CN110755414A - Arformoterol tartrate aerosol and preparation method thereof - Google Patents
Arformoterol tartrate aerosol and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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 belongs to the field of biological medicine, and particularly relates to arformoterol tartrate aerosol and a preparation method thereof. The arformoterol tartrate aerosol provided by the invention is simple in preparation process, low in cost, high in liquid medicine stability and high in quality standard, and is suitable for patients.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to an arformoterol tartrate aerosol and a preparation method thereof.
Background
Arformoterol tartrate, common name: arformoterol Tartrate, molecular formula: c19H24N2O4·C4H6O6Molecular weight: 494.5, having the formula:
arformoterol tartrate inhalation formulation was developed and marketed by SUNOVION in 2006 under the trade name: BROVANA@The traditional Chinese medicine composition is mainly used for long-term maintenance treatment of bronchoconstriction of patients with Chronic Obstructive Pulmonary Disease (COPD) clinically, and comprises chronic bronchitis and emphysema. WHO reports that about 3 million people worldwide are suffering from asthma and about 25 million people die from the disease each year. The disease can occur in all age groups, the prevalence rate of children is on the rise globally in recent years, asthma is a disease with a high incidence rate in respiratory diseases, and becomes a main cause of chronic morbidity and mortality. Common chronic respiratory diseases include chronic obstructive pulmonary disease (COPD, chronic obstructive pulmonary disease for short), bronchial asthma, pulmonary infection, lung cancer, and the like. Currently, methods of treating or preventing asthma and COPD include the use of one or more long-acting bronchodilators, such as positive agonists, anticholinergics, inhaled corticosteroids, or combinations thereof.
Arformoterol is a long-acting selective adrenoceptor β 2 receptor agonist, arformoterol is an enantiomer of formoterol ((R, R), and currently marketed formoterol contains two configurations of R, R and S, and research shows that the biological activity of arformoterol ((R, R) -formoterol) is 2 times that of formoterol racemate and is 1000 times that of enantiomer ((S, S). the arformoterol is mainly characterized in that β 2 receptors on the surfaces of airway smooth muscles and hypertrophic cell membranes are stimulated to excite, so that the aims of relaxing airway smooth muscles, reducing hypertrophic cells, reducing permeability of microvessels, increasing oscillation of airway epithelial cilia and the like are achieved to relieve asthma symptoms.
In the prior art, the formulation patent US6667344 of SUNOVION company protects the prescription composition and content of the commercial arformoterol tartrate inhalation preparation, but the composition has poor stability, when in use, the liquid medicine needs to be atomized into fine mist drops by an atomizer device and then inhaled, the device is expensive, and the use and carrying are inconvenient.
Patent CN201380019244.8 discloses pharmaceutical compositions of arformoterol and fluticasone furoate formulated as nasal spray, nasal drops, compositions for inhalation in the form of respules or snuff powder, or compositions for inhalation from a Metered Dose Inhaler (MDI), Dry Powder Inhaler (DPI) or nebulizer. Patent CN201711492817.5 discloses an arformoterol tartrate powder inhalant capsule and a preparation method thereof. However, the compound preparation has complex prescription and process, needs an atomizer and a capsule type powder atomizer, is inconvenient to use and carry, has the granularity of dry powder or powder larger than the particle size of mist after the solution is atomized, and has low absorption effect and bioavailability.
Patent CN201611197925.5 discloses inhalation formulation composition of arformoterol and umeclidinium bromide, including inhalation aerosol, inhalation powder, inhalation aerosol. Patent CN201710504025.9 discloses a nebulant containing arformoterol and glycopyrronium bromide as active ingredients and a preparation method thereof. By searching the daily effective dose of umeclidinium bromide and glycopyrronium bromide, which is much higher than that of arformoterol, the bioactivity of arformoterol in unit mass is much higher than that of umeclidinium bromide and glycopyrronium bromide. In addition glycopyrrolate has a low oral bioavailability (about 5%), and rats given glycopyrrolate for 26 consecutive weeks show lenticular opacity and mild or punctate cataracts, possibly as species-specific changes. Squamous metaplasia of the larynx, eosinophilic globules in the respiratory/olfactory epithelium, hypertrophy/hyperplasia of goblet cells in the nasal cavity are also seen in rats. Not to mention umeclidinium bromide is still inferior to glycopyrronium bromide. On the premise of ensuring the stability of the arformoterol aerosol, the arformoterol in unit dose has better effect than the 2 compound preparations.
For the treatment of obstructive pulmonary diseases such as emphysema and the like, inhalation administration is an ideal administration mode. Currently, inhalation formulations, aerosols and dusts are being studied more. Compared with the three, the effect of inhaling the preparation is the best, but a special atomizer needs to be matched for use, the price is high, the carrying is not convenient, the powder aerosol needs a matched atomizer device on one hand, and the bioavailability is low and the preparation process is complex (a multi-step pulverization machine tool is needed, and dust pollution in a factory is easily caused) on the other hand.
Disclosure of Invention
The invention is based on the prior art, and aims at solving the problem that the existing arformoterol tartrate is clinically used for the long-term maintenance treatment of bronchoconstriction of patients with Chronic Obstructive Pulmonary Disease (COPD), including chronic bronchitis and emphysema, is very effective, but is used together with an atomizing device, so that inconvenience in use and high economic cost are brought to the patients, the liquid medicine cannot be effectively isolated from contacting with the outside, the stability of the liquid medicine cannot be guaranteed, and the popularization difficulty of the product is limited. The invention provides the arformoterol tartrate aerosol which has simple and stable formulation, can be carried about, is simple and convenient to use, can reduce the economic burden of patients, has high quality standard and can take effect quickly, and the method thereof.
The object of the invention can be achieved by the following measures:
an arformoterol tartrate aerosol takes arformoterol tartrate as an active ingredient, and further comprises a stabilizer, a cosolvent, a propellant, an osmotic pressure regulator, a pH value regulator and water for injection as a solvent.
Further, the concentration of the arformoterol tartrate is as follows: 7.5 ug/mL-7.9 ug/mL.
Further, the stabilizer is selected from thiourea, glycine, nicotinamide, sodium caprylate, lauryl alcohol, oleic acid and the like, and preferably at least one of thiourea, glycine and nicotinamide.
Further, the content of the stabilizer is 0.015-0.04%.
Further, the propellant is selected from at least one of tetrafluoroethane, heptafluoropropane, dimethyl ether, trichlorofluoromethane, difluoromethane, trichlorotetrafluoroethane, propane, n-butane and isobutane.
Further, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.
Further, the pH value regulator is at least one selected from acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid and sodium phosphate, and the pH value of the aerosol is 5.0-5.5.
Further, the latent solvent is ethanol or propylene glycol.
Further, the arformoterol tartrate aerosol is packaged in a multi-dose mode, and is sterilized for 10min at the temperature of 115-121 ℃ to form a quantitative aerosol.
The invention also provides a preparation method of the arformoterol tartrate aerosol, which comprises the following steps:
weighing arformoterol tartrate and a stabilizer, adding water for injection, stirring for dissolving, and adding a cosolvent;
adding an osmotic pressure regulator and a pH value regulator, stirring and dissolving, and then fixing the volume to prepare an active component concentrated solution;
filling the solution into an aerosol container, and sterilizing at high temperature;
a certain amount of propellant is pressed in by a press-fitting machine.
The invention also provides an arformoterol tartrate aerosol and a preparation method thereof, wherein the arformoterol tartrate aerosol comprises the following steps:
weighing the arformoterol tartrate and the stabilizer in the prescription amount, adding the arformoterol tartrate and the stabilizer into water for injection containing 30-40% of the injection amount, stirring and dissolving, adding the cosolvent, adding the water for injection to enable the total solution to be 80-85% of the prescription amount, adding the osmotic pressure regulator and the pH value regulator, testing the pH value and the osmotic pressure of the solution to be within a specified range, fixing the volume to obtain an active ingredient concentrated solution, filling 60mL of the liquid medicine into a 60mL aerosol bottle, installing a valve, rolling tightly, sterilizing at high temperature, and pressing a quantitative propellant to obtain the arformoterol tartrate/stabilizer.
The object of the invention can also be better achieved in that: the arformoterol tartrate aerosol contains arformoterol tartrate of 7.5-7.9 ug/mL, preferably 7.5-7.7 ug/mL. It has been found through experimentation that aerosol formulations, as opposed to inhalation formulations used with nebulizers, may not be used to the extent that the drug is not utilized, but is not so depleted that proper compensation is made in formulating the drug solution.
The object of the invention can also be better achieved in that: the stabilizer is thiourea, glycine, nicotinamide, sodium caprylate, lauryl alcohol, oleic acid and the like, and preferably thiourea, glycine and nicotinamide. According to the existing literature, arformoterol tartrate is reported to be easily oxidized, and the influence of pressure generated by a propellant on the stability of the API is considered, so that a small amount of stabilizer is introduced into the formula, and an organic small-molecule stabilizer is selected, wherein the effect is better by using the stabilizer containing an amide group. Since no stabilizer is used in the originally developed inhalation formulation, we do not know the prescribed amount of stabilizer even if we want to add it, and through a number of experiments, the prescribed amount of stabilizer was examined to be 0.015% to 0.04% (w/v), preferably 0.015% to 0.025% (w/v), and even more preferably 0.02% to 0.025% (w/v). The excessive addition of the stabilizer can generate unnecessary toxicological burden on patients, and the addition is less, so that the stabilizer cannot have good stability effect. The above dosage ranges are finally determined by long-term and accelerated stability studies.
Because the arformoterol tartrate and the stabilizer in the formula are trace/small in amount, concentration is preferably considered, the concentration ratio is 10%, 20%, 30% and 40%, and when 10% and 20% of water for injection are considered, the API can be dissolved, but lauryl alcohol and oleic acid in the stabilizer are poor in solubility, and cannot be dissolved and connected into larger oil drops under rapid stirring, so that the arformoterol tartrate and the stabilizer are not applicable. The water for injection can be completely dissolved in 30 percent and 40 percent of water for injection, and lauryl alcohol and oleic acid are not completely dissolved (have extremely fine oil drops), but the solution is relatively uniform and can meet the use requirement, and the range of 30 to 40 percent is selected in comprehensive consideration. As the arformoterol tartrate and the stabilizer are not suitable for high solution preparation temperature, the conditions of injection water solution preparation at about 40 ℃, 25 ℃ and 10 ℃ are considered, and the detection result of the liquid medicine at 40 ℃ shows that more impurities appear, and part of the impurities exceed the limit and do not meet the requirements; the liquid preparation at 25 ℃ and 10 ℃ can be carried out for acceptable time, and the impurities can be controlled; preparation BROVANA by inhalation@As can be seen from the specification, the liquid medicine can be stored for 6 weeks at 20-25 ℃, the stability is considered and the production is easily considered, and the final liquid preparation temperature is selected from 10-25 ℃, more preferably 15-25 ℃.
The object of the invention can also be better achieved in that: the osmotic pressure regulator is sodium chloride, mannitol and glucose, and the pH value regulator is a buffer system: acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid, sodium phosphate, liquid medicine and the like, and the pH value is 5.0-5.5. Considering that the osmotic pressure and the pH value change along with the change of the solution concentration, the volumes of the solutions when the osmotic pressure and the pH value are added are considered, the adjusting effects of 75%, 80%, 85% and 90% are respectively considered, and the results show that the pH value is kept unchanged in four volumes and after constant volume, but the osmotic pressure fluctuates in a range of 10mOsmol/kg in a 75% state and after constant volume, so that the proportion of 75% is abandoned, and the proportion of 80% to 85% is finally selected from the viewpoint of more convenient production and operation.
In view of production cost, the invention adopts a pressure filling method, the prepared liquid medicine is filled into an aerosol bottle at the temperature of 15-25 ℃, a valve is arranged and is tightly rolled, terminal sterilization is adopted, and specifically, the product obtained after filling is sterilized in a damp-heat sterilization cabinet for 10min at the temperature of 115-121 ℃. In the actual production, the sterility guarantee level of the terminal sterilized sterile product is that the probability of contamination of the residual microorganisms is less than or equal to 10～6The sterility assurance level of the non-terminally sterilized sterile product should at least reach a contamination probability below a 95% confidence limit<0.1 percent. Therefore, the sterility guarantee level of terminal sterilization is far higher than that of aseptic filling. Strictly sterilizing at high temperature after propellant is pressed in.
The object of the invention can also be better achieved in that: the propellant is primarily selected: tetrafluoroethane (HFA134a), heptafluoropropane (HFA227), dimethyl ether, trichlorofluoromethane, difluoromethane, trichlorotetrafluoroethane, propane, n-butane, isobutane, etc., either singly or in combination of two or more thereof, with tetrafluoroethane (HFA134a), dimethyl ether, heptafluoropropane (HFA227), propane, n-butane, isobutane being preferred. Because the invention is a solution type aerosol, the propellant is added into an aerosol bottle to form a gas-liquid two-phase with liquid, the gas phase is generated by the propellant, and the liquid phase is a homogeneous solution formed by the medicine and the propellant. The addition amount of a single bottle of the propellant is not available for reference, and is related to the volume in the bottle, the aerosol is easily heated or easily explodes after being impacted due to overlarge vapor pressure generated by the propellant and liquid medicine, and the liquid medicine in the bottle is not enough to be sprayed out of the bottle due to too little vapor pressure.
First, the change of the volume in the bottle when the selected 60mL aerosol bottle is filled with 60mL liquid medicine at the beginning of use and the last use is determined in an experiment, and a proper vapor pressure range is determined so as to meet the requirement. Taking heptafluoropropane (HFA227) as an example, according to rale's law: the vapor pressure of the solvent in the solution is proportional to its mole fraction p (0) x, (p (0) is the vapor pressure in the pure state under the same conditions, the internal volume of the bottle is V, based on the vapor pressure of heptafluoropropane at 25 ℃, the density of the liquid state and the solubility in water0And V0+60mL after the liquid medicine is completely used, only propellant is left in the empty bottle, the propellant still needs to be ejected, the maximum vapor pressure is determined, and only V is left after the liquid medicine is filled with 60mL0Space, simulating the minimum vapor pressure required, according to these 2 extreme conditions and intermediate states V0Under the condition of +30mL, the amount of heptafluoropropane (HFA227) added in each case, such as W (g), 2W (g), 3W (g) … …, is determined according to the effect of the actual aerosol (whether the aerosol can be smoothly ejected, whether the ejected aerosol is quantitatively ejected according to the preset amount of 2mL per bottle, total pressing times of each bottle and main content per pressing), the vapor pressure in the bottle in each case is calculated, and then the amount of each propellant to be added in actual need is calculated according to the pure positive vapor pressure, liquid density and solubility in water of other various propellants.
The invention finds that the actual situation has deviation of about 10-18% from the theoretical deduction in the experiment, and through analysis, the solubility of various propellants in water is considered to be different from the solubility in the liquid medicine, and the final using amount is determined according to the obtained deviation correction coefficient, as shown in the following table:
TABLE 160 mL of arformoterol tartrate aerosol with the amount of each propellant used
| Propellant | Deviation from theory | Dosage (g) |
| Tetrafluoroethane (HFA134a) | 18％ | 585 |
| Heptafluoropropane (HFA227) | 17％ | 560 |
| Dimethyl ether | 10％ | 600 |
| Propane | 12％ | 656 |
| N-butane | 15％ | 575 |
| Isobutane | 13％ | 580 |
The object of the invention can also be better achieved in that: the cosolvent is selected from ethanol or propylene glycol, so that the medicine and the propellant are more easily mixed and dissolved to form a homogeneous solution, the sprayed medicine is more easily formed into superfine fogdrops, and the using amount of the cosolvent is determined according to the shape and the granularity of the actually sprayed fogdrops in percentage by mass: 0.05-0.25%, preferably 0.05-0.15%, more preferably 0.08-0.12% (propellant is not included).
In addition, the aerosol bottle used by the invention adopts a glass bottle, and the liquid medicine is in an isolated state with the external environment after being filled in the bottle, compared with the inhalation preparation (semi-permeable material) and the inhalation capsule (the capsule shell can be eroded by the natural environment and can also destroy the stability of the content) in the prior art.
Advantageous effects
The aerosol has simple preparation process (liquid preparation), does not need to be matched with an atomizing device for use, has higher preparation uniformity and quality standard, and is more beneficial to the popularization and the use of the medicine in patients.
The product of the invention does not need to be matched with an atomizing device for use, and each bottle of 60mL single bottle (theoretically half a month usage amount) is packed in multiple doses, but different from the common multiple dose package, the bottle can be separated from the outside through a valve after being used, and the quality of the residual liquid medicine in the bottle cannot be influenced. The invention can meet the requirements that patients can use the medicine at any time and any place, particularly asthma frequently has randomness, and the medicine has higher demand for timely use, and the invention just meets the demand. In addition, the economic cost is much lower than that of inhalation preparations and inhalation capsules (atomization devices are not needed), and the method is more favorable for popularization and use in patients.
The invention relates to an arformoterol tartrate inhalation preparation and an inhalation capsule, aiming at the defects that the existing arformoterol tartrate inhalation preparation and inhalation capsule need to be matched with a special atomization device for use, are inconvenient to use and carry, have high economic cost, poor stability and the like, creatively change the preparation form, the arformoterol tartrate is taken as an active ingredient, simultaneously contains a stabilizer, a cosolvent, a propellant, an osmotic pressure regulator and a pH value regulator, and the arformoterol tartrate aerosol is developed by taking water for injection as a solvent. The invention provides the preparation method of the arformoterol tartrate aerosol, which has the advantages of simple preparation process, low cost, high liquid medicine stability and high quality standard and is suitable for patients.
Detailed Description
The first embodiment is as follows:
weighing 0.45g of arformoterol tartrate, adding the arformoterol tartrate into a 20L pre-dissolving barrel containing 18L of injection water, stirring at 15 ℃ by using a heating jacket (hot water can be introduced, and cold water can control the temperature in the tank) outside the pre-dissolving barrel to completely dissolve and clarify, weighing 9g of thiourea, adding the thiourea into the pre-dissolving barrel, and stirring at 15 ℃ to completely dissolve the thiourea. Weighing 30g of ethanol, adding the ethanol into the solution, continuously stirring at the temperature for 5min, transferring the prepared arformoterol tartrate aqueous solution into a 100L liquid preparation tank, adding water for injection at about 15 ℃ to make the total solution reach 48L, adding 455g of sodium chloride, testing the osmotic pressure to be 276mOsmol/kg, adjusting the pH value of the solution in the liquid preparation tank to be 5.0 by using acetic acid-sodium acetate buffer solution, continuously stirring in the liquid preparation tank, keeping the temperature at 15 ℃, adding 15 ℃ water for injection to fix the volume to 60L, stirring for 10min, taking 20min for the total liquid preparation, taking liquid medicine for detection, wherein the content is 99.62%, and related substances: total impurities 0.11%, maximum single impurities 0.04%. Transferring the liquid medicine to a filling station, filling 60mL of liquid medicine into a cleaned aerial fog glass bottle to obtain 968-branch arformoterol tartrate aerosol, taking a sample, placing the sample in a damp-heat sterilization cabinet ADV 09.09-12/2115 ℃, sterilizing for 10min, cooling to room temperature, and pressing 585g of tetrafluoroethane (HFA134a) into each aerial fog bottle by using a press-loading machine. And then carrying out sample detection, wherein the total pressing time of each bottle is not less than 30 times, the average main content of each pressing is 88.5 percent of the marked amount, and the medicine content in the fog particles is 56 percent of the main content of each pressing.
Example two:
weighing 0.474g of arformoterol tartrate, adding the arformoterol tartrate into a 30L pre-dissolving barrel containing 24L of injection water, stirring at 25 ℃ by using a heating jacket (hot water can be introduced, and cold water can control the temperature in the tank), completely dissolving and clarifying, weighing 24g of glycine, adding the glycine into the pre-dissolving barrel, and stirring at 25 ℃ to completely dissolve. Weighing 150g of ethanol, adding the ethanol into the solution, continuously stirring for 7min at the temperature, transferring the prepared arformoterol tartrate aqueous solution into a 100L liquid preparation tank, adding water for injection at about 25 ℃ to enable the total solution to reach 51L, adding 2680g of glucose, testing the osmotic pressure to be 282mOsmol/kg, adjusting the pH value of the solution in the liquid preparation tank to be 5.5 by using citric acid-sodium citrate buffer solution, continuously stirring in the liquid preparation tank and keeping the temperature at 25 ℃, adding 25 ℃ water for injection to be constant volume to 60L, stirring for 15min, taking 28min of the total liquid preparation time, taking liquid medicine for detection, wherein the content is 99.48 percent, and related substances: total impurity 0.15%, maximum single impurity 0.06%. And transferring the liquid medicine to a filling station, filling 60mL of liquid medicine into a cleaned aerosol glass bottle to obtain 952 arformoterol tartrate aerosol, taking a sample, placing the sample in a damp-heat sterilization cabinet ADV 09.09-12/2121 ℃, sterilizing for 10min, cooling to room temperature, and pressing 560g of heptafluoropropane (HFA227) into each aerosol bottle by using a press-loading machine. And then carrying out sample detection, wherein the total pressing time of each bottle is not less than 30 times, the average main content of each pressing is 102.8 percent of the marked amount, and the medicine content in the fog particles is 52 percent of the main content of each pressing.
Example three:
weighing 0.465g of arformoterol tartrate, adding the arformoterol tartrate into a 30L pre-dissolving barrel containing 20L of injection water, using a heating jacket (hot water can be introduced, and cold water can control the temperature in the tank) outside the pre-dissolving barrel, stirring at 20 ℃ to completely dissolve and clarify, weighing 20g of nicotinamide, adding the nicotinamide into the pre-dissolving barrel, and stirring at 20 ℃ to completely dissolve at the same temperature. Weighing 100g of propylene glycol, adding the propylene glycol into the solution, continuously stirring for 6min at the temperature, transferring the prepared arformoterol tartrate aqueous solution into a 100L liquid preparation tank, adding water for injection at about 20 ℃ to enable the total solution to reach 50L, adding 448g of sodium chloride, testing the osmotic pressure to be 288mOsmol/kg, adjusting the pH value of the solution in the liquid preparation tank to be 5.2 by using a phosphoric acid-sodium phosphate buffer solution, continuously stirring in the liquid preparation tank, keeping the temperature at 20 ℃, adding water for injection at 20 ℃ to fix the volume to 60L, stirring for 13min, taking 25min for the total liquid preparation, taking liquid medicine for detection, wherein the content is 99.55%, and related substances: total impurities 0.13%, maximum single impurities 0.05%. Transferring the liquid medicine to a filling station, filling 60mL of liquid medicine into a cleaned aerial fog glass bottle to obtain 948 arformoterol tartrate aerosol, taking a sample, placing the sample in a damp-heat sterilization cabinet ADV 09.09-12/2118 ℃, sterilizing for 10min, cooling to room temperature, and pressing 600g of dimethyl ether into each aerial fog bottle by a press-fitting machine. And then carrying out sample detection, wherein the total pressing time of each bottle is not less than 30 times, the average main content of each pressing is 99.2% of the marked amount, and the medicine content in the fog particles is 55% of the main content of each pressing.
Claims (10)
1. The arformoterol tartrate aerosol is characterized by taking arformoterol tartrate as an active ingredient, and further comprising a stabilizer, a cosolvent, a propellant, an osmotic pressure regulator and a pH value regulator, wherein water for injection is taken as a solvent.
2. Arformoterol tartrate aerosol according to claim 1, wherein the concentration of arformoterol tartrate is: 7.5 ug/mL-7.9 ug/mL.
3. Arformoterol tartrate aerosol according to claim 1, wherein said stabilizer is selected from thiourea, glycine, nicotinamide, sodium caprylate, lauryl alcohol, oleic acid and the like, preferably at least one of thiourea, glycine, nicotinamide.
4. Arformoterol tartrate aerosol according to claim 3, wherein the stabilizer is present in an amount of from 0.015 to 0.04% (w/v).
5. Arformoterol tartrate aerosol according to claim 1, wherein said propellant is selected from at least one of tetrafluoroethane, heptafluoropropane, dimethyl ether, trichloromonofluoromethane, difluoromethane, trichlorotetrafluoroethane, propane, n-butane, isobutane.
6. Arformoterol tartrate aerosol according to claim 1, wherein the tonicity modifier is selected from one or more of sodium chloride, mannitol, glucose.
7. Arformoterol tartrate aerosol according to claim 1, wherein the pH adjuster is at least one selected from acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid and sodium phosphate, and the aerosol has a pH of 5.0 to 5.5.
8. Arformoterol tartrate aerosol according to claim 1, wherein the cosolvent is ethanol or propylene glycol.
9. Arformoterol tartrate aerosol according to claim 1, wherein the arformoterol tartrate aerosol is in a multi-dose pack and is a metered dose aerosol and is sterilized at 115-121 ℃ for 10 min.
10. A preparation method of arformoterol tartrate aerosol comprises the following steps:
weighing arformoterol tartrate and a stabilizer, adding water for injection, stirring for dissolving, and adding a cosolvent;
adding an osmotic pressure regulator and a pH value regulator, stirring and dissolving, and then fixing the volume to prepare an active component concentrated solution;
filling the solution into an aerosol container, and sterilizing at high temperature;
a certain amount of propellant is pressed in by a press-fitting machine.
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