CN110876722A - Tiotropium bromide and oxdarterol spray containing surfactant - Google Patents

Tiotropium bromide and oxdarterol spray containing surfactant Download PDF

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CN110876722A
CN110876722A CN201811038751.7A CN201811038751A CN110876722A CN 110876722 A CN110876722 A CN 110876722A CN 201811038751 A CN201811038751 A CN 201811038751A CN 110876722 A CN110876722 A CN 110876722A
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tiotropium bromide
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张�杰
孙亮
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Tianjin Jinyao Group Co Ltd
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Abstract

The invention relates to a tiotropium bromide and oxdaterol spray for treating respiratory diseases, in particular asthma, chronic obstructive pneumonia, tracheitis and the like, wherein an inhalable surfactant can enable the spray particle size, the spray time and the spray speed of a composition to be more suitable by adjusting the surface tension of a tiotropium bromide and oxdaterol spray pharmaceutical composition without a propellant.

Description

Tiotropium bromide and oxdarterol spray containing surfactant
The technical field is as follows:
the invention relates to a tiotropium bromide and oxdaterol spray for treating respiratory diseases, in particular asthma, chronic obstructive pneumonia, tracheitis and the like, wherein an inhalable surfactant can enable the spray particle size, the spray time and the spray speed of a composition to be more suitable by adjusting the surface tension of a tiotropium bromide and oxdaterol spray pharmaceutical composition without a propellant.
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 stimulation smooth muscle spasm caused by bronchial mucosa inflammation, and the airway reactivity increase is also a result of bronchial epithelial cell injury caused by airway inflammation.
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 stimulation smooth muscle spasm caused by bronchial mucosa inflammation, and the airway reactivity increase is also a result of bronchial epithelial cell injury caused by airway inflammation.
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 point of view, the compounds are classified into M1, M2, M3 and M4 according to their affinity for receptor subtype-specific antagonists. Among them, the receptor M1, which has high affinity for pirenzepine and 4-DAMP; m2 receptor with high affinity for AF-DXll 6; the receptor known as M3, 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 mAChR-encoding genes, designated m1, m2, m3, m4, m5, and the human genes are at chromosomal locations 1lq l 2-13, 7q 35-36, lq 43-44, 11q 12-11.2, 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 the corresponding functional pharmacological expression is not found at present, so that M5 is not found 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 airway are closely related, the M3 receptor is mainly used for dominating submucosal glands, 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 may 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 asthma treatment to control the symptoms at the time of acute attack. Tiotropium bromide appeared in the early 2000 years and its duration of action was 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 form of Soft Mist Inhaler (SMI) has emerged.
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 one or more than one drug, enters respiratory tract in a dry powder form after being administrated by a special administration device and plays a role of whole body or local; 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. Spray refers to a formulation that does not contain a propellant and sprays a liquid into a mist by means of the pressure of a manual pump. It is obvious that the spray and the aerosol are most different from the former spray by external force, and the latter spray by internal pressure and propellant. The latter has the following disadvantages compared with the former: 1 are costly (due to the internal pressure vessels, valve systems and special production equipment). 2 the propellant has refrigerating effect, and is not suitable for stimulation caused by being used on wounded skin wound for many times. 3 the propellant has certain toxicity and is not suitable for patients with heart disease to use as inhalation aerosol. 4, explosion easily occurs.
Ipratropium bromide is a drug with a relatively short duration of action, typically only 4 to 8 hours. Administration may 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 asthma treatment to control the symptoms at the time of acute attack. Tiotropium bromide appeared in the early 2000 years and its duration of action was 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 form of Soft Mist Inhaler (SMI) has emerged.
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 one or more than one drug, enters respiratory tract in a dry powder form after being administrated by a special administration device and plays a role of whole body or local; 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 patients suffering from asthma and COPD, the inhalation device as an ideal inhalation device should realize easy inhalation, ensure high-efficiency medicine 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 BDA0001791565950000031
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.
CN03808233.0 discloses tiotropium salts in pharmaceutical formulations at a concentration between 0.01 g per 100ml of formulation and 0.06 g per 100ml of formulation, water as the sole solvent, and an acid to adjust the pH between 2.7 and 3.1, preferably between 2.8 and 3.05, together with a pharmacologically acceptable bacteriostatic agent, such as benzalkonium chloride, and a pharmacologically acceptable complexing agent, such as salts of ethylenediaminetetraacetic acid. In which edta or salt has the function of altering spray abnormalities, such as those that occur in aerosols without edta or salt addition after an interruption of 3 or more days, for example, the spray droplet size may change, so that the patient's precise dosage may be affected, possibly as a result of fine deposits in the nozzle opening area.
However, none of these documents describes the effect of surface tension on the spray particle size, spray time and spray rate of such propellant-free sprayable pharmaceutical compositions.
Tiotropium bromide (tiotropium bromide) is a given once daily LAMA, increasing a range of functions and improving patient outcome in COPD patients, reducing moderate and severe exacerbations, reducing the number of episodes and reducing mortality. Ondaterol (Olodatero) is a novel once daily LABA that is specifically designed by Boringer Invitrogen, Germany, for combination with tiotropium bromide, and has a duration of 24 hours, and is capable of improving the lung function, improving the symptoms and improving exercise capacity of the patient. Tiotropium bromide and olodaterol have complementary pharmacokinetic and pharmacodynamic characteristics, and a once-daily fixed dose combination can treat COPD patients to maintain bronchiectasis.
Chinese patents CN200580012621.0 and CN200680037725.1 disclose technical schemes of tiotropium bromide oxdalterol sprays.
The invention content is as follows:
it has been surprisingly found that in a composition comprising tiotropium bromide or its hydrate, a pharmaceutically acceptable salt of olodaterol, an inhalable surfactant, an inorganic acidic PH regulator and water, the inhalable surfactant has a better control range of the spray particle size of the propellant-free pharmaceutical spray composition after the surface tension is adjusted, and the spray time can be prolonged and the spray speed can be reduced.
The compound tiotropium bromide spray composition without propellant is characterized by comprising tiotropium bromide or hydrate thereof, pharmaceutical salt of odaterol, an inhalable surfactant, an inorganic acidic pH value regulator and water, wherein the surface tension of the tiotropium bromide spray composition is regulated to 52 +/-2 mN/m by the inhalable surfactant.
The above pharmaceutical composition, characterized in that the manner of measuring surface tension is a hanging drop method.
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 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/100 ml. The medicine composition is characterized in that the content of benzalkonium chloride or benzalkonium bromide is 8-12mg/100 ml.
The pharmaceutical composition as described above, characterized in that tiotropium bromide or its hydrate is present in an amount of 0.2-0.5 mg/ml calculated as tiotropium.
The composition is characterized in that the inorganic acidic pH value regulator is one or more of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid.
The composition is characterized in that the pharmaceutical salt of the olodaterol is one of hydrochloride, phosphate and acetate.
The composition is characterized in that the pharmaceutical salt of the odaterol is hydrochloride.
The surfactant is used as an auxiliary material for changing the spray particle size and the spray speed of the tiotropium bromide spray pharmaceutical composition without a propellant.
The pharmaceutical composition is characterized in that the inhalable surfactant is one or more of dipalmitoylphosphatidylcholine, phosphatidylglycerol, hexadecanol, tyloxapol, phospholipid and dipalmitoylphosphatidylglycerol. The medicinal composition is characterized in that the phospholipid is soybean phospholipid.
The pharmaceutical composition is characterized by a pH of 3.0 + -0.2.
The surface tension in the present invention is measured using the pendant drop method.
Detailed Description
The surface tension in the examples of the invention was determined by the pendant drop method at 20 ℃ using the DSA25S from Kruss (kluss) germany.
Example 1
The preparation method comprises the following steps: tiotropium bromide or tiotropium bromide monohydrate, the pharmaceutical salt of olodaterol and water with the pH value adjusted by hydrochloric acid are mixed uniformly, and the surface tension of the whole solution is adjusted to the following table by an aqueous solution of an inhalable surfactant.
100ml of pharmaceutical formulation:
Figure BDA0001791565950000051
Figure BDA0001791565950000061
example 2
The preparation method comprises the following steps: tiotropium bromide or tiotropium bromide monohydrate, the pharmaceutical salt of the olodaterol, the bacteriostatic agent and water with the pH value adjusted by hydrochloric acid are mixed uniformly, and the surface tension of the aqueous solution is adjusted to the following table by using the surfactant.
100ml of pharmaceutical formulation:
Figure BDA0001791565950000062
Figure BDA0001791565950000071
Figure BDA0001791565950000081
example 3
The preparation method comprises the following steps: tiotropium bromide or tiotropium bromide monohydrate, the pharmaceutical salt of the olodaterol, the bacteriostatic agent and water with the pH value adjusted by hydrochloric acid are mixed uniformly, and the surface tension of the aqueous solution is adjusted to the following table by using the surfactant.
100ml of pharmaceutical formulation:
Figure BDA0001791565950000082
comparative example 1
The preparation method comprises the following steps: tiotropium bromide or tiotropium bromide monohydrate, the pharmaceutical salt of olodaterol and water with the pH value adjusted by hydrochloric acid are mixed uniformly, and the surface tension of the whole solution is adjusted to the following table by an aqueous solution of an inhalable surfactant.
100ml of pharmaceutical formulation:
Figure BDA0001791565950000083
Figure BDA0001791565950000091
Figure BDA0001791565950000101
spray particle size test
The pharmaceutical compositions obtained in examples and comparative examples were sprayed with a BI spray device, neruole, and the spray droplet size was measured with a german SYMPATEC laser particle sizer (HELOS-spray). The detection method comprises spraying 2 times before discarding the medicinal composition, measuring the average spray droplet diameter after spraying the medicinal composition, standing for 4 days, spraying 10 times again, and measuring the average spray droplet diameter.
Figure BDA0001791565950000102
Figure BDA0001791565950000111
Spray time test
The test method comprises the following steps: the pharmaceutical compositions obtained in examples and comparative examples were sprayed using a spray device available from BI corporation, nerolida, and the time from the start to the end of spraying was measured 10 times and averaged.
Figure BDA0001791565950000112
Figure BDA0001791565950000121
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 BDA0001791565950000122
Figure BDA0001791565950000131
The above examples demonstrate the application of surfactant to properly change the surface tension of a propellant-free pharmaceutical composition spray comprising tiotropium bromide or its hydrate, water, and the surface tension of the pharmaceutical composition is verified to have better effect by spray particle size test, spray time test, and spray speed test.

Claims (10)

1. The tiotropium bromide compound spray medicine composition without propellant is characterized by comprising tiotropium bromide or hydrate thereof, pharmaceutical salt of odaterol, an inhalable surfactant, an inorganic acidic pH value regulator and water, wherein the surface tension of the tiotropium bromide compound spray medicine composition is regulated to be 52 +/-2 mN/m by the inhalable surfactant.
2. The pharmaceutical composition of claim 1, wherein the means for measuring surface tension is by hanging drop method.
3. The pharmaceutical composition of claim 1, further comprising a bacteriostatic agent.
4. The pharmaceutical composition of claim 3, wherein the bacteriostatic agent is one of benzalkonium chloride and benzalkonium bromide.
5. A pharmaceutical composition according to claim 1, characterized in that tiotropium bromide or its hydrates is present in an amount of 0.2-0.5 mg/ml calculated as tiotropium.
6. A pharmaceutical composition according to claim 4, characterised in that the benzalkonium chloride or benzalkonium bromide content is between 8 and 12mg/100 ml.
7. The composition according to claim 1, wherein the pharmaceutically acceptable salt of olodaterol is the hydrochloride salt.
8. The surfactant is used as an auxiliary material for changing the spray particle size and the spray speed of the tiotropium bromide spray pharmaceutical composition without a propellant.
9. The pharmaceutical composition according to claims 1 and 12, wherein the inhalable surfactant is one or more of dipalmitoylphosphatidylcholine, phosphatidylglycerol, hexadecanol, tyloxapol, phospholipids, dipalmitoylphosphatidylglycerol.
10. The pharmaceutical composition of claim 1, wherein the PH is 3.0 ± 0.2.
CN201811038751.7A 2018-09-06 2018-09-06 Tiotropium bromide and oxdarterol spray containing surfactant Pending CN110876722A (en)

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CN114028364A (en) * 2021-11-26 2022-02-11 南京华盖制药有限公司 Oldaterol inhalation solution
CN114259481A (en) * 2021-11-26 2022-04-01 南京华盖制药有限公司 Compound inhalation solution of odaterol
CN115397417A (en) * 2020-04-16 2022-11-25 广州谷森制药有限公司 Inhalable solution formulations containing tiotropium bromide and olduterol
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