflow obstruction that can further progress to common Chronic Diseases of Pulmonary heart disease and respiratory failure. The incidence and mortality of COPD tends to increase due to factors such as air pollution and an increase in the number of smokers.
Bronchial asthma (asthma for short) is a chronic airway disease that is characterized by airway inflammation, increased mucus secretion, and airway hyperresponsiveness. Th2 cells, eosinophils, macrophages, neutrophils and other inflammatory factors, chemokines and the like are commonly involved in the inflammatory response of allergic asthma.
Long-acting β -receptor agonists (L ABA), long-acting anticholinergic drugs (L AMA) and inhaled glucocorticoids (ICS) are the main drugs for treating COPD and asthma, GO L D has been shown to improve lung function, symptoms, health-related quality of life better and further reduce the risk of acute exacerbations by triple ICS/L ABA/L AMA therapy than by single or dual therapy.
The inhalation preparation is a drug-mechanical combined preparation, the normative operation of an inhalation device is equally important while the normative medication is adhered to for a long time, no triple preparation of tiotropium bromide, arformoterol and fluticasone exists in the prior art, patients need to learn the use of different inhalers when the three medicines are combined, and the medication compliance of the patients is poor.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a pharmaceutical composition preparation.
In order to achieve the above purpose, the solution of the invention is as follows:
a pharmaceutical composition formulation comprising an anticholinergic, β 2-receptor agonist, and an inhaled glucocorticoid.
The anticholinergic medicine comprises tiotropium salt or hydrate thereof, the administration range is 2.5-200 mu g, and the structure of the tiotropium salt is shown as a compound (I):
wherein, X-The pharmaceutically acceptable anion is more than one selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, preferably bromide.
β 2-receptor agonist includes arformoterol or its salt, the administration range is 4-200 μ g, and the arformoterol has the structure shown in compound (II):
the arformoterol salt is selected from more than one of tartrate, maleate, sulfate, hydrochloride, hydrobromide, phosphate, acetate, fumarate and citrate.
The inhaled glucocorticoid comprises fluticasone or an ester derivative thereof, the administration range is 25-500 mu g, and the structure of the ester derivative of the fluticasone is shown as a compound (III):
in the compound (III), R is C represented by the formula (a)2H5CO-or C of formula (b)4H3O-CO-
Among them, arformoterol is a long-acting β 2-receptor agonist, which relaxes airway smooth muscle, reduces the release of mast cell and basophil degranulation and mediators, decreases permeability of microvessels, and increases ciliary beat of airway epithelium by exciting β 2-receptors on the surface of airway smooth muscle and mast cell membranes.
Tiotropium bromide is a long-acting anticholinergic drug, which can inhibit the cholinergic (bronchoconstriction) action of acetylcholine released from the parasympathetic nerve terminals by binding with muscarinic receptors on bronchial smooth muscle, and can last for more than 24 hours. Tiotropium bromide is locally (broncho-) selective when administered by inhalation, thereby achieving a therapeutic effect without producing systemic anticholinergic effects. Its bronchodilatory action is essentially a local (airway) action, not a systemic one.
Inflammation is an important pathogenesis of asthma and COPD. Fluticasone furoate is a synthetic glucocorticoid trifluoride with anti-inflammatory activity. Glucocorticoids have been shown to act broadly on a variety of cells involved in the inflammatory response (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines). The furoic acid fluticasone/propionic acid fluticasone has anti-inflammatory effect in vitro and in vivo, and comprises activating glucocorticoid reaction components, inhibiting proinflammatory transcription factors, and inhibiting pulmonary eosinophilia induced by sensitized rat antigen.
Preferably, compound (i), compound (ii) and compound (iii) are provided in a form suitable for sequential administration.
Preferably, compound (i), compound (ii) and compound (iii) are provided in a form suitable for simultaneous administration.
Preferably, at least one of compound (I), compound (II) and compound (III) is formulated with a pharmaceutically acceptable carrier or excipient.
Due to the adoption of the scheme, the invention has the beneficial effects that:
the arformoterol acts on β 2-receptors on cell membranes of airway smooth muscles to relax the airway smooth muscles, the tiotropium bromide acts on muscarinic receptors on the bronchial smooth muscles to block muscle tension, the fluticasone is an effective anti-inflammatory drug, and three mechanisms jointly play roles of relaxing the bronchi and resisting inflammation when the three drugs are used together.
Detailed Description
The invention provides a pharmaceutical composition preparation, and relates to a pharmaceutical composition of a long-acting anticholinergic drug, a long-acting β 2-receptor agonist and an inhaled glucocorticoid, wherein the active ingredients comprise tiotropium bromide, arformoterol and fluticasone.
(1) Mode of administration
It is described in the patent publication CN107412229A, "combination of muscarinic receptor antagonist and β 2-adrenoceptor agonist", that the individual compounds of the pharmaceutical combination product may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations/compositions, thus compound (i), compound (ii) and compound (iii) may be formulated separately and provided in separate packages or devices, or the separately formulated components may be provided in a single package or device.
In a further aspect, the invention thus provides:
a pharmaceutical combination comprising separately provided compound (i), compound (ii) and compound (iii) for sequential or simultaneous administration.
A pharmaceutical combination comprising compound (i), compound (ii) and compound (iii) for sequential or simultaneous administration, provided separately but in the same package or device.
And a pharmaceutical combination comprising compound (I), compound (II) and compound (III) mixed with each other for simultaneous administration.
(2) Pharmaceutical preparation
The dosage of the active substance of the pharmaceutical combination is 5-500 mug, preferably 15-200 mug per dose. In order for the active substance to reach the lungs efficiently, the active substance needs to be controlled in particle size, the optimum particle size being usually 1 to 10 μm, preferably 1 to 5 μm. Is generally realized by a micronization and pulverization process of the raw material medicaments. Common micronization equipment comprises an air flow pulverizer, a high-speed ball mill, a planetary ball mill, a disc mill and the like, and the equipment can break loose active ingredients into particles with respirable size by driving particles in a container to collide with each other, extrude and rub through air flow, stirring paddles, grinding rods, grinding balls, a container wall and the like. The most common method of jet milling is to use a milling pressure of more than 0.2MPa to drive the particles to move at a high speed by the jet, so that the particles collide with each other to achieve the effect of reducing the particle size.
The invention provides an inhalation preparation of a combination of tiotropium bromide, arformoterol and fluticasone, which comprises an inhalation aerosol, an inhalation powder aerosol and an inhalation atomization liquid. The compositions may be prepared by any method well known in the art of pharmacy. Generally, the method comprises admixing the active ingredient with a carrier that constitutes one or more accessory ingredients. The compositions are generally prepared by: the active ingredient is mixed homogeneously and intimately with liquid carriers or \ and finely divided solid carriers, and the product is shaped, if necessary, to give the desired composition, for example to form agglomerated particles.
When the active ingredient of the composition is to be administered as an aerosol, it may be suspended or dissolved in a mixture of propellants, including hydrofluoroalkanes (preferably HFA227 and HFA134A, R-152A), carbon dioxide, nitrogen, propane, isobutane, where each propellant may be used in the composition alone or in admixture with other propellants. In this formulation, the preferred propellant is FA134 and or HFA 227; more preferably a mixture of HFA-134A and HFA-227, wherein the density of the mixture of HFA-134A and HFA-227 is the same as or similar to the density of the particles in which the composition is suspended: and optionally adding dispersant such as anhydrous alcohol, isopropanol, propylene glycol, etc., and surfactant such as oleic acid, polyvinylpyrrolidone, lecithin, tween, etc.
When the active ingredient of the composition is administered as an inhalation liquid (i.e., an inhalation spray), the optional solvent may be one or more of water, ethanol, propylene glycol, polyethylene glycol, glycerol, etc., or surfactant such as polyvinylpyrrolidone, oleic acid, ethyl oleate, lecithin, sorbitan fatty acid ester such as tween, etc., or osmotic pressure regulator such as glucose, sodium chloride, etc., or pH regulator such as EDTA sodium chelate, etc. may also be added.
When the active ingredient of the composition is administered as an inhaled powder spray, compound (I), compound (II) and compound (III) may be formulated with or without pharmaceutical carriers or additives, respectively.
Powder aerosols are usually provided with mono-, di-or polysaccharides such as lactose, dextran, mannitol, glucose, arabinose, fructose, ribose, mannose, sucrose, trehalose, maltose or starch, lactose is preferably used, lactose may be anhydrous lactose or α -lactose monohydrate, in addition to the active ingredient and the carrier, the powder aerosols may contain further additives such as fine lactose, magnesium stearate, calcium stearate, leucine, acetylcysteine, glycine, phospholipids, aerosil and polyethylene glycol, or the active ingredient may be provided without a carrier or additive.
(3) Inhalation device
In the patent publication CN107412229A, "combination of muscarinic receptor antagonist and β -adrenoceptor agonist", it is described that a composition suitable for administration by inhalation may be placed in a plurality of sealed dose containers provided on a pharmaceutical package placed in a suitable inhalation container, which may be a tearable, peelable or otherwise openable container of one type at a time, as is known in the art, and the dose of dry powder composition is administered by inhalation at the inhalation port of the inhalation deviceTM、DISKUSTMDevice, marketed by GlaxoSmithKline, DISKUSTMInhalation devices are described, for example, in GB 2242134A.
Dry powder inhalationThe composition may also be provided in an inhalation device as a filled reservoir, the device being provided with a metering mechanism to meter a dose of the composition from the reservoir to an inhalation passage where the metered dose can be inhaled by a patient at the inhalation port of the deviceTMDistha L ER from ScheringTMAnd Innovata C L ICKHA L ERTM。
Another delivery method for delivering a dry powder inhalable composition is to provide a metered dose of the composition in a capsule (one capsule for each dose), place the capsule within an inhalation device, and place the capsule within the inhalation device, typically by the patient, when neededTMAnd HANDIHA L ER from Boehringer IngelheimTM。
In addition, the delivery device allows for each compound, independently comprising compound (I), compound (II) and compound (III), optionally mixed with one or more excipients, to be administered simultaneously but stored independently, as described, for example, in WO 2003/061743 Al, WO 2007/012871A 1 and/or WO 2007/068896 the delivery device, independently comprising the active components, is an inhaler device having two or three drug packs in the form of peelable blister strips, each pack containing a pre-metered dose in a blister pocket disposed along its lengthTM. Allowing independent inclusion of different compoundsAnother device for the object is the DUOHA L ER from InnovataTM. The individual compounds of the combination may also be administered sequentially but stored separately as a delivery system as described in publication CN 110237373A.
The present invention will be further described with reference to the following examples.
Example 1:
the pharmaceutical composition formulation of this example was:
micronizing tiotropium bromide monohydrate raw material medicine, arformoterol tartrate and fluticasone furoate in a jet mill under the crushing pressure of 0.6MPa, wherein the particle size D50 of the obtained product is below 5 mu m.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following proportioning, one third of lactose in required amount is taken and weighed tiotropium bromide monohydrate bulk drug, arformoterol tartrate and fluticasone furoate (shown in table 1) are manually mixed in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, the mixture is manually mixed for 10min again, the three-dimensional mixer is moved for mixing for 60min, then the mixture is taken out and manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 1 Components of pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Tiotropium bromide monohydrate | 0.21% | 25μg |
Arformoterol tartrate | 0.12% | 15μg |
Fluticasone furoate | 0.82% | 100μg |
α lactose monohydrate | 98.85% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 1:
the formulation of the pharmaceutical composition of this comparative example was:
micronizing the tiotropium bromide monohydrate raw material medicine in a jet mill under the crushing pressure of 0.6MPa, wherein the particle size D50 of the obtained product is below 5 mu m.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following mixture ratio, one third of lactose in required amount and weighed tiotropium bromide monohydrate raw material medicine (shown in table 2) are manually mixed in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, the mixture is manually mixed for 10min again, the mixture is moved into a three-dimensional mixer for mixing for 60min, then the mixture is taken out and manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 2 Components of pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Tiotropium bromide monohydrate | 0.21% | 25μg |
α lactose monohydrate | 99.79% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 2:
the formulation of the pharmaceutical composition of this comparative example was:
the arformoterol tartrate raw material medicine is micronized in a jet mill, the grinding pressure is 0.6MPa, and the particle size D50 of the obtained product is below 5 mu m.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following mixture ratio, one third of lactose in required amount and weighed arformoterol tartrate raw material medicine (shown in table 3) are manually mixed in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, the mixture is manually mixed for 10min again, the mixture is moved into a three-dimensional mixer for mixing for 60min, then the mixture is taken out and manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 3 Components in pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Arformoterol tartrate | 0.12% | 15μg |
α lactose monohydrate | 99.88% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 3:
the formulation of the pharmaceutical composition of this comparative example was:
micronizing raw materials of fluticasone furoate in an air flow pulverizer, wherein the pulverization pressure is 0.6MPa, and the particle size D50 of the obtained product is below 5 μm.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following mixture ratio, one third of lactose in required amount and weighed fluticasone furoate bulk drug (shown in table 4) are manually mixed in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank and mixed by a single-arm mixer for 30min, then the mixture is taken out, then the mixture is manually mixed for 10min again, the mixture is moved into a three-dimensional mixer for mixing for 60min, then the mixture is taken out and manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 4 Components in pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Fluticasone furoate | 0.83% | 100μg |
α lactose monohydrate | 99.17% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 4:
the formulation of the pharmaceutical composition of this comparative example was:
carrying out micronization on the tiotropium bromide monohydrate raw material medicine and the arformoterol tartrate in a jet mill, wherein the grinding pressure is 0.6MPa, and the particle size D50 of the obtained product is below 5 mu m.
Where commercial lactose procured (DEF corporation L H200) was classified using a classifierThe grading feeding speed is 1-2kg/h, the feeding pressure is 0.55-0.65MPa, the grading rotating speed is controlled at 6500 and 7500rpm, and the secondary gas flow is controlled at 0.5-0.8Nm3/min。
According to the following mixture ratio, one third of lactose in required amount is taken to be manually mixed with weighed tiotropium bromide monohydrate bulk drug and arformoterol tartrate (shown in table 5) in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, is manually mixed for 10min again, is moved into a three-dimensional mixer for mixing for 60min, then is taken out, is manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 5 Components in pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Tiotropium bromide monohydrate | 0.21% | 25μg |
Arformoterol tartrate | 0.12% | 15μg |
α lactose monohydrate | 99.67% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 5:
the formulation of the pharmaceutical composition of this comparative example was:
micronizing tiotropium bromide monohydrate raw material medicine and fluticasone furoate in an air flow pulverizer, wherein the pulverizing pressure is 0.6MPa, and the particle size D50 of the obtained product is below 5 mu m.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following mixture ratio, one third of lactose in required amount is taken to be manually mixed with weighed tiotropium bromide monohydrate bulk drug and fluticasone furoate (shown in table 6) in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, is manually mixed for 10min again, is moved into a three-dimensional mixer for mixing for 60min, then is taken out, is manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 6 Components in pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Tiotropium bromide monohydrate | 0.21% | 25μg |
Fluticasone furoate | 0.82% | 100μg |
α lactose monohydrate | 98.97% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
Comparative example 6:
the formulation of the pharmaceutical composition of this comparative example was:
the raw material medicines of the arformoterol tartrate and the fluticasone furoate are micronized in an airflow pulverizer, the pulverizing pressure is 0.6MPa, and the particle size D50 of the obtained product is below 5 mu m.
Commercial lactose purchased (DEF L H200) was fractionated using a classifier at a feed rate of 1-2kg/H, a feed pressure of 0.55-0.65MPa, a classifying rotation rate of 6500-7500rpm, and a secondary gas flow rate of 0.5-0.8Nm3/min。
According to the following proportioning, one third of lactose in required amount is taken and mixed with weighed arformoterol tartrate and fluticasone furoate bulk drug (shown in table 7) manually in a mixing cup for 10min, then the rest lactose is added, the mixture is filled in a mixing tank, a single-arm mixer is used for mixing for 30min, then the mixture is taken out, is mixed for 10min manually again, is moved into a three-dimensional mixer for mixing for 60min, then is taken out, is manually mixed for 10min again, and the mixed material is collected in a sealed bag after the mixing is finished.
TABLE 7 Components in pharmaceutical compositions
Components | Ratio of occupation of | Content of single agent |
Arformoterol tartrate | 0.12% | 15μg |
Fluticasone furoate | 0.83 | 100μg |
α lactose monohydrate | 99.05% | 12mg |
The above composition is filled into blisters and the filled blisters are assembled into a sultone inhaler.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (7)
1. A pharmaceutical composition formulation characterized in that it comprises an anticholinergic agent, β 2-receptor agonist and inhaled glucocorticoid;
the anticholinergic drug comprises tiotropium salts or hydrates thereof, the administration range is 2.5-200 mu g, and the structure of the tiotropium salts is shown as a compound (I):
wherein, X-Is a pharmaceutically acceptable anion;
the β 2-receptor agonist comprises arformoterol or its salt, the administration range is 4-200 mug, and the arformoterol has the structure shown in compound (II):
the inhalation glucocorticoid comprises fluticasone or an ester derivative thereof, the administration range is 25-500 mu g, and the structure of the ester derivative of the fluticasone is shown as a compound (III):
2. the pharmaceutical composition formulation of claim 1, wherein: in compound (i), the pharmaceutically acceptable anion is selected from one or more of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
3. The pharmaceutical composition formulation of claim 1, wherein: in the compound (ii), the salt of arformoterol is one or more selected from the group consisting of tartrate, maleate, sulfate, hydrochloride, hydrobromide, phosphate, acetate, fumarate and citrate.
4. The pharmaceutical composition formulation of claim 1, wherein: in the compound (III), R is C represented by the formula (a)2H5CO-or C of formula (b)4H3O-CO-
5. The pharmaceutical composition formulation of any one of claims 1-4, wherein: said compound (i), said compound (ii) and said compound (iii) are provided in a form suitable for sequential administration.
6. The pharmaceutical composition formulation of any one of claims 1-4, wherein: said compound (I), said compound (II) and said compound (III) are provided in a form suitable for simultaneous administration.
7. The pharmaceutical composition formulation of any one of claims 1-4, wherein: at least one of said compound (I), said compound (II) and said compound (III) is formulated with a pharmaceutically acceptable carrier or excipient.
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Cited By (2)
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WO2021227868A1 (en) * | 2020-05-14 | 2021-11-18 | 王兆霖 | Pharmaceutical composition preparation |
CN115266987A (en) * | 2022-07-31 | 2022-11-01 | 浙江知一药业有限责任公司 | Pharmaceutical composition for treating respiratory diseases |
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