CN109464429A - A kind of suction pressure quantitative aerosol pharmaceutical composition and preparation method thereof - Google Patents
A kind of suction pressure quantitative aerosol pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN109464429A CN109464429A CN201811522217.3A CN201811522217A CN109464429A CN 109464429 A CN109464429 A CN 109464429A CN 201811522217 A CN201811522217 A CN 201811522217A CN 109464429 A CN109464429 A CN 109464429A
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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
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
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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
- A61P11/06—Antiasthmatics
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Abstract
The present invention provides a kind of suction pressure quantitative aerosol pharmaceutical composition and preparation method thereof.Pharmaceutical composition of the invention includes active constituent Formoterol or its pharmaceutically acceptable salt, lactose, solvent, polyethylene glycol (PEG) and hydrofluoroalkane propellant.Pharmaceutical composition uniformity of the invention is good and physical stability is good, and administration performance is obviously improved, and has a clear superiority and good market prospects.
Description
Technical field
The invention belongs to Sucked medicine preparation technique fields, and in particular to a kind of suction pressure quantitative aerosol pharmaceutical composition
Object and preparation method thereof.
Background technique
Research finds that bronchiectasis can be relieved bronchial asthma, chronic bronchitis, asthma type brochitis, lung
Expiratory dyspnea caused by the airway obstructive diseases such as wind-puff.The drug of the pulmonary diseases such as treatment asthma mainly has following several at present
Kind: (1) β 2 receptor agonist；(2) glucocorticoid；(3) antiallergic；(4) xanthine drug；(5) anticholinergic agent.Good fortune is not
A kind of long-acting selective ' beta '3 adrenergic beta 2 receptor excitomotor of special Luo Zuowei, has certain bronchiectatic activity, Neng Gouming
It is aobvious to alleviate expiratory dyspnea caused by above-mentioned disease, and then reach therapeutic effect.
Aerosol and Foradil Aerolizer formoterol fumarate are to treat the common imbedibility respiratory tract preparation of airway obstructive disease.Aerosol is
The lotion or suspension for referring to drug containing are packaged in the pressure vessel with special quantitative valve system jointly with suitable propellant,
Content object fog-like is sprayed by the pressure of propellant when use, a kind of preparation for lung's sucking.Foradil Aerolizer formoterol fumarate
Refer to one or more of drugs, after being packed into the containers such as capsule, bubble-cap, reservoir, with dry powder after special drug delivery device administration
Form enters respiratory tract, plays a kind of pharmaceutical dosage form of whole body or local action.Aerosol be in more solution-type and suspension type and
Using propellant, and Foradil Aerolizer formoterol fumarate is then the solid containing carrier, from there are bright between two kinds of dosage forms for galenic pharmacy angle
Aobvious difference, the key of aerosol formulation are to study the uniformity and stability of lotion or suspension, the system of Foradil Aerolizer formoterol fumarate
Agent key is then the micromeritics technology between the different solid particles of research.
Often there is the problem of drug inhomogeneities after placing in aerosol suspension.The airway obstructive diseases such as asthma are can be with
Fatal disease, when carrying out maintenance therapy to such illness using suspension, this inhomogeneities just seems particularly critical.Drug
Adverse reaction can be caused more than labelled amount by feeding dosage, and drug feeds dosage and will cause administration deficiency less than labelled amount, increases
A possibility that palindromia.
The formoterol fumarate sucking product clinically used has 2 kinds: Formoterol inhalation aerosol, triumphant by Italy
West research and development are only listed in European a few countries, which obtained clinical official written reply in China in 2009, but at home without product
Listing；Foradil is developed by AstraZeneca, and in Discussion on Chinese Listed.The Formoterol sucking of Kai Xi listing
Aerosol is solution aerosol, guarantees physical stability to improve solubility, more ethyl alcohol and cosolvent is added in prescription,
The unstable chemcial property of solution-type product is caused, more harshness is required to storage condition, is only capable of saving l5 in refrigerator cold-storage
A month, room temperature 3 months.AstraZeneca exploitation Foradil use turbuhaler device, medicine storage in
It is more sensitive for humidity in storage cavern, dosage packing depend on user operating technology, homogeneity susceptible, in addition by
Complicated in turbuhaler apparatus structure, the product price is more expensive, and acceptance level is not high in low-end market.
CN1638730 discloses a kind of Formoterol pressurised metered dose inhalers (pMDIs), but it is solution type preparation, and good fortune is not
Special sieve is dissolved completely in system, and in addition said preparation needs to be added strong acid to adjust pH, and the solution type preparation is relative to the present invention
Suspension type preparation the disadvantages of there are effective pulmonary deposition is low and stability is poor, while it is obvious to container material requirement to introduce strong acid
It improves, there are the security risks such as harmful substance dissolution.
The patent of EP1400239 and US6054488 is only containing the metered dose inhalation aerosol of formoterol fumarate, the system
Agent does not contain polyethylene glycol, and preparation physical stability and dosage uniformity are lower.
Summary of the invention
Present inventor is through studying it was unexpectedly observed that the addition of polyethylene glycol and lactose can significantly improve medical fluid body
The dosage uniformity of main ingredient in being.
Therefore, in order to overcome the drawbacks of the prior art, the object of the present invention is to provide a kind of suckings comprising Formoterol
Metered dose inhaler pharmaceutical composition and preparation method thereof.
The purpose of the present invention is achieved through the following technical solutions.
On the one hand, the present invention provides a kind of suction pressure quantitative aerosol pharmaceutical composition, which includes to live
Property ingredient Formoterol or its pharmaceutically acceptable salt, lactose, solvent, polyethylene glycol (PEG) and hydrofluoroalkane propellant.
Preferably, the pharmaceutically acceptable salt is selected from formoterol fumarate and fumarate fumarate dihydrate.
Preferably, the lactose is selected from one of lactose monohydrate and Lactis Anhydrous or a variety of.
Preferably, the solvent is selected from one of glycerol, propylene glycol and ethyl alcohol or a variety of, preferably ethyl alcohol.
Preferably, the polyethylene glycol is selected from one of PEG100~2000 or a variety of, preferably PEG100,
PEG300, PEG500, PEG1000, PEG1300, PEG1500 or PEG2000, more preferably PEG1000.
Preferably, the hydrofluoroalkane propellant be selected from HFA 134a (HFA 134a) and 1,1,1,2,3,3,
One of 3- heptafluoro-propane (HFA 227) is a variety of, preferably HFA227.
Preferably, the D of the active constituent90Partial size is 0.1~10 μm, preferably 0.1~7 μm, more preferably 0.1~5 μ
m；D50Partial size is 0.1~7 μm, preferably 0.1~5 μm, more preferably 0.1~3 μm；D10Partial size is 0.1~5 μm, preferably
0.1~3 μm, more preferably 0.1~1.5 μm.
Preferably, the D of the lactose90Partial size is 0.1~30 μm, preferably 0.1~10 μm, more preferably 0.1~5 μm；
D50Partial size is 0.1~15 μm, preferably 0.1~5 μm, more preferably 0.1~3 μm；D10Partial size be 0.1~5 μm, preferably 0.1
~3 μm, more preferably 0.1~1.5 μm.
Preferably, it is 0.004~0.085% that the active constituent, which accounts for the weight percent of described pharmaceutical composition, preferably
It is 0.017%~0.085%.
Preferably, it is 0.008~0.085% that the lactose, which accounts for the weight percent of described pharmaceutical composition, preferably
0.008~0.043%, more preferably 0.008%~0.014%.
Preferably, it is 0.0%~10%, preferably 0.0% that the solvent, which accounts for the weight percent of described pharmaceutical composition,
~5%；More preferably 0.0%~2%.
Preferably, it is 0.0001%~0.1% that the polyethylene glycol, which accounts for the weight percent of described pharmaceutical composition, preferably
It is 0.001%~0.02%.
Preferably, described pharmaceutical composition can also include other low volatility components, such as other alcohol, vegetable oil have
Machine acid etc., wherein alcohol can be alkanol, such as decyl alcohol (decyl alcohol), D-sorbite, mannitol, lactitol, maltitol sugar
Alcohol, tetrahydrofuran base methanol and dipropylene glycol；Organic acid is dodecanoic acid and tetradecanoic acid and stearic saturated carboxylic acid,
Such as sorbic acid.Following component may be added in this prescription simultaneously, these ingredients are as dispersing agent for keeping suspended particulate
Not agglomeration is aerosol commonly known pharmaceutic adjuvant, such as: saccharin, Vitamin C to improve the physical stability of drug suspension
Acid, cyclamic acid, amino acid or Aspartame；Alkane such as dodecane and octadecane；Terpenes such as menthol, eucalyptol, lemon
Alkene；Sugar such as glucose, sucrose；Polysaccharide such as ethyl cellulose, dextran；Antioxidant such as butylated hydroxytoluene, Vitamin C
Acid, sodium pyrosulfite, butylated hydroxyanisol；Polymer such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone；
Amine such as ethanol amine, diethanol amine, triethanolamine；Steroid such as cholesterol, cholesteryl ester.
On the other hand, the present invention provides a kind of preparation process of above-mentioned suction pressure quantitative aerosol pharmaceutical composition, packet
Include following steps:
(a) by active constituent Formoterol or its pharmaceutically acceptable salt, lactose is micronized；
(b) the micronization product of step (a), solvent, polyethylene glycol are mixed, Zha Gai seals valve；
(c) propellant of recipe quantity is filled in the mixture of step (b) by quantitative valve.
Wherein, in the above-mentioned methods, optional that ultra sonic bath is carried out to increase suspension ability of the main ingredient in system to aerosol bottle
Energy.
The present invention also provides the preparation process of another suction pressure quantitative aerosol pharmaceutical composition, this method includes such as
Lower step:
(a) by active constituent Formoterol or its pharmaceutically acceptable salt, lactose is micronized；
(b) micronization product, solvent, the polyethylene glycol of step (a) are distributed in the propellant after pre-cooling, are mixed under low temperature
It is even, by medical fluid again quantitative separating into aerosol container.
In the above-mentioned methods, in step (b), the low temperature is -80 DEG C~-60 DEG C.
When Formoterol and lactose, inhalable suspension type pressure is especially made with the lactose close with Formoterol partial size
When quantitative aerosol pharmaceutical composition, medicine of the Formoterol in suspension type metered dose inhaler system can be effectively improved
Object stability and content uniformity, this may be that lactose molecule and Formoterol drug microparticles are electrically charged mutual in suspending system
It influences, changes the physicochemical properties of Formoterol particle, be easier Formoterol particle molten with propellant, other auxiliary materials
The suspension of agent composition is faster uniformly mixed, to keep preferably suspension stability, while also being improved drug and is made
The content uniformity of used time, it can be ensured that patient takes the photograph the consistency of pharmaceutical quantities during entire medication.
The invention has the benefit that
The present invention is by being added suitable auxiliary material and technique, so that product obtains preferable preparation uniformity and physically stable
Property, administration performance is obviously improved, has a clear superiority and good market prospects.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.
Well known mechanical crushing method can be used in present invention micronization.Mechanical crushing method refers to the method point using fluid energy mill
Active constituent Formoterol and pharmaceutic adjuvant lactose required partial size is not ground into.
Micromill process: suction (air inlet) pressure 8bar crushes pressure 12bar, charging rate 30g/h, after the completion of crushing
Powder is repeatedly crushed again after whole micro mists in collection receiving warehouse, until D90Partial size, D50Partial size and D10Partial size reaches required model
It encloses.
D90Partial size refers to that the cumulative particle sizes percentile an of sample reaches particle size parameters corresponding when 90%.
D50Partial size refers to that the cumulative particle sizes percentile an of sample reaches particle size parameters corresponding when 50%.
D10Partial size refers to that the cumulative particle sizes percentile an of sample reaches particle size parameters corresponding when 10%.
Examples 1 to 7: aerosol prepares (100 bottles)
Lactis Anhydrous used is micro mist to D90Partial size is 3.5 μm, D50Partial size is 1.8 μm of D simultaneously10The cream that partial size is 0.7 μm
Sugar, active constituent additional amount are 0.017%, and lactose additional amount is 0.014%, and solvent is dehydrated alcohol (0.5%) He Juyi bis-
Alcohol 1000 (0.02%), propellant HFA227ea, active constituent used are micro mist to D90Partial size is 0.1~10 μm, D50Partial size
It is 0.1~7 μm while D10The fumarate fumarate dihydrate that partial size is 0.1~5 μm, as shown in table 1.Using different size
Quantitative valve system (for 50 μ l) aerosol obtained to reach required often to press dosage.
1. aerosol of table prepares Examples 1 to 7 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol and Lactis Anhydrous, liquid is added
HFA227ea is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then (50 μ l are sealing-in quantitative valve system
Example) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.Intake performance measurement is carried out to embodiment 1-7, the results showed that
In addition to embodiment 6 and 7, remaining embodiment sample has good effective pulmonary deposition, and NGI-FPF is 38% or more, while DCU
Measurement result also all meets States Pharmacopoeia specifications.
Embodiment 8~14: aerosol prepares (100 bottles)
Lactose monohydrate used is micro mist to D90Partial size is 0.1~30 μm, D50Partial size is 0.1~15 μm of D simultaneously10Partial size is
0.1~5 μm of lactose, active constituent additional amount are 0.015%, and lactose additional amount is 0.012%, and solvent is dehydrated alcohol
(0.5%) and cetomacrogol 1000 (0.02%), propellant HFA134a, active constituent used are micro mist to D90Partial size is 4.2
μm、D50Partial size is 1.6 μm of D simultaneously10The fumarate fumarate dihydrate that partial size is 0.5 μm, as shown in table 2.Using different rule
The quantitative valve system (for 63 μ l) of lattice aerosol obtained to reach required often to press dosage.
2. aerosol of table prepares embodiment 8~14 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol and lactose monohydrate, liquid is added
HFA134a is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then sealing-in quantitative valve system (for 63 μ l),
To obtain the final product.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.Intake performance measurement is carried out to embodiment 8-14, the results showed that remove
Outside embodiment 13 and 14, remaining embodiment sample has good effective pulmonary deposition, and NGI-FPF is 38% or more, while DCU
Measurement result also all meets States Pharmacopoeia specifications.
Embodiment 15~20: aerosol prepares (100 bottles)
Lactose monohydrate used is micro mist to D90Partial size is 3.5 μm, D50Partial size is 1.8 μm of D simultaneously10The cream that partial size is 0.7 μm
Sugar, active constituent additional amount be 0.004%~0.085%, lactose additional amount be 0.008%~0.085%, active constituent with plus
The weight ratio for entering lactose is 1:0.1~1:20, and solvent is dehydrated alcohol (0.5%) and cetomacrogol 1000 (0.02%), is cast
Agent is HFA227ea, active constituent used be micro mist to D90 partial size be 4.5 μm, D50 partial size be 1.9 μm simultaneously D10 partial size be
0.6 μm of fumarate fumarate dihydrate, as shown in table 3.Made using the quantitative valve system (for 50 μ l) of different size
Aerosol obtained can reach required and often press dosage.
3. aerosol of table prepares embodiment 15~20 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol and lactose monohydrate, liquid is added
HFA227ea is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then (50 μ l are sealing-in quantitative valve system
Example) to get.From embodiment 15~20, dosage, which is followed successively by, often to be pressed containing 3 μ g of Formoterol, 60 μ g, 12 μ g, 12 μ g, 3 μ g and 60 μ
G 170 is pressed totally.Intake performance measurement is carried out to embodiment 15-20, the results showed that in addition to embodiment 15, remaining embodiment sample
There is good effective pulmonary deposition, NGI-FPF is 38% or more, while DCU measurement result also all meets States Pharmacopoeia specifications.
Embodiment 21~26: aerosol prepares (100 bottles)
Lactose monohydrate used be micro mist to D90 partial size be 3.6 μm, D50 partial size be 1.7 μm simultaneously D10 partial size be 0.6 μm
Lactose, active constituent additional amount are 0.015%~0.016%, and lactose additional amount is 0.012%~0.013%, are dehydrated alcohol
(0.0%~10%) and cetomacrogol 1000 (0.02%), propellant HFA134a, active constituent used are micro mist to D90
Diameter is 4.2 μm, D50 partial size is 1.6 μm of fumarate fumarate dihydrate that D10 partial size is 0.5 μm simultaneously, as shown in table 4.It adopts
Enable aerosol obtained to reach required with the quantitative valve system (for 63 μ l) of different size and often presses dosage.
4. aerosol of table prepares embodiment 21~26 (100 bottles)
The preparation process of embodiment 21: recipe quantity Formoterol, lactose monohydrate, polyethylene glycol are added in aerosol container,
Sealing-in quantitative valve system (for 63 μ l), then by the HFA134a of recipe quantity be pressed into the aerosol container of packaged valve to get.
Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.
The preparation process of embodiment 22~26: being added ethyl alcohol and polyethylene glycol for recipe quantity Formoterol and lactose monohydrate,
Liquid HFA134a is added, is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then sealing-in quantitative valve system (63
For μ l) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.Intake performance measurement, knot are carried out to embodiment 21-26
Fruit shows: the sample of embodiment 21-26 has good effective pulmonary deposition, and NGI-FPF is 38% or more；DCU measurement simultaneously
As a result also all meet States Pharmacopoeia specifications.
Embodiment 27~32: aerosol prepares (100 bottles)
Lactose monohydrate used is micro mist to D90Partial size is 3.5 μm, D50Partial size is 1.8 μm of D simultaneously10The cream that partial size is 0.7 μm
Sugar, active constituent additional amount are 0.017%, and lactose additional amount is 0.014%, and solvent is dehydrated alcohol (1%) and polyethylene glycol
1000 (0.0001%~0.1%), propellant HFA227ea, active constituent used are micro mist to D90Partial size is 4.5 μm, D50
Partial size is 1.9 μm of D simultaneously10The fumarate fumarate dihydrate that partial size is 0.6 μm, as shown in table 5.Using determining for different size
Amount valve system (for 50 μ l) aerosol obtained to reach required often to press dosage.
5. aerosol of table prepares embodiment 27~32 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol and lactose monohydrate, liquid is added
HFA227ea is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then (50 μ l are sealing-in quantitative valve system
Example) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.Intake performance measurement is carried out to embodiment 27-32, as a result table
It is bright: 27~32 sample NGI-FPF of embodiment 38% hereinafter, but DCU measurement result all meet States Pharmacopoeia specifications.
Embodiment 33~35: aerosol prepares (100 bottles)
Lactose monohydrate used is micro mist to D90Partial size is 3.5 μm, D50Partial size is 1.8 μm of D simultaneously10The cream that partial size is 0.7 μm
Sugar, active constituent additional amount are 0.017%, and lactose additional amount is 0.014%, and solvent is dehydrated alcohol (1%) and polyethylene glycol
1000 (0.0001%~0.1%), propellant HFA227ea, active constituent used are micro mist to D90Partial size is 4.5 μm, D50
Partial size is 1.9 μm of D simultaneously10In addition the fumarate fumarate dihydrate that partial size is 0.6 μm adds 0.01% sorbic acid or ten
Dioxane or polyvinylpyrrolidone, as shown in table 6.Made using the quantitative valve system (for 50 μ l) of different size obtained
Aerosol can reach required and often press dosage.
6. aerosol of table prepares embodiment 33~35 (100 bottles)
Preparation process: recipe quantity Formoterol, lactose monohydrate, sorbic acid (or dodecane or polyvinylpyrrolidone) are added
Enter ethyl alcohol and polyethylene glycol, liquid HFA227ea is added, is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then
Sealing-in quantitative valve system (for 50 μ l) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.To embodiment 33-35
Carry out intake performance measurement, the results showed that the sample of embodiment 33-35 has good effective pulmonary deposition, and NGI-FPF exists
38% or more；DCU measurement result also all meets States Pharmacopoeia specifications simultaneously.
Embodiment 36~39: aerosol prepares (100 bottles)
Lactis Anhydrous used be micro mist to D90 partial size be 3.7 μm, D50 partial size be 1.6 μm simultaneously D10 partial size be 0.5 μm
Lactose, active constituent additional amount are 0.013~0.015%, and Lactis Anhydrous additional amount is 0.010~0.012%, and solvent is anhydrous
Ethyl alcohol (1%) and cetomacrogol 1000 (do not add or 0.02%), propellant is HFA134a or HFA227ea, activity used at
It is divided into the two hydration fumaric acid Fu Mote that micro mist to D90 partial size is 4.2 μm, D50 partial size is 1.6 μm while D10 partial size is 0.5 μm
In addition sieve adds prescription ratio 7 × 10-7~9 × 10-7Polyvinylpyrrolidone K25, as shown in table 7.Using different size
Quantitative valve system (for 63 μ l) aerosol obtained to reach required often to press dosage.
7. aerosol of table prepares embodiment 36~39 (100 bottles)
Preparation process: ethyl alcohol and poly- second two is added in recipe quantity Formoterol, Lactis Anhydrous, polyvinylpyrrolidone K25
Alcohol is added liquid HFA134a or HFA227ea, is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then sealing-in is fixed
Measure valve system (for 63 μ l) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.The result shows that embodiment 37,39
Sample have good effective pulmonary deposition, NGI-FPF is more much higher than embodiment 36,38, while the DCU of embodiment 36,38
Measurement result does not meet States Pharmacopoeia specifications, and the DCU measurement result of embodiment 37,39 complies fully with States Pharmacopoeia specifications, it was demonstrated that addition PEG can
To effectively improve preparation uniformity and physical stability.
Embodiment 40: aerosol prepares (100 bottles)
Solvent for use is dehydrated alcohol (1%) and cetomacrogol 1000 (0.02%), propellant HFA134a, work used
Property ingredient be micro mist to D90 partial size be 4.2 μm, D50 partial size be 1.6 μm simultaneously D10 partial size be 0.5 μm two hydration fumaric acid good fortune
Mo Teluo, active constituent additional amount are 0.015%, in addition add prescription ratio 7 × 10-7~9 × 10-7Polyvinylpyrrolidine
Ketone K25, as shown in table 8.Using the quantitative valve system (for 63 μ l) of different size aerosol obtained is reached
Required often presses dosage.
8. aerosol of table prepares embodiment 40 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol, polyvinylpyrrolidone K25, liquid is added
State HFA134a is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then (63 μ l are sealing-in quantitative valve system
Example) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.The result shows that the sample NGI-FPF of embodiment 40 is 38%
Below；But DCU measurement result meets States Pharmacopoeia specifications.
Aerosol formulation process example 41 and 42 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in the corresponding recipe quantity Formoterol of embodiment 4 and Lactis Anhydrous, is added
Enter liquid HFA134a or HFA227ea, is stirred at -30 DEG C and -100 DEG C of low temperature of low temperature, according to dosage tinning, then sealing-in are quantitative
Valve system (for 50 μ l) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.The result shows that having in embodiment 41
When gymnastics is made, since temperature is already close to propellant boiling point, propellant volatilization is serious when filling, directly results in sample size
It is abnormal higher；Embodiment 42 when specific operation, since temperature is already close to propellant fusing point, liquid medicine flow is deteriorated, can not
Guarantee the good homogeneity of medical fluid.
Embodiment 43~48: aerosol prepares (100 bottles)
Lactose monohydrate used is micro mist to D90Partial size is 3.5 μm, D50Partial size is 1.8 μm of D simultaneously10The cream that partial size is 0.7 μm
Sugar, active constituent additional amount are 0.017%, and lactose additional amount is 0.014%, and solvent is dehydrated alcohol (1%) and polyethylene glycol
(0.0001%~0.1%), propellant HFA227ea, active constituent used are micro mist to D90Partial size is 4.5 μm, D50Partial size
It is 1.9 μm while D10The fumarate fumarate dihydrate that partial size is 0.6 μm, as shown in table 9.Using the proportional valve of different size
Door system (for 50 μ l) aerosol obtained to reach required often to press dosage.
9. aerosol of table prepares embodiment 43~48 (100 bottles)
Preparation process: ethyl alcohol and polyethylene glycol is added in recipe quantity Formoterol and lactose monohydrate, liquid HFA134a is added
Or HFA227ea, it is stirred under low temperature (- 80 DEG C~-60 DEG C), according to dosage tinning, then (50 μ l are sealing-in quantitative valve system
Example) to get.Dosage is often to press 12 μ g of Formoterol, totally 170 is pressed.Intake performance measurement is carried out to embodiment 43-48, as a result table
It is bright: 43~48 sample NGI-FPF of embodiment 38% hereinafter, but DCU measurement result all meet States Pharmacopoeia specifications.
Embodiment 49
Choose embodiment 3,4,5,6,7,10,11,12,13,14,15,16,17,18,20,21,23,24,27,29,30,
31,32,36,37,38,39,40,43,44,45,46,47,48 samples prepared carry out intake performance measurement respectively, comprising: (1)
Aerodynamic size measurement is carried out to sample using Cascade Impactor of new generation (NGI), with the effective pulmonary deposition of clear drug
Rate (NGI-FPF)；(2) dosage delivered homogeneity (DCU) measurement is carried out to sample using single dose sampler.Experimental result is such as
Shown in table 10:
Interpretation of result:
1, the NGI-FPF of 3,4,5,10,11,12,16,17,18,20,21,23,24,29,30 sample of embodiment exists
38% or more, it was demonstrated that sample has good effective pulmonary deposition.The DCU measurement result of 15 embodiment samples is whole simultaneously
Meet States Pharmacopoeia specifications (according to 2015 editions standards of Chinese Pharmacopoeia, that is, to meet the one of following conditions, can be judged to meet regulation: (1) 10
In a measurement result, no less than 9 measured values between the 75%~125% of average value, and all average value 65%~
Between 135%；In (2) 10 measurement results, if 2~3 measured values exceed 75%~125%, but all in average value
Between 65%~135%, 2 bottles of test sample measurements are separately taken.If in 30 dosage, the measured value beyond 75%~125% is no more than 3
It is a, and all between the 65%~135% of average value), it was demonstrated that have good preparation uniform by the sample that the present invention prepares
Property and physical stability.
2, the NGI-FPF of 15 sample of embodiment is lower than 38%, it was demonstrated that effective pulmonary deposition of sample is undesirable, embodiment 17
NGI-FPF with 18 samples is 38% or more, it was demonstrated that sample has good effective pulmonary deposition.3 groups of embodiment samples simultaneously
Though DCU measurement result meet States Pharmacopoeia specifications and (according to 2015 editions standards of Chinese Pharmacopoeia, that is, meet the one of following conditions, can sentence
To meet regulation: (1) in 10 measurement results, no less than 9 measured values are between the 75%~125% of average value, and whole
Between the 65%~135% of average value；In (2) 10 measurement results, if 2~3 measured values exceed 75%~125%, but
All between the 65%~135% of average value, 2 bottles of test sample measurements are separately taken.If in 30 dosage, exceeding 75%~125%
Measured value no more than 3, and all between the 65%~135% of average value), but still have 1 value the 65% of average value
Between~135%, the SD value that embodiment 15,17 and 18 prepares 10 dosage delivered data of sample is calculated, it is seen that SD is high respectively
In 0.25 μ g, 1.0 μ g and 1.0 μ g, it was demonstrated that three embodiment sample preparation uniformities and physical stability are not ideal enough, compare it
His embodiment sample is better than model as a result, know embodiment effect of the weight ratio range of API/ lactose in 1:0.1~1:0.8
It is trapped among embodiment when 1:1~1:5, is more better than embodiment of the range in 1:5~1:20.
3, the NGI-FPF of embodiment 6,7,13 and 14 samples is lower than 38%, it was demonstrated that effective pulmonary deposition of sample is undesirable.
Respectively compared with embodiment 4 and 11, it is known that with the increase of the partial size of API/ lactose, NGI-FPF is gradually reduced.The partial size of API
Range 4 effect of embodiment that D90 is 0.1~5 μm, D50 is 0.1~3 μm and D10 is 0.1~1.5 μm better than D90 be 0.1~
7 μm, the embodiment 6 that D50 is 0.1~5 μm and D10 partial size is 0.1~3 μm are more 0.1~10 μm better than D90, D50 0.1
The embodiment 7 that~7 μm and D10 partial size are 0.1~5 μm.The particle size range of lactose is D90 is 0.1~5 μm, D50 is 0.1~3 μm
11 effect of embodiment for being 0.1~1.5 μm with D10 better than D90 be 0.1~10 μm, D50 is 0.1~5 μm and D10 partial size is 0.1
~3 μm of embodiment 13, more better than the reality that D90 is 0.1~30 μm, D50 is 0.1~15 μm and D10 partial size is 0.1~5 μm
Apply example 14.
4, the NGI-FPF of embodiment 27,31 and 32 samples is lower than 38%, it was demonstrated that effective pulmonary deposition of sample is undesirable.
Though the DCU measurement result of the embodiment sample meets States Pharmacopoeia specifications and (according to 2015 editions standards of Chinese Pharmacopoeia, that is, meets following simultaneously
The one of condition can be judged to meet regulation: (1) in 10 measurement results, no less than 9 measured values average value 75%~
Between 125%, and all between the 65%~135% of average value；In (2) 10 measurement results, if 2~3 measured values are super
Out 75%~125%, but all between the 65%~135% of average value, separately take 2 bottles of test samples measurements.If in 30 dosage,
Beyond 75%~125% measured value no more than 3, and all between the 65%~135% of average value), but still have 1 value
Between the 65%~135% of average value, the SD that embodiment 27,31 and 32 prepares 10 dosage delivered data of sample is calculated
Value, it is seen that SD is higher than 1.0 μ g, it was demonstrated that the embodiment sample preparation uniformity and physical stability are not ideal enough, compare other realities
Apply a sample result, it is known that embodiment effect when PEG content is below 0.02% is better than 0.02% or more embodiment, simultaneously
The embodiment effect of PEG is not added than adding the embodiment of PEG poor.
5, the NGI-FPF of 43~48 sample of embodiment is lower than 38%, it was demonstrated that effective pulmonary deposition of sample is undesirable.Simultaneously
Though the DCU measurement result of the embodiment sample meets States Pharmacopoeia specifications and (according to 2015 editions standards of Chinese Pharmacopoeia, that is, meets following conditions
One, can be judged to meet regulation: (1) in 10 measurement results, no less than 9 measured values are the 75%~125% of average value
Between, and all between the 65%~135% of average value；In (2) 10 measurement results, if 2~3 measured values exceed 75%
~125%, but all between the 65%~135% of average value, separately take 2 bottles of test sample measurements.If exceeding in 30 dosage
75%~125% measured value no more than 3, and all between the 65%~135% of average value), but still have 1 value flat
Between the 65%~135% of mean value, the SD value that embodiment 43~48 prepares 10 dosage delivered data of sample is calculated, it is seen that SD
Higher than 1.0 μ g, it was demonstrated that embodiment sample preparation uniformity and physical stability are not ideal enough, 4 sample result of comparative example, can
Know cetomacrogol 1000 effect better than other types.
6, the NGI-FPF of the sample of embodiment 37 and 39 is apparently higher than embodiment 36 and 38, illustrates the system of embodiment 37 and 39
Agent uniformity and stability are higher, this tends to be advantageous in that factor in drug research, especially sucking preparation research.It is right simultaneously
36~39 sample of embodiment carries out dosage delivered homogeneity (DCU) measurement respectively, and embodiment 36 and 38 is matched as can be seen from the results
The sample of system does not meet States Pharmacopoeia specifications and (according to 2015 editions standards of Chinese Pharmacopoeia, that is, meets the one of following conditions, can be judged to meet
Regulation: (1) in 10 measurement results, no less than 9 measured values are being averaged between the 75%~125% of average value, and all
Between the 65%~135% of value；In (2) 10 measurement results, if 2~3 measured values exceed 75%~125%, but all exist
Between the 65%~135% of average value, 2 bottles of test sample measurements are separately taken.If in 30 dosage, beyond 75%~125% measurement
It is worth no more than 3, and all between the 65%~135% of average value), 10 for calculating the preparation sample of embodiment 36 and 38 pass
Send the SD value of dose data, it is seen that SD is above 1.5 μ g, prepares sample much larger than embodiment 37 and 39, it was demonstrated that drug is in preparation
It is uneven in system, further prove that addition PEG can effectively improve preparation uniformity and physical stability.
7, embodiment 41 when specific operation, since temperature is already close to propellant boiling point, propellant is waved when filling
Hair is serious, and it is extremely higher to directly result in sample size；Embodiment 42 when specific operation, since temperature is molten already close to propellant
Point, liquid medicine flow are deteriorated, and not can guarantee the good homogeneity of medical fluid.Therefore sample preparation temperature is preferably -60 DEG C~-80
℃。
8, the prior art is compared, the NGI-FPF of the Foradil of AstraZeneca exploitation is 21%~37%
Between, 30% or so, the present invention is suitble to the NGI-FPF of the formoterol solution type inhalation aerosol of Kai Xi listing by being added
Auxiliary material and technique so that product obtains preferable preparation uniformity and physical stability, while all preferred embodiments
NGI-FPF can reach 38% or more, and administration performance is obviously improved, and have a clear superiority and good market prospects.
Claims (10)
1. a kind of suction pressure quantitative aerosol pharmaceutical composition, which includes active constituent Formoterol or its medicine
Acceptable salt, lactose, solvent, polyethylene glycol (PEG) and hydrofluoroalkane propellant on.
2. aerosol drug composition according to claim 1, which is characterized in that the pharmaceutically acceptable salt is selected from
Formoterol fumarate and fumarate fumarate dihydrate.
3. aerosol drug composition according to claim 1 or 2, which is characterized in that the lactose is selected from lactose monohydrate
With one of Lactis Anhydrous or a variety of.
4. aerosol drug composition according to any one of claim 1 to 3, which is characterized in that the solvent is selected from
One of glycerol, propylene glycol and ethyl alcohol are a variety of, preferably ethyl alcohol.
5. aerosol drug composition according to any one of claim 1 to 4, which is characterized in that the polyethylene glycol
Selected from one of PEG100~2000 or a variety of, preferably PEG100, PEG300, PEG500, PEG1000, PEG1300,
PEG1500 or PEG2000, more preferably PEG1000.
6. aerosol drug composition according to any one of claim 1 to 5, which is characterized in that the hydrofluoroalkane
Propellant is selected from one of 1,1,1,2- tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3- heptafluoro-propane (HFA 227)
Or a variety of, preferably HFA227.
7. aerosol drug composition according to any one of claim 1 to 6, which is characterized in that the active constituent
D90Partial size is 0.1~10 μm, preferably 0.1~7 μm, more preferably 0.1~5 μm；D50Partial size is 0.1~7 μm, preferably
0.1~5 μm, more preferably 0.1~3 μm；D10Partial size is 0.1~5 μm, preferably 0.1~3 μm, more preferably 0.1~1.5 μm；
Preferably, the D of the lactose90Partial size is 0.1~30 μm, preferably 0.1~10 μm, more preferably 0.1~5 μm；D50Grain
Diameter is 0.1~15 μm, preferably 0.1~5 μm, more preferably 0.1~3 μm；D10Partial size is 0.1~5 μm, preferably 0.1~3 μ
M, more preferably 0.1~1.5 μm.
8. aerosol drug composition according to any one of claim 1 to 7, which is characterized in that the active constituent
The weight percent for accounting for described pharmaceutical composition is 0.004~0.085%, preferably 0.017%~0.085%；
Preferably, the lactose account for described pharmaceutical composition weight percent be 0.008~0.085%, preferably 0.008~
0.043%, more preferably 0.008%~0.014%；
Preferably, the solvent account for described pharmaceutical composition weight percent be 0.0%~10%, preferably 0.0%~
5%；More preferably 0.0%~2%；
Preferably, it is 0.0001%~0.1% that the polyethylene glycol, which accounts for the weight percent of described pharmaceutical composition, preferably
0.001%~0.02%.
9. the preparation process of suction pressure quantitative aerosol pharmaceutical composition described in a kind of any one of claims 1 to 8, including
Following steps:
(a) by active constituent Formoterol or its pharmaceutically acceptable salt, lactose is micronized；
(b) the micronization product of step (a), solvent, polyethylene glycol are mixed, Zha Gai seals valve；
(c) propellant of recipe quantity is filled in the mixture of step (b) by quantitative valve.
10. the preparation process of suction pressure quantitative aerosol pharmaceutical composition described in a kind of any one of claims 1 to 8, packet
Include following steps:
(a) by active constituent Formoterol or its pharmaceutically acceptable salt, lactose is micronized；
(b) micronization product, solvent, the polyethylene glycol of step (a) are distributed in the propellant after pre-cooling, are mixed under low temperature,
By medical fluid again quantitative separating into aerosol container；
Preferably, in step (b), the low temperature is -80 DEG C~-60 DEG C.
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