CN110302184B - Application of lysine in quaternary ammonium salt M receptor antagonist aerosol - Google Patents

Application of lysine in quaternary ammonium salt M receptor antagonist aerosol Download PDF

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CN110302184B
CN110302184B CN201810257706.4A CN201810257706A CN110302184B CN 110302184 B CN110302184 B CN 110302184B CN 201810257706 A CN201810257706 A CN 201810257706A CN 110302184 B CN110302184 B CN 110302184B
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bromide
quaternary ammonium
ammonium salt
pharmaceutical composition
lysine
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CN110302184A (en
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张�杰
孙亮
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Tianjin Jinyao Group Co Ltd
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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
    • 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
    • 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
    • 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
    • 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 invention relates to application of lysine in a propellant-free quaternary ammonium salt M receptor antagonist aerosol pharmaceutical composition, wherein the lysine can improve the spray particle size and spray speed of the composition and can improve the lung deposition rate of the corresponding composition, and the quaternary ammonium salt M receptor antagonist relates to tiotropium bromide, ipratropium bromide, aclidinium bromide, amebic bromide and glycopyrronium bromide.

Description

Application of lysine in quaternary ammonium salt M receptor antagonist aerosol
The technical field is as follows:
the invention relates to application of lysine in a propellant-free quaternary ammonium salt M receptor antagonist aerosol pharmaceutical composition, wherein the lysine can improve the spray particle size and spray speed of the composition and can improve the lung deposition rate of the corresponding composition, and the quaternary ammonium salt M receptor antagonist relates to tiotropium bromide, ipratropium bromide, aclidinium bromide, amebic bromide and glycopyrronium bromide.
Background art:
asthma is a chronic airway inflammation characterized by reversible airway obstruction and airway reactivity increase, the airway obstruction is caused by two factors of secretion increase, mucosal edema and inflammation-stimulated smooth muscle spasm caused by bronchial mucosa inflammation; the increased airway reactivity is also a result of damage to bronchial epithelial cells caused by airway inflammation. It is recognized that only by controlling the inflammation of the airway mucosa, the ultimate reduction of airway hyperresponsiveness and relief of asthma symptoms is achieved. At present, the following medicines are mainly used for treating lung diseases such as asthma and the like: the composition comprises (1) a beta 2-receptor stimulant, (2) a xanthine drug, (3) an anticholinergic agent, (4) a glucocorticoid and (5) an antiallergic agent.
Asthma is a chronic airway inflammation characterized by reversible airway obstruction and airway reactivity increase, the airway obstruction is caused by two factors of secretion increase, mucosal edema and inflammation-stimulated smooth muscle spasm caused by bronchial mucosa inflammation; the increased airway responsiveness is also a result of damage to bronchial epithelial cells caused by airway inflammation. It is recognized that only by controlling the inflammation of the airway mucosa, the ultimate reduction of airway hyperresponsiveness and relief of asthma symptoms can be achieved. At present, the drugs for treating lung diseases such as asthma are mainly as follows: the composition comprises (1) a beta 2-receptor stimulant, (2) a xanthine drug, (3) an anticholinergic agent, (4) a glucocorticoid and (5) an antiallergic agent.
Among them, potent anticholinergic drugs having high selectivity for airway muscarinic acetylcholine receptors (M receptors) have been attracting attention in recent years, the transmitter of parasympathetic postganglionic neurons that innervate the airways is acetylcholine, and the receptor on the effector is the M receptor. From the pharmacological viewpoint, the affinity of the receptor subtype-specific antagonists is classified into M1, M2, M3 and M4. Among them, the receptor having high affinity for pirenzepine, 4-DAMP is called M1 receptor; the receptor with high affinity for AF-DXll6 is called M2 receptor; m3 receptor, which has high affinity for 4-DAMP; the receptor with high affinity to P-F-HHSID is called M4 receptor. However, there are at least 5 different genes encoding mAChR, designated m1, m2, m3, m4, m5, and the human genes are at chromosomal locations 1lq l2-13, 7q 35-36, lq 43-44, 11q 12-11.2, and 15q 26, respectively. M1, M2, M3 and M4 correspond to pharmacological M1, M2, M3 and M4, respectively. The protein expressed by the M5 gene exists only in an independent area of the brain, and corresponding functional pharmacological expression is not found at present, so M5 is not available temporarily. Airway M receptors play important roles in regulating airway smooth muscle tone, mucus glycoprotein and mucus synthesis and secretion, mucociliary clearance, and the like. The distribution and the function of each subtype of M receptor in the air passage are closely related, the M3 receptor is mainly used for dominating the submucosal gland, the M2 receptor has a regulation effect on secretion, and the direct effects of the M4 receptor and the M5 receptor are not found at present. Cholinergic innervation may also occur in goblet cells. M receptor antagonists are capable of dilating bronchi and inhibiting mucus secretion, and are important in the treatment of COPD, bronchial asthma, and the like. Anticholinergic agents have been used as first line agents in the treatment of COPD.
Ipratropium bromide is a drug with a relatively short duration of action, typically only 4 to 8 hours. Administration can be by means of a Metered Dose Inhaler (MDI) or an aerosol. In addition, it can be used as the maintenance drug of COPD by putting salbutamol and the combined preparation prepared in the same device. It is mainly limited in the treatment of asthma to control the symptoms at the time of acute episodes. Tiotropium bromide appeared early in 2000, with a duration of action of at least 24 hours, so once daily dosing was recommended as a maintenance medication for COPD. Tiotropium bromide can be inhaled in the form of a dry powder formulation (DPI), but recently a new administration of Soft Mist Inhalants (SMIs) has emerged. Glycopyrrolate inhalational capsules (Seebri, 50 mcg) were administered by the Breezhaler device as a once daily, long-term, inhalational maintenance bronchodilator for relief of symptoms in patients with chronic obstructive pulmonary disease, approved by the japan department of health and labour welfare (MHLW) in 2012. Ultramipramine (umeclidinium bromide) dry powder inhaler (Incrose Ellipta) is used as a long-term, once-a-day, maintenance bronchodilator for the treatment of airflow obstruction (airflow obstruction) in patients with Chronic Obstructive Pulmonary Disease (COPD), including chronic bronchitis and emphysema, marketed in the European Commission (EC) batch 4 months 2014. The application of the aclidinium bromide of 400ug twice a day in COPD patients can effectively improve the lung function of the patients, obviously improve the life quality of the patients compared with a placebo control group, reduce the acute exacerbation rate and the hospitalization frequency caused by the acute exacerbation rate, and have relatively less adverse reactions.
Common respiratory tract inhalation preparations for treating asthma and the like comprise aerosol and dry powder inhalants, wherein the aerosol refers to a preparation which is packaged in a pressure-resistant container with a special valve system together with emulsion or suspension containing medicaments and a proper propellant, and the content is sprayed out in the form of mist by the pressure of the propellant when the aerosol is used for lung inhalation; the dry powder inhalant is a drug dosage form which is prepared by feeding one or more drugs into respiratory tract in a dry powder form after being administrated by a special administration device to exert systemic or local effects; the aerosol is liquid and uses propellant, while the dry powder inhalant is solid containing carrier, there are obvious differences between two formulations from the view point of formulation, the key point of the aerosol formulation is to study the uniformity and stability of emulsion or suspension, and the key point of the dry powder inhalant formulation is to study the particle science technology between different solid particles.
According to the actual situation of inhalation of asthma and COPD patients, the inhalation device should realize easy inhalation, ensure high-efficiency drug deposition and airway (avoiding oral cavity deposition) and be convenient to operate and carry. In order to achieve the above effects, the inhalation device should have the characteristics of low inhalation starting flow rate, slow fogging release, low-speed operation of aerosol, less deposition in the oropharynx, ideal particle content, high lung deposition rate, simple operation, proper size and the like. The faster mist speed and the longer release time are not favorable for the particles to pass through the tortuous path between the oropharynx and the trachea, so that the lung deposition rate is easy to reduce, and the oropharynx deposition rate is improved.
In recent years, new soft mist inhalant silihua (tiotropium bromide) and device (nerware) from germany pharmaceutical giant bristle berg invager company (BI) have been marketed globally.
Soft mist inhalers are an upgraded version of aerosols. Compared with a soft mist inhalant, the traditional inhalant has short spray duration which is only 0.2-0.3 seconds, and many patients with poor coordination ability cannot inhale the inhalant sufficiently. Meanwhile, the traditional atomizer is inconvenient to operate and not easy to carry; the pressure quantitative inhalant needs a propellant and is not environment-friendly. The soft mist inhalant realizes active spraying through the device, does not need a patient to inhale, has longer duration of the aerosol, is prolonged to more than 1.2 seconds, has slow aerosol injection speed, has ideal particle content of up to 70 percent, ensures the high-efficiency deposition of the medicine in the lung, reaches 51.6 percent, is easy to carry, and greatly improves the compliance of the patient.
Compared with the conventional aerosol device, the soft aerosol is driven by mechanical potential energy (without using a propellant) to trigger active spraying, has long duration and slower running speed, can provide longer inhalation time for a patient, and has low requirement on the synchronism of the coordination of the eyes and the mouth.
Figure BDA0001609405940000031
The soft fogging concentrate is a new formulation with the advantage of treating respiratory diseases, has higher technical threshold on an inhalation device, has higher technical difficulty for drug imitation, and can better avoid malignant competition caused by excess productivity.
Lysine is a common medicine, and particularly, amino acid can be used as a carrier in a dry powder inhalant (aerosol), and the aerosol is not reported.
CN03808233.0 discloses a pharmaceutical preparation comprising tiotropium salt in a concentration of between 0.01 g per 100ml of preparation and 0.06 g per 100ml of preparation, water as the sole solvent, and an acid to adjust the pH to between 2.7 and 3.1, preferably between 2.8 and 3.05, and a pharmacologically acceptable bacteriostatic agent, such as benzalkonium chloride, and a pharmacologically acceptable complexing agent, such as salts of ethylenediaminetetraacetic acid. Where the edta or salt has the ability to alter spray abnormalities, such as those that occur in the aerosol without edta or salt addition after an interruption of 3 or more days, for example, the spray droplet size may change, which may affect the patient's precise dosage, possibly as a result of fine deposits in the nozzle opening area.
The invention content is as follows:
it has been surprisingly found that the addition of lysine or its hydrochloride salt improves the spray size and spray rate when a Nepeter or similar device is used in a pharmaceutical composition containing a water-soluble quaternary ammonium salt M receptor blocker or its hydrate, and the use of the adjuvant of claim 1 is modified to increase the lung deposition rate and decrease the oropharyngeal deposition rate of the drug in the patient.
A propellant-free aerosol pharmaceutical composition is characterized by comprising a water-soluble quaternary ammonium salt M receptor blocking agent or a hydrate thereof, lysine or a hydrochloride thereof and water.
The pharmaceutical composition is characterized in that the quaternary ammonium salt M receptor blocker is one or more of ipratropium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide and umeclidinium bromide.
The pharmaceutical composition is characterized in that the quaternary ammonium salt M receptor blocker is one or more of ipratropium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide.
The pharmaceutical composition is characterized by containing a quaternary ammonium salt M receptor blocker.
The pharmaceutical composition is characterized by also comprising a bacteriostatic agent. The medicinal composition is characterized in that the bacteriostatic agent is one of benzalkonium chloride and benzalkonium bromide. The medicine composition is characterized in that the content of benzalkonium chloride or benzalkonium bromide is 8-12mg/100ml. The medicinal composition is characterized in that the bacteriostatic agent is benzalkonium chloride. The medicinal composition is characterized in that the content of the bacteriostatic agent is 8-12mg/100ml.
The pharmaceutical composition is characterized in that the content of the quaternary ammonium salt M receptor blocker or the hydrate thereof is 0.1-1 mg/ml calculated by quaternary ammonium.
The pharmaceutical composition is characterized in that the content of the quaternary ammonium salt M receptor blocker or the hydrate thereof is 0.2-0.7 mg/ml calculated by quaternary ammonium.
The pharmaceutical composition is characterized in that the content of the quaternary ammonium salt M receptor blocker or the hydrate thereof is 0.2-0.4 mg/ml calculated by quaternary ammonium.
The pharmaceutical composition is characterized in that the content of lysine or hydrochloride thereof is 10-20mg/100ml of lysine.
The pharmaceutical composition described above, characterized by a pH <6.
The pharmaceutical composition as described above, characterized by a pH <4.
Use of lysine or its hydrochloride as an adjuvant to modify the spray size and spray rate of a pharmaceutical composition according to claim 1.
Detailed Description
In the following examples, the weight error of the water-soluble quaternary ammonium salt M receptor blocker is within. + -. 0.001 g.
Example 1
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000041
Figure BDA0001609405940000051
the preparation method comprises the following steps: mixing tiotropium bromide or tiotropium bromide monohydrate, bacteriostatic agent, lysine and water, dissolving completely, and adjusting pH with hydrochloric acid.
Example 2
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000052
the preparation method is the same as example 1.
Example 3
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000053
Figure BDA0001609405940000061
the preparation method comprises the following steps: mixing tiotropium bromide or tiotropium bromide monohydrate, bacteriostatic agent, lysine and water, dissolving completely, and adjusting pH with hydrochloric acid.
Example 4
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000062
the preparation method is the same as example 3.
Example 5
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000071
the preparation method comprises the following steps: mixing water soluble quaternary ammonium salt M receptor blocking agent or its hydrate, bacteriostatic (as prescription), lysine and water, dissolving completely, and adjusting pH with hydrochloric acid.
Example 6
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000072
Figure BDA0001609405940000081
the preparation method is the same as example 5. Comparative example 1
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000082
the preparation method is the same as example 1.
Comparative example 2
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000083
Figure BDA0001609405940000091
the preparation method is the same as example 3.
Comparative example 3
100ml pharmaceutical formulation prescription:
Figure BDA0001609405940000092
the preparation method is the same as example 1.
Spray particle size test
The pharmaceutical compositions obtained in examples and comparative examples were sprayed using a spray apparatus available from BI corporation, nengle, and the spray droplet size was measured using a German SYMPATEC laser particle sizer (HELOS-SPRAYER). The test method was to spray the pharmaceutical composition at 10 strokes, measure the average spray droplet size, and after standing for 4 days, spray the pharmaceutical composition at 10 strokes again, and measure the average spray droplet size.
Figure BDA0001609405940000093
Figure BDA0001609405940000101
Figure BDA0001609405940000102
Figure BDA0001609405940000111
Figure BDA0001609405940000112
Figure BDA0001609405940000121
Spray velocity test
An experimental instrument: particle Dynamics Analysis (PDA) from Danish Dantec Dynamics A/S Using phase Doppler technology
The test method comprises the following steps: the pharmaceutical compositions obtained in examples and comparative examples were sprayed using a BI spray device-nerolides, and the axial velocity of the spray was measured at 0.8 second after the start of spraying.
Figure BDA0001609405940000122
Figure BDA0001609405940000131
Figure DA00016094059436284037
The experiment adopts a detection instrument for measurement.
Spray NGI (Next Generation Pharmaceutical Impactor) test
The test mode is as follows: the pharmaceutical compositions obtained in examples and comparative examples were sprayed using a spray device of BI corporation, nengle, and the deposition rate of the respiratory tract was measured using Copley Scientific Limited NGI. The test method comprises spraying the medicinal composition for 10 times, measuring the deposition rate of different respiratory tract positions, standing for 4 days, spraying for 10 times, and measuring the deposition rate of different respiratory tract positions.
Figure BDA0001609405940000141
Figure BDA0001609405940000142
Figure BDA0001609405940000151

Claims (8)

1. A propellant-free aerosol pharmaceutical composition is characterized by comprising the following components: the water-soluble quaternary ammonium salt M receptor blocker is one or more of ipratropium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide and umeclidinium bromide; the bacteriostatic agent is one of benzalkonium chloride and benzalkonium bromide; the content of the quaternary ammonium salt M receptor blocker or the hydrate thereof is 0.1-1 mg/ml calculated by quaternary ammonium; the content of the bacteriostatic agent is 8-12mg/100ml; the content of lysine or hydrochloride thereof is 10-20mg/100ml of lysine.
2. A pharmaceutical composition according to claim 1, wherein the quaternary ammonium salt M receptor blocker is one or more of ipratropium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide.
3. The pharmaceutical composition of claim 1, wherein the bacteriostatic agent is benzalkonium chloride.
4. The pharmaceutical composition according to claim 1, wherein the quaternary ammonium salt-type M receptor blocker or its hydrate is contained in an amount of 0.2 to 0.7 mg/ml based on quaternary ammonium.
5. The pharmaceutical composition according to claim 1, wherein the quaternary ammonium salt-type M receptor blocker or a hydrate thereof is present in an amount of 0.2 to 0.4 mg/ml based on quaternary ammonium.
6. The pharmaceutical composition of claim 1, wherein the PH is <6.
7. The pharmaceutical composition of claim 1, wherein PH is <4.
8. Use of lysine or its hydrochloride as an adjuvant to modify the spray size and spray rate of a pharmaceutical composition according to claim 1.
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* Cited by examiner, † Cited by third party
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
CN1557308A (en) * 2004-01-19 2004-12-29 复旦大学 Tiotropium aerosol inhalant and its preparation method

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Publication number Priority date Publication date Assignee Title
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Patent Citations (2)

* Cited by examiner, † Cited by third party
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
CN1557308A (en) * 2004-01-19 2004-12-29 复旦大学 Tiotropium aerosol inhalant and its preparation method

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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》.2017,第22卷(第3期),第245-248页. *

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