CN110876723A - Isopropyl tropium bromide spray containing surfactant - Google Patents
Isopropyl tropium bromide spray containing surfactant Download PDFInfo
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- CN110876723A CN110876723A CN201811039426.2A CN201811039426A CN110876723A CN 110876723 A CN110876723 A CN 110876723A CN 201811039426 A CN201811039426 A CN 201811039426A CN 110876723 A CN110876723 A CN 110876723A
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- pharmaceutical composition
- spray
- surfactant
- ipratropium bromide
- bromide
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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
-
- 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
- A61K47/08—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
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
Abstract
The invention relates to an ipratropium bromide 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 the composition to be more suitable by adjusting the surface tension of an ipratropium bromide spray pharmaceutical composition without a propellant.
Description
The technical field is as follows:
the invention relates to a tiotropium bromide 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 tiotropium bromide aerosol pharmaceutical composition to be more suitable by adjusting the surface tension of the tiotropium bromide aerosol 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, they 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 with high affinity for 4-DAMP is called M3 receptor; the M4 receptor is called as the receptor with high affinity with P-F-HHSID. However, there are at least 5 different genes encoding mAChR, designated m1, m 2, m 3, m4, m 5, and the human genes have chromosomal locations 1lql 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 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 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.
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.
The patent CN201610353067.2 describes an ipratropium bromide aerosol formulation containing anhydrous citric acid, anhydrous ethanol, and 1,1,1, 2-tetrafluoroethane.
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.
The invention content is as follows:
it has been surprisingly found that in a composition comprising ipratropium bromide or a hydrate thereof, an inhalable surfactant, an inorganic acidic PH regulator and water, the surface tension of the inhalable surfactant is regulated to provide a better control range of the spray particle size of the propellant-free pharmaceutical spray composition, thereby prolonging the spray time and reducing the spray rate.
The ipratropium bromide aerosol medicine composition without propellant is characterized by comprising ipratropium bromide or hydrate thereof, an inhalable surfactant, an inorganic acid pH value regulator and water, wherein the surface tension of the inhalable surfactant is regulated to 52 +/-2 mN/m.
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 is characterized in that the content of ipratropium bromide or the hydrate thereof is 0.2-0.5 mg/ml calculated by tiotropium.
The surfactant is used as an auxiliary material for changing the spraying particle size and the spraying speed of the ipratropium bromide aerosol medicine 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.
As the ipratropium bromide monohydrate and the ipratropium bromide are all dissolved in water within the technical scheme, the ipratropium bromide monohydrate and the ipratropium bromide have no influence on the preparation.
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: isoipratropium bromide or ipratropium bromide monohydrate is mixed uniformly with water adjusted to pH with hydrochloric acid, and the surface tension of the overall solution is adjusted to the table below with an aqueous solution of an inhalable surfactant.
100ml of pharmaceutical formulation:
example 2
The preparation method comprises the following steps: the ipratropium bromide or ipratropium bromide monohydrate, the bacteriostatic agent and the water with the pH value adjusted by hydrochloric acid are mixed evenly, and the surface tension of the aqueous solution is adjusted to the following table by the surfactant.
100ml of pharmaceutical formulation:
example 3
The preparation method comprises the following steps: the ipratropium bromide or ipratropium bromide monohydrate, the bacteriostatic agent and the water with the pH value adjusted by hydrochloric acid are mixed evenly, and the surface tension of the aqueous solution is adjusted to the following table by the surfactant.
100ml of pharmaceutical formulation:
comparative example 1
The preparation method comprises the following steps: isoipratropium bromide or ipratropium bromide monohydrate is mixed uniformly with water adjusted to pH with hydrochloric acid, and the surface tension of the overall solution is adjusted to the table below with an aqueous solution of an inhalable surfactant.
100ml of pharmaceutical formulation:
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.
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.
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.
The above examples demonstrate the application of surfactant to properly change the surface tension of aerosol pharmaceutical composition comprising ipratropium bromide or its hydrate and water, which contains no propellant, 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 ipratropium bromide aerosol medicine composition without propellant is characterized by comprising ipratropium bromide or hydrate thereof, an inhalable surfactant, an inorganic acid pH value regulator and water, wherein the surface tension of the inhalable surfactant is regulated to 52 +/-2 mN/m.
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. The pharmaceutical composition according to claim 1, wherein ipratropium bromide or its hydrate is present in an amount of 0.2 to 0.5 mg/ml calculated as tiotropium.
6. A pharmaceutical composition according to claim 3, characterised in that the benzalkonium chloride or benzalkonium bromide content is 8-12mg/100 ml.
7. The surfactant is used as an auxiliary material for changing the spraying particle size and the spraying speed of the ipratropium bromide aerosol medicine composition without a propellant.
8. The pharmaceutical composition of claim 1, wherein the inhalable surfactant is one or more of dipalmitoylphosphatidylcholine, phosphatidylglycerol, cetyl alcohol, tyloxapol, phospholipids, dipalmitoylphosphatidylglycerol.
9. The pharmaceutical composition of claim 10, wherein the phospholipid is soybean phospholipid.
10. The pharmaceutical composition of claim 1, wherein the PH is 3.0 ± 0.2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811039426.2A CN110876723A (en) | 2018-09-06 | 2018-09-06 | Isopropyl tropium bromide spray containing surfactant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811039426.2A CN110876723A (en) | 2018-09-06 | 2018-09-06 | Isopropyl tropium bromide spray containing surfactant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110876723A true CN110876723A (en) | 2020-03-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811039426.2A Pending CN110876723A (en) | 2018-09-06 | 2018-09-06 | Isopropyl tropium bromide spray containing surfactant |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018280A (en) * | 2021-03-01 | 2021-06-25 | 石家庄四药有限公司 | Solution preparation for ipratropium bromide inhalation and preparation method thereof |
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2018
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018280A (en) * | 2021-03-01 | 2021-06-25 | 石家庄四药有限公司 | Solution preparation for ipratropium bromide inhalation and preparation method thereof |
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Application publication date: 20200313 |