CN117180235A - Amorphous Lei Fen narasin inhalation preparation - Google Patents
Amorphous Lei Fen narasin inhalation preparation Download PDFInfo
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- CN117180235A CN117180235A CN202311207904.7A CN202311207904A CN117180235A CN 117180235 A CN117180235 A CN 117180235A CN 202311207904 A CN202311207904 A CN 202311207904A CN 117180235 A CN117180235 A CN 117180235A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- VHKXXVVRRDYCIK-CWCPJSEDSA-N Narasin Chemical compound C[C@H]1C[C@H](C)[C@H]([C@@H](CC)C(O)=O)O[C@H]1[C@@H](C)[C@H](O)[C@H](C)C(=O)[C@H](CC)[C@@H]1[C@@H](C)C[C@@H](C)[C@@]2(C=C[C@@H](O)[C@@]3(O[C@@](C)(CC3)[C@@H]3O[C@@H](C)[C@@](O)(CC)CC3)O2)O1 VHKXXVVRRDYCIK-CWCPJSEDSA-N 0.000 title claims description 11
- VHKXXVVRRDYCIK-UHFFFAOYSA-N Narasin Natural products CC1CC(C)C(C(CC)C(O)=O)OC1C(C)C(O)C(C)C(=O)C(CC)C1C(C)CC(C)C2(C=CC(O)C3(OC(C)(CC3)C3OC(C)C(O)(CC)CC3)O2)O1 VHKXXVVRRDYCIK-UHFFFAOYSA-N 0.000 title claims description 11
- 229960001851 narasin Drugs 0.000 title claims description 11
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an inhalation preparation of an amorphous crystal form of raffinacin. The inhalation preparation prepared from the Lei Fen nataxin amorphous crystal has the advantages of good stability, high deposition ratio of effective parts in vivo, good curative effect and low side effect, and provides a new drug choice for the treatment of COPD patients.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to an amorphous Lei Fen natamycin inhalation preparation.
Background
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) is a chronic bronchitis and/or emphysema characterized by airflow obstruction that can further develop into common chronic diseases of pulmonary heart disease and respiratory failure. With the increase in environmental pollution and aging population, the number of COPD patients increases year by year, and respiratory diseases have become the third leading cause of death following cardiovascular and cerebrovascular diseases and malignant tumors. Global COPD patients have been more than 3 million people, with about 500 tens of thousands of deaths per year, based on incomplete statistics. The incidence rate of respiratory diseases in China is about 6.9%, and the respiratory diseases have a sudden growth trend.
The pathogenesis of slow-blocking lung is complex, and is generally thought to be related to several mechanisms, 1, inflammation: chronic inflammation of airways, lung parenchyma and pulmonary blood vessels is a characteristic change of chronic obstructive pulmonary disease, and inflammatory cells such as neutrophils, macrophages, T lymphocytes and the like are involved in the pathogenesis of chronic obstructive pulmonary disease; 2. protease-anti-protease imbalance mechanism: proteolytic enzymes have a damaging and destroying effect on tissues; the anti-protease has an inhibitory function on various proteases such as elastase, and among them, α1 antitrypsin (α1-AT) is one of the most active. Increased protease or insufficient protease resistance can lead to tissue structure destruction, resulting in emphysema; 3. oxidative stress mechanism: oxides such as superoxide anions, hydroxyl radicals, hypochlorous acid, H2O2, nitric oxide and the like can directly act and destroy many biochemical macromolecules such as proteins, lipids, nucleic acids and the like, so that cell dysfunction or cell death is caused, and can destroy extracellular matrix, cause protease-antiprotease imbalance and promote inflammatory reaction. 4. Other mechanisms: including autonomic dysfunction, malnutrition, air temperature changes, etc.
The mechanisms work together to ultimately produce two important lesions: 1. small airway lesions, including small airway inflammation, small airway fibrous tissue formation, small airway lumen mucus plug and the like, cause the small airway resistance to be obviously increased; 2. the pulmonary emphysema lesion reduces the normal tension of the alveoli on the small airways, which are more prone to collapse. Meanwhile, pulmonary emphysema obviously reduces the elastic retraction force of pulmonary alveoli. This small airway lesion works together with emphysema lesions to create persistent airflow limitation characteristic of slow lung obstruction.
Inhalation formulations are the preferred dosage form for the treatment of COPD respiratory diseases. Common inhaled drugs can be divided into two main categories according to pharmacological actions: (1) bronchodilators: bronchodilators are basic first-line therapeutic drugs for chronic obstructive pulmonary disease, which relieve the symptoms of chronic obstructive pulmonary disease by dilating bronchi by relaxing airway smooth muscle and improving airflow limitation, and the main bronchodilators are beta 2 The receptor agonist, anticholinergic and methylxanthine can be selected according to the drug effect and the therapeutic response of patients. (2) inhalation of glucocorticoid: chronic obstructive pulmonary stabilization with single application of ICS therapy alone does not prevent FEV 1 There is no significant improvement in mortality, so it is not recommended to use a single ICS treatment for patients with stable phase slow pulmonary resistance.
Lei Fen Naxin is a long-acting anticholinergic drug which inhibits the tracheal contraction caused by the release of acetylcholine from parasympathetic nerve ends by binding to M3 muscarinic receptors on bronchial smooth muscle, and is clinically mainly used for the maintenance treatment of chronic obstructive pulmonary disease, including the maintenance treatment of chronic bronchitis and emphysema accompanied with dyspnea and the prevention of acute attacks. The current Lei Fen nataxin marketed formulation is Lei Fen nataxin solution for inhalation, developed by the company Irelaveland theravelance biopharmaceutical, inc. in conjunction with Mylan pharmaceutical, U.S. and approved for marketing by the U.S. FDA at month 11 in 2018 under the trade name Yupelri.
The deposition rate of the inhaled solution agent in the lung is very low and is only 10% -20%, most patients can only carry out atomization treatment in hospitals, the equipment is large in size and inconvenient to carry, the convenience of administration is greatly reduced, and the treatment effect is affected. The lung deposition rate of the inhalation powder spray is obviously higher than that of inhalation solution, can reach more than 50 percent, is convenient to carry, and can well meet clinical administration requirements.
Chinese patent document CN101163677a discloses Lei Fen crystalline forms of naproxen diphosphate, monosulfate, hydrogen oxalate, and Lei Fen crystalline forms i and ii of naproxen free base. Lei Fen Naxin free base form I in this document uses H 2 O and ACN are prepared, and crystal formsII was prepared using ACN and MTBE. Chinese patent CN102470130a discloses Lei Fen natacine free base forms III and iv. The free base form III was prepared using MeCN or isopropyl acetate. The free base form IV is converted from form III. In practical research, the inventor finds that Lei Fen natamycin free alkali is easy to form a solvate, solvent residues are difficult to remove completely in the preparation process of the crystal form, the yield of the crystal form I and the crystal form II is low, and the stability is poor. The preparation method of the crystal form IV is complex. None of the above forms are suitable for commercial production, and only form III is currently used in commercial formulation products.
Disclosure of Invention
According to the invention, research is carried out on the Lei Fen nadine amorphous crystal form, the inhalation powder fog agent is further prepared, and the Lei Fen nadine amorphous crystal form has the best preparation performance through the comparison of the preparation performances and the stability among different crystal forms. In addition, animal pharmacokinetic experiments and tissue distribution experiments show that the inhalation powder fog agent prepared by using the Lei Fen nadir amorphous crystal form has lower peak blood drug concentration and systemic exposure, and the deposition of the inhalation powder fog agent on an effective part is higher, so that the Lei Fen nadir amorphous crystal form inhalation powder fog agent has better drug curative effect and lower drug side effect.
The specific technical scheme of the invention is as follows:
an amorphous crystalline form of raffinacin having the following structural formula:
the Lei Fen nataxin amorphous form is a typical dispersive peak and has an X-ray powder diffraction peak pattern as shown in figure 1.
The Lei Fen nataxin amorphous crystal form has a DSC spectrum shown in figure 2.
The Lei Fen narasin amorphous crystal form has the infrared spectrum characteristics shown in figure 3. The infrared spectrum of the crystal form has infrared absorption at 3195+ -3 cm-1, 3057+ -3 cm-1, 1206+ -3 cm-1 and 1009+ -3 cm-1. Further at 3419 + -3cm -1 、2943±3cm -1 、2806±3cm -1 、1918±3cm -1 、1731±3cm -1 、1673±3cm -1 、1615±3cm -1 、1518±3cm -1 、1493±3cm -1 、1488±3cm -1 、1401±3cm -1 、1339±3cm -1 、1141±3cm -1 、1044±3cm -1 、934±3cm -1 、858±3cm -1 、749±3cm -1 、702±3cm -1 、556±3cm -1 There is infrared absorption.
The Lei Fen narasin amorphous crystal form can be prepared by the following method:
a) Dissolving Lei Fen nacin in a corresponding organic solvent to obtain Lei Fen nacin solution;
b) Heating to dissolve, stirring and filtering;
c) Evaporating the organic solvent under reduced pressure to obtain amorphous Lei Fen natacine.
The solvent is one or more of ethyl acetate, acetone and absolute ethyl alcohol.
Furthermore, the invention also provides a preparation for inhalation of the raffinancin, and the Lei Fen amorphous crystal form of the raffinancin is adopted as a main active ingredient of the medicine.
The inhalation preparation can be inhalation aerosol, inhalation spray and inhalation powder spray.
The inhalation powder spray provided by the invention further comprises one or more of a carrier and a dispersing aid.
The carrier is one or more selected from lactose, dextran and mannitol.
The dispersing aid is one or more selected from sodium stearate, magnesium stearate, calcium stearate and colloidal silicon dioxide.
The carrier is preferably lactose.
The dispersing aid is magnesium stearate.
In the inhalation preparation, the particle size distribution of the Lei Fen narasin amorphous crystal form is D 10 ：0.3～1.2μm；D 50 ：1.5～4μm；D 90 : 2.5-10 mu m. Preferably Lei Fen NaxinThe particle size distribution of the shaped crystal form is D 10 ：0.4～1.0μm；D 50 ：2～3.5μm；D 90 ：3～7μm。
The preparation method of the inhalation powder spray comprises the following steps:
1) After stirring and mixing part of the prescription amount of magnesium stearate and amorphous Lei Fen nacin raw materials, transferring the mixture to a jet mill for co-micronization to prepare Lei Fen nacin compound conforming to the particle size distribution.
2) The remaining prescribed amount of magnesium stearate and the total prescribed amount of lactose were placed in a TRV high shear mixing apparatus, and the mixing speed and mixing time were set to prepare a lactose premix.
3) The Lei Fen total lactose blend was prepared by sequentially tiling about 1/2 of the lactose premix, all Lei Fen of the total lactose premix, and the remaining about 1/2 of the lactose premix into the TRV mixing apparatus, setting the mixing speed and mixing time.
4) Lei Fen Naxin total mixture powder was taken and filled into capsules at a fill level of 25 mg.+ -.1 mg to prepare Lei Fen Naxin inhalation powder aerosol capsules which could be delivered to the lungs for administration by a dry powder inhalation device.
5) And (5) packaging the medicine-carrying capsules by double aluminum.
The Lei Fen nadine amorphous crystal form can be used for preparing medicines for treating chronic obstructive pulmonary disease, chronic bronchitis and emphysema.
The invention has the advantages that:
1. the inhalation powder fog agent prepared by the Lei Fen nadine amorphous crystal form has higher micro-particle fraction compared with the commercial Lei Fen nadine inhalation solution agent.
2. Compared with inhalation powder mists prepared by using other crystal forms (such as free base crystal form I and crystal form III), the inhalation powder mists prepared by the Lei Fen nataxin amorphous crystal form provided by the invention have higher micro-particle fraction and preparation stability.
3. The inhalation powder spray prepared by using the Lei Fen nadine amorphous crystal form has lower peak blood concentration and systemic exposure, and has higher deposition on the effective part, which indicates that the Lei Fen nadine amorphous crystal form inhalation powder spray has better drug curative effect and lower drug side effect.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of amorphous Lei Fen natacine.
FIG. 2 Differential Scanning Calorimetry (DSC) curve of amorphous Lei Fen nataxin.
Figure 3 infrared spectrum of amorphous Lei Fen natacine.
Detailed Description
The present invention is described in detail below in connection with specific embodiments and exemplary examples, but these descriptions should not be construed as limiting the invention in any way. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, and these all fall within the scope of the present invention. The scope of the invention is defined by the appended claims. Specific examples are set forth below:
example 1 preparation of Lei Fen amorphous form of Naxin
To a 1000mL round bottom flask was added 25.0g Lei Fen of the free base and 200mL of ethyl acetate. Stirring is started, the temperature is raised to 40 ℃ to Lei Fen ℃ for dissolving the natamycin, and the heat filtration is carried out after the solution is cleared. The filtrate was distilled off under reduced pressure to obtain amorphous Lei Fen natacine.
The Lei Fen narasin PXRD, DSC, IR detection method comprises the following steps:
x-ray powder diffraction (PXRD): model Empyrean, step width 0.026 °, step time 50s. The X-ray powder diffraction pattern is shown in FIG. 1.
Differential scanning thermal analyzer (DSC): model DSC214Polyma gas purge gas 40ml/min and shielding gas 60ml/min. The temperature rising rate is 10K/min. The temperature ranges from 25 ℃ to 200 ℃. The Differential Scanning Calorimetry (DSC) curve is shown in figure 2.
Infrared spectrometry test (IR), model: the Nicolet iS5 infrared spectrophotometer and was detected using KBr pellet. The infrared spectrum is shown in figure 3.
EXAMPLE 2 preparation of Lei Fen Naxin free base form I (Chinese patent document CN 101163677A)
5.04g Lei Fen of the free alkali was dissolved in 14.4ml of a water/acetonitrile (1:1) mixture. The suspension was left in the vial (the cap was loosely placed on top) to allow for slower evaporation times. Refrigerating the vial at 4 ℃ for 6 days, filtering the obtained precipitate, and then carrying out vacuum drying at 35-40 ℃ to remove all solvents, thereby obtaining white solid which is Lei Fen natamycin free alkali crystal form I.
Example 3 preparation of Lei Fen Naxin form III (Chinese patent document CN 102470130A)
Lei Fen the free base of that which was present (3.07 g) was dissolved in acetonitrile (15 mL). The solution was stirred at room temperature for 80 minutes and a white solid precipitate formed. The mixture was placed in an oscillator zone (block) to be thermally cycled (0 ℃ C. To 40 ℃ C. In a 1 hour zone) for 48 hours. A white dense static solid was observed. Acetonitrile (15 mL) was added to flow the slurry. The mixture was then placed back into the shaker section and held for 2 hours. The solid was isolated by vacuum filtration using a sintered funnel, followed by vacuum drying at 35-40 ℃ for 15.5 hours to produce crystalline form III Lei Fen natamycin.
Example 4 preparation of Lei Fen Naxin amorphous form inhalation powder
1) Weighing 0.054g of magnesium stearate and 1.0200g of amorphous Lei Fen nacin, stirring and mixing for 10min, transferring into a jet mill, and co-micronizing at 5bar pulverizing pressure to D 10 ：0.6μm；D 50 ：2.5μm；D 90 :4.7 μm to obtain Lei Fen natacine complex.
2) 1.646g of magnesium stearate with the remaining prescription amount and 337.280g of lactose with the total prescription amount are weighed and placed in a TRV high shear mixing device to be mixed for 6min at a mixing speed of 500.0r/min, and then discharged to obtain a lactose premix.
3) Sequentially, about 1/2 lactose premix, all Lei Fen nacin compound and the remaining about 1/2 lactose premix were added in a flat manner to the TRV mixing apparatus, the mixing speed was set at 1150r/min, mixing was carried out for 3min, and the Lei Fen nacin total mixture was obtained.
4) Lei Fen Naxin total mixture powder was taken and filled into capsules at a fill level of 25 mg.+ -.1 mg to prepare Lei Fen Naxin inhalation powder aerosol capsules which could be delivered to the lungs for administration by a dry powder inhalation device.
5) And (5) packaging the medicine-carrying capsules by double aluminum.
Table 1 Lei Fen Incine inhalation powder (amorphous Lei Fen Incine) formulation
| Composition of the components | Prescription dosage | Action |
| Lactose and lactose | 337.28g | Carrier body |
| Magnesium stearate | 1.70g | Dispersing aid |
| Lei Fen Naxin (amorphous) | 1.020g | Active ingredient |
EXAMPLE 5 preparation of Lei Fen Naxin free base form I inhalation powder
1) Weighing 0.054g of magnesium stearate and 1.0200g of Lei Fen nafion free alkali crystal form I, stirring and mixing for 10min, transferring into a jet mill, and co-micronizing to D at 5bar pulverizing pressure 10 ：0.6μm；D 50 ：2.6μm；D 90 :4.9 μm to obtain Lei Fen natacine complex.
2) 1.646g of magnesium stearate with the remaining prescription amount and 337.280g of lactose with the total prescription amount are weighed and placed in a TRV high shear mixing device to be mixed for 6min at a mixing speed of 500.0r/min, and then discharged to obtain a lactose premix.
3) Sequentially, about 1/2 lactose premix, all Lei Fen nacin compound and the remaining about 1/2 lactose premix were added in a flat manner to the TRV mixing apparatus, the mixing speed was set at 1150r/min, mixing was carried out for 3min, and the Lei Fen nacin total mixture was obtained.
4) Lei Fen Naxin total mixture powder was taken and filled into capsules at a fill level of 25 mg.+ -.1 mg to prepare Lei Fen Naxin inhalation powder aerosol capsules which could be delivered to the lungs for administration by a dry powder inhalation device.
5) And (5) packaging the medicine-carrying capsules by double aluminum.
Table 2 Lei Fen prescription of inhalation powder for foggy (Lei Fen Naxin free base form I)
| Composition of the components | Prescription dosage | Action |
| Lactose and lactose | 337.28g | Carrier body |
| Magnesium stearate | 1.70g | Dispersing aid |
| Lei Fen Naxin (free base form I) | 1.020g | Active ingredient |
Example 6 preparation of Lei Fen Naxin Crystal form III inhalation powder
1) Weighing 0.054g of magnesium stearate and 1.0200g of Lei Fen nacin crystal form III, stirring and mixing for 10min, transferring into a jet mill, and co-micronizing to D at 5bar pulverizing pressure 10 ：0.5μm；D 50 ：2.3μm；D 90 :4.4 μm to obtain Lei Fen natacine complex.
2) 1.646g of magnesium stearate with the remaining prescription amount and 337.280g of lactose with the total prescription amount are weighed and placed in a TRV high shear mixing device to be mixed for 6min at a mixing speed of 500.0r/min, and then discharged to obtain a lactose premix.
3) Sequentially, about 1/2 lactose premix, all Lei Fen nacin compound and the remaining about 1/2 lactose premix were added in a flat manner to the TRV mixing apparatus, the mixing speed was set at 1150r/min, mixing was carried out for 3min, and the Lei Fen nacin total mixture was obtained.
4) Lei Fen Naxin total mixture powder was taken and filled into capsules at a fill level of 25 mg.+ -.1 mg to prepare Lei Fen Naxin inhalation powder aerosol capsules which could be delivered to the lungs for administration by a dry powder inhalation device.
5) And (5) packaging the medicine-carrying capsules by double aluminum.
Table 3 Lei Fen Incine inhalation powder for inhalation (Lei Fen Incine form III) formulation
| Composition of the components | Prescription dosage | Action |
| Lactose and lactose | 337.28g | Carrier body |
| Magnesium stearate | 1.70g | Dispersing aid |
| Lei Fen Naxin (Crystal form III) | 1.020g | Active ingredient |
EXAMPLE 7 study of stability of different crystalline forms of Lei Fen Naxin inhaled powder formulations
The Lei Fen-narsin inhalation powder foggers of different crystal forms prepared in examples 4 to 6 were placed in an environment of 40℃and 75% RH, and the changes in the dose, content, relative substances, etc. of the fine particles of the products were measured at intervals, and the results are shown in Table 5.
The method for detecting Lei Fen narasin related substances is as follows:
the method is based on the following steps: liquid chromatography (chinese pharmacopoeia 2010 edition two appendix vd).
Chromatographic conditions:
high Performance Liquid Chromatograph (HPLC): model Waters e2695, mobile phase a:0.01mol/L monoammonium phosphate solution (pH is adjusted to 2.95 by phosphoric acid), and filtering and ultrasonic treatment are carried out to obtain the catalyst. Mobile phase B: acetonitrile, column temperature: 40 ℃, detection wavelength: 230nm, column: YMC Triart C18 column (4.6 mm. Times.150 mm,3 μm).
Preparing a solution:
(1) A diluent: acetonitrile mobile phase a=20:80.
(2) Test solution: taking 10mg of the product, precisely weighing, placing into a 20ml measuring flask, adding a proper amount of diluent to dissolve completely, diluting to scale with the diluent, and shaking uniformly to obtain the solution of the sample.
Gradient elution:
| time (min) | Mobile phase A% | Mobile phase B% |
| 0 | 85 | 15 |
| 3 | 85 | 15 |
| 30 | 35 | 65 |
| 35 | 35 | 65 |
| 37 | 85 | 15 |
| 45 | 85 | 15 |
Table 4 stability investigation conditions
| Investigation of conditions | Specific conditions |
| Acceleration of | Temperature: 40 ℃ +/-2 ℃ and relative humidity of 75% +/-5% |
Table 5 stability investigation results
The dosage and the fraction of the fine particles of the inhalation powder spray prepared by using the amorphous Lei Fen natacine are obviously higher than those of the inhalation powder spray prepared by using Lei Fen natacine free alkali crystal forms I and III. In the stability investigation test, the dose and the fraction of the fine particles of the amorphous Lei Fen natamycin inhalation powder fog agent are kept stable within 3 months, and the dose and the fraction of the fine particles of the Lei Fen natamycin free alkali crystalline form I and the crystalline form III inhalation powder fog agent are in a descending trend within 3 months. The amorphous Lei Fen nataxin inhalation powder fog agent has slow growth of related substances within 3 months of acceleration, and Lei Fen nataxin free alkali crystal form I and crystal form III inhalation powder fog agent has obvious acceleration of related substances within 3 months of acceleration.
EXAMPLE 8 pharmacokinetic manifestation of different crystalline forms of Lei Fen Naxin inhaled powder in rats
Male SD rats (SPF grade) aged 9 months and weighing 180-220 g were used in this example. Throughout the experiment, rats were fed water freely. SD rats for testing were grouped into Lei Fen and Lei Fen naproxen free base form I and Lei Fen naproxen form III inhalation powder aerosol groups, each group being 24. The administration was carried out by inhalation into the mouth and nose of rats, and the administration dose was 375. Mu.g/kg (Lei Fen, xin Ji).
0.5ml venous blood is collected from the fundus venous plexus at 0.1h, 0.2h, 0.5h,2h,6h,12h,24h,48h,60h,72h,96h and 120h after administration and placed in an anticoagulated EP tube of EDTA (4 mM) labeled in advance, whole blood is collected and placed on ice, plasma is collected immediately by centrifugation at 8000rpm for 5min at 4 ℃, transferred to a 96-well plate, and stored at-20 ℃ until LC-MS/MS detection. The drug concentration in EDTA (4 mM) anticoagulated SD rat plasma was determined using the LC/MS/MS (Agilent 6460) method. The relevant pharmacokinetic parameters of the concentrations at each time point after each group of administration were calculated according to the statistical distance theory using winnonlin5.2 software, and are shown in table 6.
TABLE 6 in vivo pharmacokinetic manifestations of different crystalline forms Lei Fen Naxin inhaled powder nebuliser rats
The in vivo pharmacokinetic results of rats show that the Lei Fen narsin amorphous crystal form inhalation powder aerosol has the lowest peak blood concentration C max And AUC 0-∞ The Lei Fen nadine amorphous crystal form inhalation powder spray agent is obviously superior to Lei Fen nadine free alkali crystal form I inhalation powder spray agent group and Lei Fen nadine crystal form III inhalation powder spray agent group in safety.
EXAMPLE 9 manifestation of different crystalline forms of Lei Fen Naxin inhaled powder mist in rat tissue distribution
Preparation selection: lei Fen narasin inhalation powder foggers of three different crystal forms prepared in examples 4 to 6
Frequency of administration: single administration
Route of administration: inhalation through the mouth and nose
Test animals: SD rat
Grouping: a total of 108 SD rats are divided into a 375 mug/kg dose group of amorphous Lei Fen nataxin inhalation powder fog agent, a 375 mug/kg dose group of Lei Fen nataxin free base crystal form I inhalation powder fog agent and a 375 mug/kg dose group of Lei Fen nataxin crystal form III inhalation powder fog agent, and 36 rats are in each group. The drug concentrations of alveolar lavage fluid, lung tissue, main trachea, bronchi, bladder, heart, liver and kidneys of the animals were collected 0.5h after dosing, respectively.
TABLE 7 distribution of Lei Fen Naxin in vivo in major organs and tissues after 0.5h inhalation of the two formulations in rats
Lei Fen Naxin is a long acting anticholinergic with similar affinity to the sarcosine receptor M1-M5 subtype. In the airway, it exhibits pharmacological actions by inhibiting bronchiectasis caused by smooth muscle M3 receptors. Smooth muscle M3 receptors are mainly located in the tracheal and bronchial regions, the main pharmacodynamic site of Lei Fen natacine. As can be seen from the animal tissue distribution test, after 0.5h of inhalation administration, the concentration of the amorphous Lei Fen-sodium inhalation powder spray at the lung tissue, main air duct and bronchus of the drug effect part is obviously higher than that of Yu Leifen-sodium inhalation powder spray and Lei Fen-sodium inhalation powder spray of crystal form III, and the concentration of the amorphous Lei Fen-sodium inhalation powder spray at the bladder, heart and the like which can generate clinical side effects (such as urinary retention) is obviously lower than that of Lei Fen-sodium inhalation powder spray of other two crystal forms, which suggests that the amorphous Lei Fen-sodium inhalation powder spray can generate higher bronchodilations than that of Lei Fen-sodium inhalation powder spray of crystal form I and Lei Fen-sodium inhalation powder spray of crystal form III and lower clinical side effects.
Claims (10)
1. An inhaled preparation of raffinancin, characterized in that the amorphous form of Lei Fen financin is used as the main active ingredient, and the X-ray powder diffraction pattern of the amorphous form of Lei Fen financin is shown in figure 1.
2. The inhalation formulation according to claim 1, characterized in that the inhalation formulation is an inhalation aerosol, an inhalation spray, an inhalation powder mist.
3. The inhalation formulation according to claim 2, characterized in that the inhalation formulation is an inhalation powder aerosol.
4. The inhalation formulation according to claim 3, wherein the inhalation powder comprises one or more of a carrier and a dispersing aid.
5. The inhalation formulation according to claim 4, wherein the carrier is selected from one or more of lactose, dextran, mannitol; the dispersing aid is one or more selected from sodium stearate, magnesium stearate, calcium stearate and colloidal silicon dioxide.
6. The inhalation formulation according to claim 5, characterised in that the carrier is lactose; the dispersing aid is magnesium stearate.
7. The inhalation formulation according to claim 1, characterized in that the Lei Fen narasin amorphous form has a particle size distribution D 10 ：0.3～1.2μm；D 50 ：1.5～4μm；D 90 ：2.5～10μm。
8. The inhalation formulation according to claim 7, characterized in that the Lei Fen narasin amorphous form has a particle size distribution D 10 ：0.4～1.0μm；D 50 ：2～3.5μm；D 90 ：3～7μm。
9. Inhalation formulation according to claims 1 to 8, characterized in that the inhalation formulation has the following components in parts by weight:
lei Fen narasin 0.5-10 parts;
982 to 997.5 portions of lactose;
2-8 parts of magnesium stearate.
10. Use of an inhaled formulation of Lei Fen naproxen according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease, chronic bronchitis, emphysema.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101163677A (en) * | 2005-03-10 | 2008-04-16 | 施万制药 | Crystalline forms of a biphenyl compound |
| CN102470130A (en) * | 2009-07-15 | 2012-05-23 | 施万制药 | Crystalline freebase forms of a biphenyl compound |
| IN202011029286A (en) * | 2020-07-10 | 2020-10-09 | Mankind Pharma Ltd. | |
| CN114276290A (en) * | 2021-12-24 | 2022-04-05 | 浙江和泽医药科技股份有限公司 | Rifenacin anhydrous crystal form and preparation method thereof |
| CN116077471A (en) * | 2021-11-08 | 2023-05-09 | 上海臣邦医药科技股份有限公司 | Powder aerosol composition for inhalation and preparation method and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101163677A (en) * | 2005-03-10 | 2008-04-16 | 施万制药 | Crystalline forms of a biphenyl compound |
| CN102470130A (en) * | 2009-07-15 | 2012-05-23 | 施万制药 | Crystalline freebase forms of a biphenyl compound |
| IN202011029286A (en) * | 2020-07-10 | 2020-10-09 | Mankind Pharma Ltd. | |
| CN116077471A (en) * | 2021-11-08 | 2023-05-09 | 上海臣邦医药科技股份有限公司 | Powder aerosol composition for inhalation and preparation method and application thereof |
| CN114276290A (en) * | 2021-12-24 | 2022-04-05 | 浙江和泽医药科技股份有限公司 | Rifenacin anhydrous crystal form and preparation method thereof |
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