CN110302184A - Application of the lysine in quaternary ammonium salt m receptor antagonist aerosol - Google Patents
Application of the lysine in quaternary ammonium salt m receptor antagonist aerosol Download PDFInfo
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- CN110302184A CN110302184A CN201810257706.4A CN201810257706A CN110302184A CN 110302184 A CN110302184 A CN 110302184A CN 201810257706 A CN201810257706 A CN 201810257706A CN 110302184 A CN110302184 A CN 110302184A
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- quaternary ammonium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- 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
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/12—Aerosols; Foams
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Abstract
The present invention relates to application of the lysine in the quaternary ammonium salt m receptor antagonist aerosol drug composition of no propellant, lysine can improve the spray particle diameter and spray velocity of above-mentioned composition, the pulmonary deposition ratio of correspondent composition can be improved, quaternary ammonium salt m receptor antagonist is related to Tiotropium Bromide, Ipratropium Bromide, aclidinium bromide, Wumei bromo-amine, glycopyrronium bromide, the drug is inhalable aerosol, and the invention further relates to the preparation methods of the drug.
Description
Technical field:
The present invention relates to lysine answering in the quaternary ammonium salt m receptor antagonist aerosol drug composition of no propellant
With lysine can improve the spray particle diameter and spray velocity of above-mentioned composition, and the pulmonary deposition of correspondent composition can be improved
Rate, quaternary ammonium salt m receptor antagonist are related to Tiotropium Bromide, Ipratropium Bromide, aclidinium bromide, Wumei bromo-amine, glycopyrronium bromide, the medicine
Object is inhalable aerosol, and the invention further relates to the preparation methods of the drug.
Background technique:
Asthma is a kind of chronic airway inflammation, it is characterized in that Reversible airway obstruction and airway reactivity increase, air flue resistance
Plug secretion as caused by tunica mucosa bronchiorum inflammation increases, two kinds of factors of myxedema and inflammatory stimulus smooth muscle spasm cause；
And airway reactivity increases the result of the damage of bronchial epithelial cell caused by being also due to airway inflammation.It is recognized that only
There is the inflammation of control airway mucus, can be only achieved the final purpose for reducing airway hyperreactivity, alleviating asthma symptoms.Treatment at present
The drug of the pulmonary diseases such as asthma is mainly include the following types: (1) broxaterol, (2) xanthine drug, (3) cholinolytic
Medicine, (4) glucocorticoid, (5) antiallergic.
Asthma is a kind of chronic airway inflammation, it is characterized in that Reversible airway obstruction and airway reactivity increase, air flue resistance
Plug secretion as caused by tunica mucosa bronchiorum inflammation increases, two kinds of factors of myxedema and inflammatory stimulus smooth muscle spasm cause；
And airway reactivity increases the result of the damage of bronchial epithelial cell caused by being also due to airway inflammation.It is recognized that only
There is the inflammation of control airway mucus, can be only achieved the final purpose for reducing airway hyperreactivity, alleviating asthma symptoms.Treatment at present
The drug of the pulmonary diseases such as asthma is mainly include the following types: (1) broxaterol, (2) xanthine drug, (3) cholinolytic
Medicine, (4) glucocorticoid, (5) antiallergic.
Wherein there is more highly selective potent anticholinergic agent in recent years for air flue Muscarinic acetylcholine energy receptor (m receptor)
It is concerned always, the mediator for dominating neuron after the parasympathetic ganglion of air flue is acetylcholine, and the receptor on effector is
For m receptor.According to the height with receptor subtype specific antagonist affinity, it is divided into M1, M2, M3, M4 from pharmacological point.Its
In with pirenzepine, 4-DAMP affinity it is high be known as M1 receptor；The high referred to as M2 receptor with AF-DXll6 affinity；With 4-
The high referred to as M3 receptor of DAMP affinity；The high referred to as M4 receptor with P-F-HHSID affinity.But at least 5 kinds coding mAChR
Different genes, be respectively designated as m1, m2, m3, m4, m5, human gene chromosome location is 1lq l2-13,7q respectively
35―36,lq 43―44,11q 12―11.2,15q 26.M1, m2, m3, m4 respectively correspond pharmacological M1, M2, M3, M4.
The albumen of m5 gene expression exists only in the isolated area of brain, not yet finds corresponding functional pharmacological performance at present, therefore temporarily
Without M5.Air flue m receptor synthesizes the side such as secretion, mucociliary clearance in adjusting Tension of Airway Smooth Muscle, mucin glycoprotein and mucus
Face plays an important role.Each hypotype of m receptor is closely related with function in the distribution of air flue, and dominate submucosal glands is mainly
M3 receptor, M2 receptor have adjustment effect to secretion, not yet find the direct effect of M4 receptor and M5 receptor at present.Goblet cell
There may be cholinergic innervations.M receptor antagonist not only can be with expansion bronchus, but also can inhibit mucin glycoprotein and mucus
Hypersecretion has consequence in the treatment of COPD and bronchial asthma etc..Anticholinergic agent has been used as COPD to treat
First-line drug.
Ipratropium Bromide is a kind of drug that action time is relatively short, general only 4 to 8 hours.It can be by quantitative
The mode of inhalator (MDI) or aerosol is administered.In addition, it is placed on salbutamol and manufactured in the same device combines system
Agent can be used as the maintenance medication of COPD.In treating asthma its be mainly limited to control acute attack when symptom.2000
There is Tiotropium Bromide in early stage, and action time is at least 24 hours, therefore maintains to recommend once a day when medication as COPD
Administration.Tiotropium Bromide can be sucked by way of dry powder doses (DPI), but have recently emerged this one kind of soft mist inhalant (SMI)
New administration mode.Glycopyrronium bromide imbedibility capsule (Seebri, 50mcg) is administered by Breezhaler equipment, as one kind
Once a day, for a long time, imbedibility safeguard bronchodilator, for alleviating the symptom of patients with chronic obstructive pulmonary diseases, 2012
Obtain the approval of Japanese hygienic workfare portion (MHLW).Wumei bromo-amine (umeclidinium bromide) Foradil Aerolizer formoterol fumarate
(Incruse Ellipta) as maintenance bronchiectasis medicine a kind of long-term, once a day, for treating chronic resistance
The airflow obstruction (airflow obstruction) of plug property tuberculosis (COPD) (including chronic bronchitis and pulmonary emphysema) patient,
Obtain EU Committee (EC) batch listing in April, 2014.Aclidinium bromide 400ug, the application in COPD patient twice daily can have
Effect improves its lung function, compared with placebo group, significantly improves the quality of life of patient, reduces acute exacerbation rate and therefore
Caused by hospitalizations, and adverse reaction is relatively fewer.
The imbedibilities respiratory tract preparations such as treatment asthma common are aerosol and Foradil Aerolizer formoterol fumarate, and wherein aerosol, which refers to, contains
The lotion or suspension of medicine and suitable propellant are filled jointly and are encapsulated in the pressure vessel with special valve system, and when use borrows
The pressure of propellant is helped to spray content object fog-like, the preparation for lung's sucking；Foradil Aerolizer formoterol fumarate refer to or it is a kind of or
Above drug enters respiratory tract after special drug delivery device administration in dry powder form, plays the one of whole body or local action
Kind pharmaceutical dosage form；Aerosol is liquid and uses propellant, and Foradil Aerolizer formoterol fumarate is then the solid containing carrier, from galenic pharmacy
Exist apparent different for angle between two kinds of dosage forms, the key of aerosol formulation is to study the uniform of lotion or suspension
Degree and stability, the preparation key of Foradil Aerolizer formoterol fumarate are then the micromeritics technologies between the different solid particles of research.
According to the actual conditions that asthma, COPD patient suck, light suction should be realized as a kind of ideal suction apparatus
Enter, guarantees drug high effective deposition and air flue (oral cavity is avoided to deposit) and convenient for operation and carrying.In order to reach said effect, suck
Device should have sucking start velocity low, haze and discharge slowly, and aerosol low speed is run, oropharyngeal deposition is few, ideal particle
Content, high pulmonary deposition ratio, easy to operate, the features such as size is suitable.Very fast mist speed and release time are unfavorable for particle and pass through mouth
The pharyngeal zigzag channel between tracheae, be easy to cause pulmonary deposition ratio to decline, and oropharyngeal deposition rate improves.
In recent years, completely new soft mist inhalant Si Lihua (the thiophene support bromine of German pharmaceutical giant Boehringer Ingelheim company (BI)
Ammonium) and device (can times happy) it is available worldwide.
Soft mist inhalant is the upgrade version of aerosol.Traditional inhalant spraying duration compared with soft mist inhalant is short,
Only 0.2 second~0.3 second, the patient of many coordination ability differences was unable to fully suck.Meanwhile conventional atomizers are inconvenient, and
It is not portable；And metered dose inhalant needs propellant, not environmentally.And soft mist inhalant is realized actively by spraying via device,
Patient breaths are not needed, the aerosol duration is longer, has extended to 1.2 seconds or more, and aerosol jet velocity is slow, ideal granule content
Up to 70%, it ensure that drug reaches 51.6% in the high effective deposition of lung, and be easy to carry about with one, the compliance of patient is significantly
It is promoted.
Soft mist agent is driven using mechanical potential (without using propellant), triggering master compared with Conventional aerosol device
Dynamic spraying, the duration is long and aerosol that the speed of service is slower, and patient can be given to provide longer respiratory time, and counterpart eye is assisted
The synchronism of tune is of less demanding.
Soft mist agent is as a kind of novel form with treatment respiratory disease advantage, the skill with higher on suction apparatus
Art threshold copies technical difficulty with higher for drug, can preferably avoid harmful competition caused by excess capacity.
Lysine is a kind of common drug, and especially amino acid can be used as the carrier in Foradil Aerolizer formoterol fumarate (powder spray)
It uses, is had not been reported in aerosol.
It is between 0.01 gram of every 100 ml of formulation that its concentration of tiotropium salt in pharmaceutical preparation is disclosed in CN03808233.0
Between 0.06 gram of every 100 ml of formulation, water is unique solvent, is allowed between 2.7 and 3.1 with acid adjustment pH value, excellent
It is selected as between 2.8 and 3.05, there are also pharmacologically acceptable bacteriostatic agent, such as benzalkonium chloride, pharmacologically acceptable complexing agent, such as
The salt of ethylenediamine tetra-acetic acid.Wherein ethylenediamine tetra-acetic acid or salt have the function of changing spraying exception, be such as spaced 3 or 3 days or more
Interruption after, be added without aerosol at ethylenediamine tetra-acetic acid or salt and spraying exception occur, such as spray droplet partial size changes
Become, so that the accurate dosage of patient will receive influence, the reason is that may be since nozzle opening regions are by microscopic deposits
Result.
Summary of the invention:
We have surprisingly found that, containing water soluble quaternary ammonium salt m receptor blocking agent or its be hydrated in medicine composition and make
With can times happy or similar device when, spray particle diameter and spray velocity that lysine or its hydrochloride can improve is added, changes power
Benefit require 1 described in auxiliary material application make to improve patient pulmonary deposition ratio and patient's oropharyngeal drug deposition rate drop
It is low.
One kind not containing propellant aerosol drug composition, it is characterised in that hinders containing water soluble quaternary ammonium salt m receptor
Disconnected agent or its hydrate, lysine or its hydrochloride and water.
Above-mentioned pharmaceutical composition, it is characterised in that quaternary ammonium salt m receptor blocking agent be Ipratropium Bromide, Tiotropium Bromide,
One or more of glycopyrronium bromide, aclidinium bromide, Wumei bromo-amine.
Above-mentioned pharmaceutical composition, it is characterised in that quaternary ammonium salt m receptor blocking agent be Ipratropium Bromide, Tiotropium Bromide,
One or more of glycopyrronium bromide, Wumei bromo-amine.
Above-mentioned pharmaceutical composition, it is characterised in that the quaternary ammonium salt m receptor blocking agent contained.
Above-mentioned pharmaceutical composition, it is characterised in that also contain bacteriostatic agent.Above-mentioned pharmaceutical composition, it is characterised in that suppression
Microbial inoculum is one of benzalkonium chloride, benzalkonium bromide.Above-mentioned pharmaceutical composition, it is characterised in that benzalkonium chloride or benzalkonium bromide
Content is 8-12mg/100ml.Above-mentioned pharmaceutical composition, it is characterised in that bacteriostatic agent is benzalkonium chloride.Above-mentioned pharmaceutical composition
Object, it is characterised in that antibacterial agent content is 8-12mg/100ml.
Above-mentioned pharmaceutical composition, it is characterised in that quaternary ammonium salt m receptor blocking agent or its hemihydrate content is with quaternary ammoniums
Count 0.1-1 mg/ml.
Above-mentioned pharmaceutical composition, it is characterised in that quaternary ammonium salt m receptor blocking agent or its hemihydrate content is with quaternary ammoniums
Count 0.2-0.7 mg/ml.
Above-mentioned pharmaceutical composition, it is characterised in that quaternary ammonium salt m receptor blocking agent or its hemihydrate content is with quaternary ammoniums
Count 0.2-0.4 mg/ml.
Above-mentioned pharmaceutical composition, it is characterised in that lysine or its hydrochloride content is with lysine 10-20mg/
100ml。
Above-mentioned pharmaceutical composition, it is characterised in that PH < 6.
Above-mentioned pharmaceutical composition, it is characterised in that PH < 4.
Lysine or its hydrochloride are as the spray particle diameter and spray velocity for changing pharmaceutical composition described in claim 1
Auxiliary material application.
Specific embodiment
The weight error of water soluble quaternary ammonium salt m receptor blocking agent is within ± 0.001g in following embodiment.
Embodiment 1
The pharmaceutical preparation prescription of 100ml:
Preparation method: Quan Rong after Tiotropium Bromide or tiotropium bromide monohydrate, bacteriostatic agent, lysine and water are mixed is used
Hydrochloric acid adjusts pH value.
Embodiment 2
The pharmaceutical preparation prescription of 100ml:
The preparation method is the same as that of Example 1.
Embodiment 3
The pharmaceutical preparation prescription of 100ml:
Preparation method: Quan Rong after Tiotropium Bromide or tiotropium bromide monohydrate, bacteriostatic agent, lysine and water are mixed is used
Hydrochloric acid adjusts pH value.
Embodiment 4
The pharmaceutical preparation prescription of 100ml:
Preparation method is the same as embodiment 3.
Embodiment 5
The pharmaceutical preparation prescription of 100ml:
Preparation method: by water soluble quaternary ammonium salt m receptor blocking agent or its monohydrate, bacteriostatic agent (having in such as prescription),
Quan Rong after lysine and water mixing, adjusts pH value with hydrochloric acid.
Embodiment 6
The pharmaceutical preparation prescription of 100ml:
Preparation method is the same as embodiment 5.Comparative examples 1
The pharmaceutical preparation prescription of 100ml:
The preparation method is the same as that of Example 1.
Comparative examples 2
The pharmaceutical preparation prescription of 100ml:
Preparation method is the same as embodiment 3.
Comparative examples 3
The pharmaceutical preparation prescription of 100ml:
The preparation method is the same as that of Example 1.
Spray particle diameter test
Embodiment, comparative examples are obtained into pharmaceutical composition, pleasure can be sprayed again using the spraying device-of BI company
Mist detects spray droplet partial size using German SYMPATEC laser particle analyzer (HELOS-SPRAYER).Detection mode is, for
Pharmaceutical composition carries out 10 and presses spraying, measurement average spray size droplet diameter, and after placing 4 days, progress 10 is pressed spraying again, and measurement is put down
Equal spray droplet partial size.
Spray velocity test
Laboratory apparatus: using the particle dynamic point of the Dantec Dynamics A/S company, Denmark of phase-Doppler particle analyzer
It analyses (PDA) (Particle Dynamic Analyzer, PDA)
Test method: obtaining pharmaceutical composition for embodiment, comparative examples, using spraying device-energy times of BI company
Pleasure is sprayed, spraying axial velocity when measuring after starting by spraying 0.8 second.
| Serial number | Axial velocity (meter per second) |
| Embodiment | |
| 4-1 | 0.85 |
| 4-2 | 0.82 |
| 4-3 | 0.83 |
| 4-4 | 0.83 |
| 4-5 | 0.83 |
| 4-6 | 0.84 |
| 4-7 | 0.83 |
| 4-8 | 0.82 |
| 4-9 | 0.84 |
| 4-10 | 0.81 |
| 4-11 | 0.81 |
| 4-12 | 0.82 |
| Comparative examples | |
| 2-1 | 0.94 |
| 2-2 | 0.94 |
| 2-3 | 0.92 |
| 2-4 | 1.01 |
| 2-5 | 0.98 |
| 2-6 | 0.96 |
| 2-7 | 0.97 |
| 2-8 | 0.94 |
| 2-9 | 0.93 |
| 2-10 | 0.97 |
| 2-11 | 0.95 |
| 2-12 | 0.93 |
This experiment using be used as detecting instrument, measurement.
Spraying NGI (Next Generation Pharmaceutical Impactor) test
Test method: obtaining pharmaceutical composition for embodiment, comparative examples, using spraying device-energy times of BI company
Pleasure is sprayed, using the deposition of Copley Scientific Limited NGI detection respiratory tract.Detection mode is, right
10 are carried out in pharmaceutical composition and presses spraying, the deposition of measurement respiratory tract different location, after placing 4 days, are carried out 10 again and are pressed spray
Mist measures the deposition of respiratory tract different location.
Claims (10)
1. one kind does not contain propellant aerosol drug composition, it is characterised in that blocked containing water soluble quaternary ammonium salt m receptor
Agent or its hydrate, lysine or its hydrochloride and water.
2. pharmaceutical composition as described in claim 1, it is characterised in that quaternary ammonium salt m receptor blocking agent be Ipratropium Bromide,
One or more of Tiotropium Bromide, glycopyrronium bromide, aclidinium bromide, Wumei bromo-amine.
3. pharmaceutical composition as described in claim 1, it is characterised in that quaternary ammonium salt m receptor blocking agent be Ipratropium Bromide,
One or more of Tiotropium Bromide, glycopyrronium bromide, Wumei bromo-amine.
4. pharmaceutical composition as described in claim 1, it is characterised in that the quaternary ammonium salt m receptor blocking agent contained.
5. pharmaceutical composition as described in claim 1, it is characterised in that also contain bacteriostatic agent.
6. pharmaceutical composition as claimed in claim 5, it is characterised in that bacteriostatic agent is benzalkonium chloride, one in benzalkonium bromide
Kind.
7. pharmaceutical composition as described in claim 1, it is characterised in that quaternary ammonium salt m receptor blocking agent or its hemihydrate content
For the 0.1-1 mg/ml in terms of quaternary ammonium.
8. pharmaceutical composition as described in claim 1, it is characterised in that lysine or its hydrochloride content is with lysine 10-
20mg/100ml。
9. pharmaceutical composition as described in claim 1, it is characterised in that PH < 6.
10. lysine or its hydrochloride are as the spray particle diameter and spray velocity for changing pharmaceutical composition described in claim 1
Auxiliary material application.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810257706.4A CN110302184B (en) | 2018-03-27 | 2018-03-27 | Application of lysine in quaternary ammonium salt M receptor antagonist aerosol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810257706.4A CN110302184B (en) | 2018-03-27 | 2018-03-27 | Application of lysine in quaternary ammonium salt M receptor antagonist aerosol |
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| CN110302184B CN110302184B (en) | 2023-01-17 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| US20020146373A1 (en) * | 1996-05-24 | 2002-10-10 | The Penn State Research Foundation | Aerodynamically light particles for pulmonary drug delivery |
| CN1557308A (en) * | 2004-01-19 | 2004-12-29 | 复旦大学 | Tiotropium aerosol inhalant and its preparation method |
-
2018
- 2018-03-27 CN CN201810257706.4A patent/CN110302184B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020146373A1 (en) * | 1996-05-24 | 2002-10-10 | The Penn State Research Foundation | Aerodynamically light particles for pulmonary drug delivery |
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN1557308A (en) * | 2004-01-19 | 2004-12-29 | 复旦大学 | Tiotropium aerosol inhalant and its preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 罗泽如等: "COPD患者使用噻托溴铵吸乐装置转换为能倍乐装置的效果研究", 《岭南急诊医学杂志》, vol. 22, no. 3, 30 June 2017 (2017-06-30), pages 247 * |
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