CN115267024A - Pharmaceutical composition for treating respiratory system diseases and detection method thereof - Google Patents
Pharmaceutical composition for treating respiratory system diseases and detection method thereof Download PDFInfo
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- CN115267024A CN115267024A CN202210912786.9A CN202210912786A CN115267024A CN 115267024 A CN115267024 A CN 115267024A CN 202210912786 A CN202210912786 A CN 202210912786A CN 115267024 A CN115267024 A CN 115267024A
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- arformoterol
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- pharmaceutical composition
- tiotropium bromide
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Abstract
The invention relates to a pharmaceutical composition for treating respiratory diseases and a detection method thereof. In particular, the invention relates to a method for detecting the quality of a pharmaceutical composition, wherein the pharmaceutical composition comprises the following components: 10-40 mug of tiotropium bromide or hydrate thereof, 5-30 mug of arformoterol or salt thereof and 5-40 mg of lactose, wherein the content of tiotropium bromide or hydrate thereof and arformoterol or salt thereof in the pharmaceutical composition is simultaneously measured by an HPLC method, and the operation is as follows: preparing buffer solution, mobile phase, standard stock solution, standard solution, test solution and other test solutions; providing liquid chromatography conditions; the content of tiotropium bromide and arformoterol was determined in a liquid chromatograph. The pharmaceutical composition can effectively treat respiratory diseases such as chronic obstructive pulmonary diseases, bronchial asthma and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition for treating respiratory diseases, a preparation method of the pharmaceutical composition and a quality detection method of the pharmaceutical composition. The pharmaceutical composition comprises both Tiotropium bromide (Tiotropium bromide), arformoterol (e.g. Arformoterol Tartrate), and optionally a pharmaceutically acceptable carrier, for use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease, bronchial asthma, etc.
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 involved in the inflammatory response of allergic asthma.
Some COPD or asthma patients are not effective on a single drug and are treated with a combination of different types of drugs. Long-acting beta 2-receptor agonists (LABA), long-acting anticholinergics (LAMA) and inhaled glucocorticoids (ICS) are the main drugs for the treatment of COPD and asthma. Global initiative for chronic obstructive pulmonary disease (GOLD) has shown evidence that dual therapy can improve lung function, symptoms, health-related quality of life better and further reduce the risk of acute exacerbations than single drugs.
The inhalation preparation is a drug-mechanical combination type preparation, and the standard operation of an inhalation device is also equally important while the standard medication is adhered to for a long time. There remains a need in the art for a dual formulation made from both tiotropium bromide and arformoterol.
As is known, when two medicines are combined, a patient needs to learn the use of different inhalers, and the medication compliance of the patient is poor. The inventor's prior application CN111481550A (Chinese patent application No. 202010406777.3) discloses a pharmaceutical composition prepared by mixing the above two drugs, which can advantageously realize the compliance problem in the combination of the two drugs. The pharmaceutical composition preparation provided by the invention comprises an anticholinergic medicament tiotropium salt or hydrate thereof, and beta 2-receptor agonist arformoterol or salt thereof; tiotropium bromide acts on muscarinic receptors on bronchial smooth muscle, can inhibit cholinergic action of acetylcholine released from parasympathetic nerve terminals, and blocks muscular tension; the arformoterol acts on a beta 2-receptor on an airway smooth muscle cell membrane, reduces the release of degranulation and mediators of mast cells and basophils, reduces the permeability of capillaries and increases the ciliary swing of airway epithelium; when the two medicines are combined, the two mechanisms jointly play the roles of dilating bronchus and resisting inflammation; the dual therapy has wider application range of indications on reducing acute exacerbation of patients with chronic obstructive pulmonary disease, reducing all cause mortality, improving pulmonary function of patients with chronic obstructive pulmonary disease, improving life quality and other important clinical indexes.
However, there is still a great need for improvement of the prior art by those skilled in the art.
Disclosure of Invention
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition for treating respiratory diseases, a preparation method of the pharmaceutical composition and a quality detection method of the pharmaceutical composition. The pharmaceutical composition comprises both Tiotropium bromide (Tiotropium bromide), arformoterol (e.g. Arformoterol Tartrate), and optionally a pharmaceutically acceptable carrier, for use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease, bronchial asthma, etc. It has been surprisingly found that the compositions of the present invention and/or methods related thereto exhibit superior technical results as described in the specification, and the present invention has been completed based on such findings.
To this end, the present invention provides in a first aspect a pharmaceutical composition comprising: anticholinergic agents, and beta 2-receptor agonists.
In one embodiment of the pharmaceutical composition according to the first aspect of the present invention, the anticholinergic agent comprises a tiotropium salt or hydrate thereof, administered in a single dose in the range of 2.5-200 μ g, such as 5-100 μ g, such as 10-50 μ g, the structure of the tiotropium salt being shown in compound (I):
wherein X-is a pharmaceutically acceptable anion selected from chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, preferably bromide. Preferably, the anticholinergic agent is tiotropium bromide.
In one embodiment of the pharmaceutical composition according to the first aspect of the present invention, the β 2-receptor agonist comprises arformoterol or a salt thereof in a single dose in the range of 2 to 200 μ g, for example 2.5 to 100 μ g, for example 5 to 50 μ g, and arformoterol has the structure shown in compound (II):
in one embodiment of the pharmaceutical composition according to the first aspect of the present invention, the salt of arformoterol is selected from the group consisting of tartrate, maleate, sulfate, hydrochloride, hydrobromide, phosphate, acetate, fumarate and citrate. Preferably, the β 2-receptor agonist is arformoterol tartrate.
In the present invention, 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 the β 2-receptors on the surface of airway smooth muscle and mast cell membranes.
In the present invention, tiotropium bromide is a long-acting anticholinergic drug that can inhibit the cholinergic (bronchoconstriction) action of acetylcholine released from the parasympathetic nerve terminals by binding to muscarinic receptors on bronchial smooth muscle, and can last for over 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, rather than a systemic one.
In the present invention, preferably, compound (I) and compound (II) are provided in a form suitable for sequential administration.
In the present invention, preferably, compound (I) and compound (II) are provided in a form suitable for simultaneous administration.
In the present invention, preferably, at least one of compound (I) and compound (II) is formulated with a pharmaceutically acceptable carrier or excipient.
Further, the second aspect of the present invention provides a method for quality control of a pharmaceutical composition comprising: an anticholinergic agent, a beta 2-receptor agonist and optionally a pharmaceutical excipient.
The method according to the second aspect of the invention, wherein the anticholinergic agent is a tiotropium salt or a hydrate thereof, such as the monohydrate.
The method according to the second aspect of the invention, wherein the anticholinergic is a tiotropium salt or a hydrate thereof, e.g. a monohydrate, administered in the range of 2.5-200 μ g, e.g. 5-100 μ g, e.g. 10-50 μ g at one time.
The method according to the second aspect of the invention, wherein said tiotropium salt is a salt of tiotropium with an anion selected from the group consisting of: chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, preferably bromide. The method according to the second aspect of the invention, wherein said tiotropium salt is tiotropium bromide.
The method according to the second aspect of the invention, wherein the β 2-receptor agonist is arformoterol or a salt thereof.
The method according to the second aspect of the invention, wherein the β 2-receptor agonist is arformoterol or a salt thereof, for a single administration in the range of 2 to 200 μ g, for example 2.5 to 100 μ g, for example 5 to 50 μ g.
The method according to the second aspect of the invention, wherein the salt of arformoterol is selected from the group consisting of: tartrate, maleate, sulfate, hydrochloride, hydrobromide, phosphate, acetate, fumarate, and citrate. The method according to the second aspect of the invention, wherein the salt of arformoterol is arformoterol tartrate.
The method according to the second aspect of the invention, wherein both the anticholinergic agent, the beta 2-receptor agonist are provided in a form suitable for sequential administration.
The method according to the second aspect of the invention, wherein both the anticholinergic drug and the beta 2-receptor agonist are provided in a form suitable for simultaneous administration.
The method according to the second aspect of the invention, wherein the pharmaceutical excipient is lactose.
The method according to the second aspect of the present invention, wherein the weight ratio of the anticholinergic agent, the β 2-receptor agonist, and lactose in the pharmaceutical composition is: 10-40 μ g: 5-30 μ g: 5-40 mg.
The method according to the second aspect of the present invention, wherein the weight ratio of the anticholinergic agent, the β 2-receptor agonist, and lactose in the pharmaceutical composition is: 15-35 μ g: 7.5-25 μ g: 7.5-30 mg.
The method according to the second aspect of the present invention, wherein the weight ratio of the anticholinergic agent, the β 2-receptor agonist, and lactose in the pharmaceutical composition is: 20-30 μ g: 10-20 μ g: 10-20 mg.
The method according to the second aspect of the present invention, wherein the weight ratio of the anticholinergic agent, the β 2-receptor agonist, and lactose in said pharmaceutical composition is: 25 μ g of: 15 μ g:12mg.
The method according to the second aspect of the present invention, which simultaneously measures the contents of both the anticholinergic drug and the β 2-receptor agonist in the pharmaceutical composition using the HPLC method, is performed as follows:
(1) Preparing a test solution:
10% phosphoric acid: taking 2mL of phosphoric acid, adding 15mL of purified water, and uniformly mixing;
buffer solution: precisely weighing 1.38g of anhydrous sodium dihydrogen phosphate and 1.22g of sodium decane sulfonate, adding 1L of purified water for dissolving, slowly dropwise adding 10% phosphoric acid to adjust the pH value to 3.0, and filtering;
mobile phase: precisely measuring 520mL of acetonitrile and 480mL of buffer solution, and uniformly mixing;
arformoterol tartrate standard stock solution: precisely weighing a standard arformoterol tartrate product 22 mg-250 mL in a brown volumetric flask, dissolving the standard arformoterol tartrate product by using a mobile phase, diluting the product to a scale, and shaking the product uniformly;
tiotropium bromide standard stock solution: precisely weighing a tiotropium bromide standard substance 20mg to 100mL in a brown volumetric flask, dissolving by using a mobile phase, diluting to a scale, and shaking up;
standard solution: transferring two standard stock solutions with certain volumes into the same volumetric flask, and diluting with mobile phase by the same method to obtain the product;
test solution: precisely weighing 25mg of the test sample of the pharmaceutical composition, placing the test sample in a 20ml measuring flask, adding the mobile phase for dissolving, diluting to scale, mixing uniformly, and filtering with a 0.22 mu m microporous filter membrane to obtain a test sample solution;
(2) Liquid chromatography conditions:
and (3) chromatographic column: octadecylsilane bonded silica gel column (for example, column size 150 mm. Times.4.6 mm,3 μm),
the column temperature is 45 ℃, the detection wavelength is 225nm, the sample injection amount is 50 mu L, and the flow rate is 1.7mL/min;
the theoretical plate number is not less than 3000 calculated by a tiotropium peak, and the separation degree of tiotropium and arformoterol is not less than 1.5;
(3) And (3) determination: respectively injecting the test solution or the standard solution into a liquid chromatograph, recording a chromatogram, and calculating the content of each active drug in the test solution by using an external standard method according to peak area.
The method according to the second aspect of the present invention, wherein the mobile phase used for preparing the stock solution, the standard solution and the test solution is supplemented with 0.1 to 0.15% (w/v) diisopropylamine and 0.15 to 0.2% (w/v) ethylene glycol.
The method according to the second aspect of the present invention, wherein the mobile phase used for preparing the stock solution, the standard solution and the test solution is supplemented with 0.1% (w/v) diisopropylamine and 0.15% (w/v) ethylene glycol.
The method according to the second aspect of the present invention, wherein the mobile phase used for preparing the stock solution, the standard solution and the test solution is supplemented with 0.15% (w/v) diisopropylamine and 0.2% (w/v) ethylene glycol.
The method according to the second aspect of the present invention, wherein in preparing the standard solution, 2mL of each of the two standard stock solutions is precisely transferred into the same 250mL brown volumetric flask, diluted to the mark with the mobile phase, and shaken up.
The method according to the second aspect of the present invention, wherein in preparing the standard solution, each 3mL of the two standard stock solutions are precisely transferred to the same 100mL brown volumetric flask, diluted to the scale with the mobile phase and shaken up.
According to the method of the second aspect of the invention, when preparing the standard solution, 4mL of the standard arformoterol tartrate stock solution and 3mL of the standard tiotropium bromide stock solution are precisely transferred to the same 250mL brown volumetric flask, and the mixture is diluted to the scale by adding the mobile phase and shaken up.
Detailed Description
The invention provides a pharmaceutical composition preparation, and relates to a pharmaceutical composition of a long-acting anticholinergic drug and a long-acting beta 2-receptor agonist, wherein the active ingredients comprise tiotropium bromide and arformoterol, and particularly comprise tiotropium bromide and arformoterol tartrate.
The various references mentioned herein are incorporated by reference in their entirety.
(1) Preparation of pharmaceutical compositions
The inventor's prior application CN111481550A (Chinese patent application No. 202010406777.3) discloses a pharmaceutical composition prepared by mixing the above two drugs, which can advantageously realize the compliance problem in the combination of the two drugs. In this example 1 of CN111467498a, a typical example for the preparation of a pharmaceutical composition is provided.
(2) Administration mode
Patent publication No. CN107412229a (201710221222. X) "combination of muscarinic receptor antagonist and β 2-adrenoceptor agonist" describes: the individual compounds of the pharmaceutical combination product may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations/compositions. Thus, compound (I) and compound (II) 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. The individual compounds can, if appropriate, be mixed within the same formulation and provided as a fixed pharmaceutical combination. Typically, such formulations include a pharmaceutical carrier or additive as described hereinafter, but combinations of compounds without any carrier or additive are also within the scope of the invention.
In a further aspect, the invention thus provides:
a pharmaceutical combination comprising separately provided compound (I) and compound (II) for sequential or simultaneous administration.
A pharmaceutical combination comprising compound (I) and compound (II) for sequential or simultaneous administration, provided separately but in the same package or device.
And a pharmaceutical combination comprising compound (I) and compound (II) in admixture with each other for simultaneous administration.
(3) Pharmaceutical preparation
The administration range of the anticholinergic drug tiotropium salt or hydrate thereof in the pharmaceutical composition is 2.5-200 mug; the beta 2-receptor agonist arformoterol or a salt thereof is administered in the range of 4-200 μ g. 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 tiotropium bromide and arformoterol medicine combination, which comprises an inhalation aerosol, an inhalation powder spray 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 uniformly and thoroughly with a liquid carrier or/and a finely divided solid carrier, and the product is formed, if necessary, to give the desired composition, e.g., to form aggregated 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 HFA227; 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) and compound (II) may be formulated with or without pharmaceutical carriers or additives, respectively.
The powder spray is usually carried by monosaccharide, disaccharide or polysaccharide, such as lactose, dextran, mannitol, glucose, arabinose, fructose, ribose, mannose, sucrose, trehalose, maltose or starch. Preferably, lactose is used. The lactose may be anhydrous lactose or alpha-lactose monohydrate. In addition to the active ingredient and the carrier, the powder spray may contain further additives, for example, fine lactose, magnesium stearate, calcium stearate, leucine, acetylcysteine, glycine, phospholipids, aerosil and polyethylene glycol. Alternatively, the active ingredient may be provided without carriers or additives.
(4) Inhalation device
Patent publication No. CN107412229a describes "a combination of a muscarinic receptor antagonist and a β 2-adrenoceptor agonist": compositions suitable for administration by inhalation may be provided in a plurality of sealed dose containers provided on a pharmaceutical package placed in a suitable inhalation container. The container may be a tearable, peelable or otherwise openable one at a time container, as is known in the art, and the dose of dry powder composition is administered by inhalation at the inhalation port of the inhalation device. The medicament package may take a number of different forms, for example a disc or an elongate strip. A representative inhalation device is the DISKHALERTM, DISKUSTM device sold by GlaxoSmithKline, the diskust inhalation device described in, for example, GB 2242134A.
The dry powder inhalation 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 over the inhalation port of the device. Exemplary commercially available devices of this type include TURBULAERTM by AstraZeneca, TWISTHALERTM by Schering and CLICKHALERTM by Innovata.
An additional delivery method for delivering a dry powder inhalable composition is to provide metered doses of the composition in capsules (one capsule for each dose), place the capsules within an inhalation device, typically by the patient placing the capsules within the inhalation device when required. The device has means to tear, puncture or otherwise open the capsule so that when the patient inhales on the device the dose can be brought into the patient's lungs. Commercially available examples are ROTAHERTM by GlaxoSmithKline and HANDIHALERTM by Boehringer Ingelheim.
Furthermore, the delivery device allows to independently comprise compound (I), compound (II) and compound (III), optionally mixed with one or more excipients. The individual compounds of the combination may be administered simultaneously but stored separately, for example as described in WO2003/061743Al, WO2007/012871A1 and/or WO 2007/068896. The delivery device which allows for independent inclusion of the active components is an inhaler device having two or three medicament packages in the form of peelable blister strips, each package containing a pre-metered dose in a blister pocket disposed along its length. The device has internally calibrated mechanisms, each time the device is opened, the pusher opens each elongated pocket and positions the package so that each newly exposed dose of each pocket is adjacent to a manifold that communicates with the intake of the device. When the patient inhales at the inhalation port, each dose is simultaneously carried from the bag in which it resides into the manifold and through the inhalation port into the patient's respiratory tract. Thus, each time the device is used, the patient will receive a combination therapy consisting of doses from each drug pack. An exemplary commercially available device of this type is GlaxoSmithKline ELLIPTATM. Another device that allows for independent inclusion of different compounds is DUOHALERTM from Innovata. The individual compounds of the combination may also be administered sequentially but stored separately as a delivery system as described in publication No. CN 110237373A.
Of the various operational steps described above, although specific steps may have been described in some detail or by language different from that described in the various examples of the detailed description section which follows, those skilled in the art will be able to fully summarize the above-described method steps in light of the detailed disclosure throughout this disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated herein by reference in their entirety and to the extent they do not conform to the teachings of the present invention, the statements made therein shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Due to the adoption of the scheme, the invention has the beneficial effects that:
arformoterol acts on beta 2-receptor on airway smooth muscle cell membrane to relax airway smooth muscle, tiotropium bromide acts on muscarinic receptor on bronchial smooth muscle to block muscle tension, and two mechanisms play a role in relaxing bronchus together when the two medicines are combined. The dual therapy has wider application range than single drug application in reducing acute exacerbation of patients with chronic obstructive pulmonary disease and reducing all-cause mortality, thereby improving the pulmonary function of the patients with chronic obstructive pulmonary disease and improving the quality of life and other important clinical indexes.
The method for detecting the quality of the pharmaceutical composition can simultaneously detect two compounds by using one chromatographic condition, thereby greatly improving the working efficiency.
Drawings
FIG. 1 is a typical chromatogram of an HPLC method of the present invention, in which TB is the tiotropium bromide peak and AF is the arformoterol tartrate peak.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
Example 1: preparation of pharmaceutical composition
The formulation of the pharmaceutical composition of this example: tiotropium bromide monohydrate 25 μ g, arformoterol tartrate 15 μ g, alpha-lactose monohydrate 12mg.
The above formula amounts are the amounts of the materials contained in each dose, and the charged amount of tiotropium bromide monohydrate is 500mg at the time of actual preparation.
The preparation method comprises the following steps:
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.
Commercial lactose (DEF company LH 200) was fractionated using a classifier at a feed rate of 1-2kg/h, a feed pressure of 0.55-0.65MPa, a classification speed of 6500-7500rpm, and a secondary air flow rate of 0.5-0.8Nm3/min.
Taking one third of lactose in the formula amount, tiotropium bromide monohydrate and arformoterol tartrate in the formula amount, manually mixing the lactose in a mixing cup for 10min, adding the rest lactose, filling the lactose in a mixing tank, mixing the lactose for 30min by using a single-arm mixer, taking out the lactose, manually mixing the lactose for 10min, transferring the lactose and the lactose into a three-dimensional mixer for mixing for 60min, taking out the lactose and the lactose again, manually mixing the lactose and the lactose for 10min, and collecting the mixed materials in a sealed bag after mixing to obtain the powdery pharmaceutical composition, namely, the powdery pharmaceutical composition, which is referred to as a powdery pharmaceutical composition in the embodiment.
The above composition is filled into blisters, each blister being filled with a powder containing 25 μ g of tiotropium bromide monohydrate (this amount of powder is the amount of active drug per dose), and the filled blisters are assembled into a Shu Lidie inhaler, i.e. an inhalation powder comprising both active ingredients. As is known, the weight ratio of the two active ingredients of the pharmaceutical composition of the embodiment is 25 μ g of tiotropium bromide monohydrate: arformoterol tartrate 15 μ g, the amount of the active agent in the composition cannot be changed after the two active ingredients have been properly compounded, but of course, when the powder composition is filled into blisters, the dosage of the active agent per dose can be varied by varying the amount of the filling and thus by proportionally changing the dosage of the active agent per dose, for example, on the basis of the above-mentioned powder containing tiotropium bromide monohydrate 25 μ g per dose (per blister), 80% thereof (i.e., powder containing tiotropium bromide monohydrate 20 μ g), 120% thereof (i.e., powder containing tiotropium bromide monohydrate 30 μ g), or other filling amounts can be filled per blister, which is quite easy to achieve in the formulation industry.
Three batches of powder compositions, designated as powder composition 1a, powder composition 1b, and powder composition 1c, were prepared in duplicate according to the formulation and preparation of example 1 above.
Example 2: quality test of the pharmaceutical composition
In this example, the powdery pharmaceutical composition prepared in example 1 was subjected to quality measurement by HPLC, i.e., the contents of both active ingredients in the composition were measured simultaneously by HPLC, as follows.
1. This example uses some of the following conventional instruments and reagents:
precision analytical balance, liquid chromatograph, pH meter, etc.;
acetonitrile (chromatographically pure), anhydrous sodium dihydrogen phosphate (analytically pure), sodium decane sulfonate (analytically pure), phosphoric acid (analytically pure), and the like;
and (3) standard substance: arformoterol tartrate standard, tiotropium bromide standard;
10% phosphoric acid: taking 2mL of phosphoric acid, adding 15mL of purified water, and uniformly mixing;
buffer (pH = 3.0): precisely weighing 1.38g of anhydrous sodium dihydrogen phosphate and 1.22g of sodium decane sulfonate, adding 1L of purified water for dissolving, slowly dropwise adding 10% phosphoric acid to adjust the pH value to 3.0, and filtering;
mobile phase (acetonitrile: buffer = 52): precisely weighing 520mL of acetonitrile and 480mL of buffer solution, and uniformly mixing;
standard arformoterol tartrate stock (88 μ g/mL): precisely weighing a standard arformoterol tartrate product 22 mg-250 mL in a brown volumetric flask, dissolving the standard arformoterol tartrate product by using a mobile phase, diluting the product to a scale, and shaking the product uniformly;
tiotropium bromide standard stock solution (200. Mu.g/mL): precisely weighing a tiotropium bromide standard substance 20mg to 100mL in a brown volumetric flask, dissolving with a mobile phase, diluting to a scale, and shaking up;
standard solution: precisely transferring two standard stock solutions with different volumes to the same volumetric flask according to the requirement, and diluting with a mobile phase to obtain the product; for example, 2mL of each of the two standard stock solutions are precisely transferred to the same 250mL brown volumetric flask, diluted to the mark with the mobile phase, and shaken up (the mixed standard solution contains about 0.704. Mu.g/mL of arformoterol tartrate and 1.6. Mu.g/mL of tiotropium bromide) to obtain a standard solution a; or precisely transferring 3mL of each of the two standard stock solutions into the same 100mL brown volumetric flask, adding the mobile phase to dilute to a scale, and shaking up (the mixed standard solution contains arformoterol tartrate 2.64 mu g/mL and tiotropium bromide 6 mu g/mL) to obtain a standard solution b; alternatively, 4mL of the standard stock solution of arformoterol tartrate and 3mL of the standard stock solution of tiotropium bromide were precisely transferred to the same 250mL brown volumetric flask, diluted to the scale with the mobile phase, and shaken up (the mixed standard solution contained about 1.408. Mu.g/mL of arformoterol tartrate and about 2.4. Mu.g/mL of tiotropium bromide) to obtain a standard solution c having a ratio close to that of the two components of the composition of example 1. [ separately, the two drugs were determined to be excellent in linearity in the following concentration ranges, respectively: 0.2-5.0 μ g/mL, tiotropium bromide =0.6-11.8 μ g/mL, and the concentrations of the standard solution and the sample solution can be adjusted according to needs ].
Test solution: precisely weighing 25mg of the powder composition obtained in example 1, placing the powder composition in a 20ml measuring flask, adding a mobile phase for dissolving, diluting to a scale, mixing uniformly, and filtering with a 0.22 mu m microporous filter membrane to obtain a test solution.
2. The following chromatographic conditions were used in this example:
a chromatographic column: octadecylsilane bonded silica gel column (classical Waters brand SPHERISORB ODS2 column, 150 mm. Times.4.6 mm,3 μm was used in this experiment),
the column temperature is 45 ℃, the detection wavelength is 225nm, the sample injection amount is 50 mu L, and the flow rate is 1.7mL/min.
Chromatographic performance of the HPLC method of this example: the theoretical plate number is not less than 3000 calculated by tiotropium peak, and the separation degree of tiotropium and arformoterol is not less than 1.5.
3. And (3) determination: respectively injecting the test solution or the standard solution into a liquid chromatograph, recording a chromatogram, calculating the amount of each active drug in the test solution by using a peak area by using an external standard method, and calculating according to the measurement result of the standard solution c.
FIG. 1 is a typical HPLC chromatogram (standard solution c).
4. And (3) measuring results:
using the above procedure, the amounts of the two active agents in the powder composition obtained in example 1 were determined and the relative amounts of the two active ingredients were calculated as a comparison of their theoretical formula amounts, with the results:
the powder composition 1a had an arformoterol tartrate content of 100.24%, a tiotropium bromide content of 99.81%,
the powder composition 1b had an arformoterol tartrate content of 99.57%, a tiotropium bromide content of 98.84%,
the powder composition 1c had an arformoterol tartrate content of 99.43% and a tiotropium bromide content of 100.34%.
In example 2, various stock solutions, standard solutions (c, hereinafter, unless otherwise noted, all refer to c), and test solutions prepared in actual measurement were measured by HPLC within 1 hour after preparation. It was unexpected that the arformoterol peak area decreased when the standard solution was left to stand at room temperature for 12 hours, and it was further found that the decrease was decreased with time; specifically, preparation of a standard stock solution and a standard solution of arformoterol tartrate is completed within half an hour, a liquid phase instrument is used for measuring the standard solution immediately after preparation is completed, the peak area of arformoterol in a chromatogram of the standard solution is recorded and is an initial peak area, then the standard solution is placed at room temperature for four time points of 3h, 6h, 9h and 12h, the standard solution is measured at the time points respectively, the peak areas of arformoterol in the standard solution are read and measured at different times, the percentages of the arformoterol peak areas relative to the initial peak areas at different times are calculated and are recorded as peak area residual rates, and the peak area residual rates at the four time points are respectively 99.34%, 98.13%, 97.27 and 96.55%, and the standard solution or the standard solution cannot be measured immediately after preparation is completed due to the fact that the standard solution or the standard solution cannot be measured immediately after preparation under normal conditions, and a portion on an HPLC instrument is needed for measurement. In addition, the peak area residual ratio was similarly calculated for the tiotropium peak in the standard solution, and the results showed that all the measurement time points were in the range of 99.5 to 99.8%, for example, the peak area residual ratio of the tiotropium peak at the fourth time point was 99.63%, indicating that another standard in the standard solution was stable.
To overcome the arformoterol problem, the inventors supplemented herein an example, referred to herein as example 2a, which was referenced above with respect to example 2 except that the mobile phase used to prepare the various stock, standard and test solutions was supplemented with 0.1% (w/v) diisopropylamine and 0.15% (w/v) ethylene glycol, and the chromatographic system mobile phase was unchanged without adding both; the peak area residual rates of the two substances in the standard solution at four time points are investigated, measured and calculated by the method, and the result shows that the peak area residual rates of the arformoterol and the tiotropium at the four time points are respectively in the range of 99.5-100.2%, for example, the peak area residual rates of the arformoterol peak and the tiotropium peak at the fourth time point are respectively 99.83% and 100.17%, which shows that the stability problem of the arformoterol after the two substances are simultaneously added into the solution preparation solvent is overcome; further, using a test solution prepared by adding two kinds of reagents as a formulating solvent, the initial peak areas of the two kinds of substances and the peak areas at four time points after 12 hours of standing at room temperature were measured, and as a result, the peak area residual rates of both arformoterol and tiotropium at the four time points were in the range of 99.4 to 100.0%, for example, the peak area residual rates of the arformoterol peak and tiotropium peak at the fourth time point were 99.82% and 99.64%, respectively. Further, in addition to another example, referred to herein as example 2b, which is referred to above as example 2a except that diisopropylamine is not added, peak area residual rates of the two substances in the standard solution at four time points were investigated, measured and calculated by the same method, and as a result, the peak area residual rates of tiotropium at the four time points were all in the range of 99.5 to 100.2%, e.g., the peak area residual rate of the tiotropium peak at the fourth time point was 99.87%, and the peak area residual rates of arformoterol at the four time points were 99.53%, 98.07%, 96.93%, 96.02%, respectively. Further, in addition to another example, referred to herein as example 2c, which is referred to above as example 2a except that ethylene glycol was not added, peak area residual rates of the two substances in the standard solution at the four time points were examined, measured and calculated by the same method, and as a result, the peak area residual rates of tiotropium at the four time points were all in the range of 99.9 to 100.4%, e.g., the peak area residual rate of tiotropium peak at the fourth time point was 100.16%, and the peak area residual rates of arformoterol at the four time points were 99.03%, 98.41%, 97.27%, and 96.34%, respectively. These results show that the supplemental addition of 0.1% (w/v) diisopropylamine and 0.15% (w/v) ethylene glycol to the mobile phase used to formulate the various stock solutions, standard solutions and test solutions advantageously improves the stability of arformoterol in the various test solutions. Thus, in one embodiment of the various aspects of the present invention, the mobile phase used to formulate the stock, standard and test solutions is supplemented with 0.1% (w/v) diisopropylamine and 0.15% (w/v) ethylene glycol.
Example 3: quality test of the pharmaceutical composition
The amounts of the two active agents in the powder composition obtained in example 1 were determined using the method of example 2a, and the relative amounts of the two active ingredients were calculated as a comparison of their theoretical formula amounts, with the results: the powder composition 1a had an arformoterol tartrate content of 99.84%, a tiotropium bromide content of 100.04%, the powder composition 1b had an arformoterol tartrate content of 99.46% and a tiotropium bromide content of 99.31%, and the powder composition 1c had an arformoterol tartrate content of 99.63% and a tiotropium bromide content of 98.74%.
Example 4: quality test of the pharmaceutical composition
A pharmaceutical composition having the following formulation, formulation 4a, was prepared according to the method of example 1: 20 mu g of tiotropium bromide monohydrate, 20 mu g of arformoterol tartrate and 20mg of alpha-lactose monohydrate; formulation 4b: 30 mu g of tiotropium bromide monohydrate, 10 mu g of arformoterol tartrate and 10mg of alpha-lactose monohydrate. The above formula amounts are the amounts of the materials contained in each dose, and the charged amount of tiotropium bromide monohydrate is 500mg at the time of actual preparation.
The amounts of the two active agents in the powder compositions obtained from formulations 4a and 4b were determined using the method of example 2a, and the relative amounts of the two active agents were calculated as a comparison of their theoretical formula amounts, with the results: the arformoterol tartrate content of formulation 4a was 99.75%, the tiotropium bromide content was 99.31%, and the arformoterol tartrate content of formulation 4b was 98.24%, and the tiotropium bromide content was 98.41%. The deviation of the two-substance content of the formula 4a from 100% is usually caused by the accuracy of the batch charging operation.
Example 5: quality test of the pharmaceutical composition
Referring to example 2a herein, except that 0.15% (w/v) diisopropylamine and 0.2% (w/v) ethylene glycol were additionally added to the mobile phase used for preparing various stock solutions, standard solutions and test solutions, and the remaining measurement conditions were not changed, the present measurement method was referred to as the E5 method.
The amounts of the two active agents in the powder composition obtained in example 1 were determined using the E5 method, and the relative amounts of the two active agents were calculated as a comparison of their theoretical formula amounts, with the results: the arformoterol tartrate content of 100.13% and the tiotropium bromide content of 99.78% for powder composition 1a, 99.81% and 98.61% for powder composition 1b, 99.52% and 100.14% for powder composition 1c.
The peak area residual rates of the two substances in the standard solution c prepared in example 2 at four time points were measured and calculated by using the E5 method, and as a result, the peak area residual rates of both arformoterol and tiotropium at the four time points were in the range of 99.3 to 100.1%, for example, the peak area residual rates of the arformoterol peak and the tiotropium peak at the fourth time point were 99.56% and 99.85%, respectively, indicating that the problem of the stability of arformoterol after the two substances were simultaneously added to the solution preparation solvent was overcome;
in addition, using a test sample solution of the powder composition 1a prepared by adding two reagents as a solution preparation solvent, the initial peak areas of the two substances and the peak areas at four time points after standing at room temperature for 12 hours were determined, and as a result, the peak area residual rates of both arformoterol and tiotropium at the four time points were in the range of 99.7 to 100.2%, for example, the peak area residual rates of the arformoterol peak and tiotropium at the fourth time point were 99.86% and 100.07%, respectively.
The amounts of the two active agents in the powder composition obtained in example 1 were determined using the E5 method, and the relative amounts of the two active agents were calculated as a comparison of their theoretical formula amounts, with the results: the content of arformoterol tartrate in the powder composition 1a was 99.86%, the content of tiotropium bromide was 99.94%, the content of arformoterol tartrate in the powder composition 1b was 99.63%, the content of tiotropium bromide was 99.56%, and the content of arformoterol tartrate and tiotropium bromide in the powder composition 1c was 99.49%, 99.12%.
The amounts of the two active agents in the powder compositions obtained from formulations 4a and 4b were determined using the E5 method, and the relative amounts of the two active agents were calculated as a comparison of their theoretical formula amounts, with the results: the arformoterol tartrate content of formulation 4a was 99.63%, the tiotropium bromide content was 99.46%, and the arformoterol tartrate content of formulation 4b was 98.04%, and the tiotropium bromide content was 98.67%. The deviation of the two-substance content of the formula 4a from 100% is usually caused by the accuracy of the batch charging operation.
According to the results of this example 5, the supplemental addition of 0.15% (w/v) diisopropylamine and 0.2% (w/v) ethylene glycol to the mobile phase used to formulate the various stock solutions, standard solutions and test solutions advantageously increased the stability of arformoterol in the various test solutions. Thus, in one embodiment of the various aspects of the present invention, the mobile phase used to formulate the stock, standard and test solutions is supplemented with 0.15% (w/v) diisopropylamine and 0.2% (w/v) ethylene glycol.
In one embodiment of the various aspects of the present invention in combination with the above, the mobile phase used to formulate the stock solution, standard solution and test solution is supplemented with 0.1-0.15% (w/v) diisopropylamine and 0.15-0.2% (w/v) ethylene glycol.
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 apparent to those skilled in the art that various modifications to these embodiments can be readily made, and the generic principles described 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 (10)
1. A method for detecting the quality of a pharmaceutical composition comprising: 10-40 mug of tiotropium bromide or hydrate thereof, 5-30 mug of arformoterol or salt thereof and 5-40 mg of lactose, wherein the content of tiotropium bromide or hydrate thereof and arformoterol or salt thereof in the pharmaceutical composition is simultaneously measured by an HPLC method, and the operation is as follows:
(1) Preparing a test solution:
10% phosphoric acid: taking 2mL of phosphoric acid, adding 15mL of purified water, and uniformly mixing;
buffer solution: precisely weighing 1.38g of anhydrous sodium dihydrogen phosphate and 1.22g of sodium decane sulfonate, adding 1L of purified water for dissolving, slowly dropwise adding 10% phosphoric acid to adjust the pH value to 3.0, and filtering;
mobile phase: precisely weighing 520mL of acetonitrile and 480mL of buffer solution, and uniformly mixing;
arformoterol tartrate standard stock solutions: precisely weighing a standard arformoterol tartrate product 22 mg-250 mL in a brown volumetric flask, dissolving the standard arformoterol tartrate product by using a mobile phase, diluting the product to a scale, and shaking the product uniformly;
tiotropium bromide standard stock solution: precisely weighing a tiotropium bromide standard substance 20mg to 100mL in a brown volumetric flask, dissolving with a mobile phase, diluting to a scale, and shaking up;
standard solution: transferring two standard stock solutions with certain volumes into the same volumetric flask, and diluting with mobile phase by the same method to obtain the product;
test solution: precisely weighing 25mg of the test sample of the pharmaceutical composition, placing the test sample in a 20ml measuring flask, adding the mobile phase for dissolving, diluting to scale, mixing uniformly, and filtering with a 0.22 mu m microporous filter membrane to obtain a test sample solution;
(2) Liquid chromatography conditions:
a chromatographic column: octadecylsilane chemically bonded silica gel column,
the column temperature is 45 ℃, the detection wavelength is 225nm, the sample injection amount is 50 mu L, and the flow rate is 1.7mL/min;
the theoretical plate number is not less than 3000 calculated by a tiotropium peak, and the separation degree of tiotropium and arformoterol is not less than 1.5;
(3) And (3) determination: respectively injecting the test solution or the standard solution into a liquid chromatograph, recording a chromatogram, and calculating the content of each active drug in the test solution by using an external standard method according to peak area.
2. The method according to claim 1, wherein the tiotropium bromide hydrate is a monohydrate.
3. A method according to claim 1, wherein the salt of arformoterol is selected from the group consisting of: tartrate, maleate, sulfate, hydrochloride, hydrobromide, phosphate, acetate, fumarate and citrate salts.
4. The method according to claim 1, wherein the salt of arformoterol is arformoterol tartrate.
5. The method according to claim 1, wherein the pharmaceutical composition comprises tiotropium bromide monohydrate, arformoterol tartrate, lactose in the following weight ratios: 15-35 μ g: 7.5-25 μ g: 7.5-30 mg.
6. The method according to claim 1, wherein the pharmaceutical composition comprises tiotropium bromide monohydrate, arformoterol tartrate, and lactose in the following weight ratios: 20-30 μ g: 10-20 μ g: 10-20 mg.
7. The method according to claim 1, wherein the pharmaceutical composition comprises tiotropium bromide monohydrate, arformoterol tartrate, lactose in the following weight ratios: 25 μ g:15 μ g:12mg.
8. The method according to claim 1, wherein the size of the column is 150mm x 4.6mm,3 μm.
9. The method according to claim 1, wherein the mobile phase used for formulating the stock solution, the standard solution and the test solution is supplemented with 0.1-0.15% w/v diisopropylamine and 0.15-0.2% w/v ethylene glycol.
10. The method according to claim 1, wherein the mobile phase used for preparing the stock solution, the standard solution and the test solution is supplemented with 0.1% w/v diisopropylamine and 0.15% w/v ethylene glycol; alternatively, the mobile phase used for preparing the stock solution, the standard solution and the test solution was supplemented with 0.15% w/v diisopropylamine and 0.2% w/v ethylene glycol.
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| CN202210912786.9A CN115267024B (en) | 2022-07-31 | 2022-07-31 | Pharmaceutical composition for treating respiratory diseases and detection method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201021792A (en) * | 2008-10-23 | 2010-06-16 | Sepracor Inc | Arformoterol and tiotropium compositions and methods for use |
| US20110243924A1 (en) * | 2007-02-21 | 2011-10-06 | Jorge Beleta Supervia | Novel methods |
| CN107233311A (en) * | 2017-06-27 | 2017-10-10 | 长风药业股份有限公司 | It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof |
| CN107666903A (en) * | 2015-05-01 | 2018-02-06 | 得克萨斯州大学系统董事会 | Multiple medicine fragility base composition |
| CN111481550A (en) * | 2020-05-14 | 2020-08-04 | 王兆霖 | Pharmaceutical formulation containing tiotropium bromide and arformoterol |
-
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- 2022-07-31 CN CN202210912786.9A patent/CN115267024B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110243924A1 (en) * | 2007-02-21 | 2011-10-06 | Jorge Beleta Supervia | Novel methods |
| TW201021792A (en) * | 2008-10-23 | 2010-06-16 | Sepracor Inc | Arformoterol and tiotropium compositions and methods for use |
| CN107666903A (en) * | 2015-05-01 | 2018-02-06 | 得克萨斯州大学系统董事会 | Multiple medicine fragility base composition |
| CN107233311A (en) * | 2017-06-27 | 2017-10-10 | 长风药业股份有限公司 | It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof |
| CN111481550A (en) * | 2020-05-14 | 2020-08-04 | 王兆霖 | Pharmaceutical formulation containing tiotropium bromide and arformoterol |
Non-Patent Citations (2)
| Title |
|---|
| SUNITA SULE 等: "A rapid and stability indicating RP-HPLC method for simultaneous determination of tiotropium, formoterol and ciclesonide in a dry powder inhaler", WORLD JOURNAL OF PHARMACEUTICAL RESEARCH, vol. 3, no. 4, pages 822 - 824 * |
| 张建忠;柯樱;沈佳琳;: "治疗COPD的新型支气管扩张剂的研发进展及市场情况", 上海医药, no. 19, pages 50 - 55 * |
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