CN112451509A - Chuangbuterol powder inhalation and preparation method thereof - Google Patents
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Abstract
The invention belongs to the field of medicinal preparations, and relates to a novel beta 2-adrenoreceptor agonist salbutamol and a powder inhalation of hydrochloride thereof, a preparation method thereof, and application of the powder inhalation in preparation of medicaments for treating asthma and chronic obstructive pulmonary disease. The invention comprises a salbutamol inhalation powder aerosol as an active ingredient and a carrier subjected to surface modification. Wherein the weight percentage of each component is as follows: 0.05-0.25% of active ingredient, 99.75-99.95% of carrier with modified surface. The surface modified carrier is as follows: one or more of magnesium stearate, lactose or leucine micropowder is/are used as a surface modifier, and one or more of lactose, mannitol or leucine is/are used as a carrier. The surface modifier of the invention is added to exert the surface modification effect on the carrier, improve the aerodynamic property of the final aerosol and facilitate better deposition of drug particles in the lung. Improves the fluidity of the powder spray, is convenient for filling, reduces the hygroscopicity of the medicine and is convenient for storage.
Description
The technical field is as follows:
the invention belongs to the field of medicinal preparations, and relates to a novel beta 2-adrenoceptor agonist-salbutamol and a powder inhalation of hydrochloride thereof, a preparation method of the powder inhalation, and application of the powder inhalation in treatment of lung diseases such as asthma, chronic obstructive pulmonary disease and the like.
Background art:
the selective beta 2 receptor agonist generates a bronchodilator effect by exciting beta 2 receptors on airway smooth muscles, and is a first-line medicament for clinically treating lung diseases such as asthma, chronic obstructive pulmonary disease and the like at present. It can rapidly improve symptoms of dyspnea and cough during acute asthma attack. The salbutamol hydrochloride is a novel high-selectivity beta 2 receptor agonist, can obviously expand airway smooth muscle, stabilize mast cells and enhance the ciliary movement capability of the airway, thereby playing the role of anti-asthma. The composition has strong antiasthmatic effect, and has effect intensity far greater than salbutamol sulfate and longer action time. In addition, compared with other similar medicines, the traditional Chinese medicine composition has less adverse reaction and high safety.
Pulmonary inhalation is the first route of administration for the treatment of pulmonary diseases such as asthma. Compared with systemic administration preparations such as oral tablets and the like, the pulmonary inhalation preparation can rapidly deliver the medicine to the lung, has high medicine concentration at the action part and lower systemic exposure, thereby having quick response and effectively reducing the toxic and side effects of the whole body of the medicine. The lung inhalation preparation comprises three forms of aerosol, powder spray and water mist. A Chuanbuterol hydrochloride aerosol (CN100431535C) was patented by Jiutai pharmaceuticals, Inc. of Jinzhou, Inc. in 2008, 1 month. The aerosol consists of 0.005-0.01 part of salbutamol hydrochloride, 5-10 parts of solvent and 90-95 parts of propellant. The aerosol has the disadvantage of poor stability due to the fact that the medicine is dispersed in the propellant in a dissolved or suspended state. In addition, the aerosol requires the patient to coordinate the spraying and deep-sucking actions during the use process, and has higher technical requirements, which is difficult for the old and the young patients. In addition, the development of aerosol formulations has been limited by the destruction of atmospheric ozone layer by propellants in the formulation.
Dry Powder aerosols, also known as Dry Powder Inhalers (DPI), are formulations in which a Dry drug Powder or a mixed Dry Powder of a drug and an excipient is actively inhaled by the mouth of a patient into the lungs through a specific delivery device. The medicine powder is dispersed by the airflow generated by the active inhalation of the patient to form aerosol which is inhaled into a respiratory system along with the airflow to generate curative effect. The powder inhalation has the advantages of good patient compliance, simple prescription, low cost, stable medicine, environmental protection, no preservative for stimulating mucous membrane and the like. The conventional process flow of the powder cloud agent comprises the steps of crushing, mixing, filling and the like of raw material medicines. Due to the extremely small (microgram level) administration dosage of the salbutamol hydrochloride, the medicine content in the powder is easy to be uneven. In addition, the aerodynamic performance and powder flowability are also key quality attributes of the powder aerosol, and the dispersibility and the lung deposition efficiency of the powder aerosol are influenced. The Fine Particle Fraction (FPF) is often used to evaluate the aerodynamic performance of inhalation formulations. The problems of nonuniform content of the powder aerosol, low FPF (Floating production Filter) and poor powder flowability are solved in the development process of the powder aerosol.
The invention content is as follows:
the invention aims to overcome the defects of the existing Chuanyterol hydrochloride preparation and provides a Chuanyterol (or Chuanyterol hydrochloride) inhalation powder inhalation and a preparation method thereof. The Chuangbuterol (or Chuangbuterol hydrochloride) inhalation powder inhalation provided by the invention has the advantages of uniform drug content, good powder fluidity, easy dispersion, very high FPF value, suitability for pulmonary inhalation administration and capability of obtaining higher pulmonary deposition rate. The invention provides a new choice with better patient compliance for treating lung diseases such as asthma, chronic obstructive pulmonary disease and the like.
The invention is realized by the following technical scheme: the Chuangbuterol powder inhalation comprises an active ingredient and a carrier subjected to surface modification. Wherein the weight percentage of each component is as follows: 0.05-0.25% of active ingredient, 99.75-99.95% of carrier with modified surface.
The active ingredient in the invention is the clenbuterol or the clenbuterol hydrochloride micro powder. The Chuanbuterol or the Chuanbuterol hydrochloride micro powder is characterized in that: wherein the median diameter (D)50) Less than 2 μm, 90% of the particle diameter (D) of the clenbuterol (or clenbuterol hydrochloride) micropowder90) Less than 3 μm.
The surface modified carrier is a carrier surface modified by a surface modifier.
The surface modifier comprises one or more of magnesium stearate, lactose or leucine micropowder. The surface modifier is characterized in that: median diameter (D) of the surface modifier micropowder after micronization50) Less than 5 μm, 90% of the fine powder of the carrier surface modifier (D)90) Less than 10 μm.
The surface modifier is preferably the combination of lactose micropowder and magnesium stearate micropowder, and the weight ratio of the magnesium stearate micropowder to the lactose micropowder is 1: 20- -1: 10.
the carrier is one or more of physiologically-friendly sugar, polyalcohol and amino acid, and is selected from one or more of lactose, sucrose, glucose, fructose, maltose, trehalose, mannitol, xylitol, sorbitol, leucine, alanine, tryptophan, valine, isoleucine, glycine, phenylalanine, proline, serine, tyrosine, cysteine, methionine, glutamic acid, threonine, aspartic acid, glutamine, lysine, arginine, histidine and asparagine. The carrier is preferably one or more of lactose, mannitol or leucine. The support material is characterized in that: d10Greater than 10 μm, D50Less than 100 μm, D90Less than 200 μm.
The surface-modified carrier can be obtained commercially, such as lactose containing 10% lactose micropowder;
the surface-modified support may also be obtained by subjecting the surface-modifying agent to a high shear mixing treatment with the support.
Further, preferred surface-modified supports of the invention are: one or more of magnesium stearate, lactose or leucine micropowder is/are used as a surface modifier, and one or more of lactose, mannitol or leucine is/are used as a carrier. Preferred are lactose carriers containing lactose micropowder, lactose carriers containing magnesium stearate micropowder, mannitol carriers containing magnesium stearate micropowder, lactose carriers containing lactose micropowder, magnesium stearate micropowder, and the like.
The weight ratio of the carrier surface modifier to the carrier is as follows: 1: 399- -25: 75, preferably: 1: 199- -11: 39.
the invention preferably selects the following salbutamol inhalation powder inhalation, which comprises salbutamol or salbutamol hydrochloride micro powder and lactose of 10% micro powder lactose, wherein the weight percentage of each component is 1: 750- -1: 500. the range of the percent fines (FPF) of the powder cloud is: 25 to 35 percent.
The invention preferably selects the following salbutamol inhalation powder inhalation, which comprises salbutamol or salbutamol hydrochloride micro powder, lactose micro powder and lactose, wherein the weight percentage of each component is as follows: 1: 75: 675- -1: 150: 600. the FPF range of the powder spray is as follows: 23 to 38 percent.
The invention preferably selects the following salbutamol inhalation powder inhalation, which comprises salbutamol or salbutamol hydrochloride micro powder, magnesium stearate micro powder and lactose, wherein the weight percentage of each component is as follows: 4: 15: 2985- -4: 45: 2955. the FPF range of the dry powder fog agent is 32-43 percent.
The invention preferably selects the following salbutamol inhalation powder inhalation, which comprises salbutamol or salbutamol hydrochloride micro powder, leucine micro powder and lactose, and the weight percentage of each component is as follows: 4: 15: 2985- -4: 45: 2955. the FPF range of the powder spray is 25-32%.
The invention preferably selects the following salbutamol inhalation powder inhalation, which comprises salbutamol or salbutamol hydrochloride micro powder, magnesium stearate micro powder, lactose micro powder and lactose, wherein the weight percentage of each component is as follows: 1: 5: 100: 1894- -1: 10: 100: 289. the FPF range of the powder spray is 40-51%.
The preparation method of the salbutamol or the salbutamol hydrochloride inhalation powder mist comprises the following steps:
(1) preparing the Chuanbuterol or the Chuanbuterol hydrochloride micro powder;
(2) preparing a surface modified carrier;
(3) the clenbuterol or the clenbuterol hydrochloride micro powder is mixed with the surface modified carrier.
The clenbuterol or the clenbuterol hydrochloride micro powder in the step (1) is prepared by adopting a jet milling method.
And (3) preparing the surface modified carrier in the step (2), namely performing high-shear mixing treatment on the carrier and the carrier surface modifier or the surface modifier micropowder by adopting a mixing granulator. The high shear mixing speed was 100-.
The surface modifier micro powder adopts a median diameter (D)50) Less than 5 μm, D90The powder is commercially available micropowder with particle size less than 10 μm, or is prepared by jet milling.
The preparation method comprises the following steps of (1) preparing the co-pulverized micro powder of the salbutamol and the surface modifier, coarsely mixing the salbutamol or the salbutamol hydrochloride and the surface modified carrier in proportion, and preparing the mixture by adopting a co-airflow pulverization method.
The final atomized powder is obtained by mixing the salbutamol or the salbutamol hydrochloride micro powder with a surface modified carrier. The method is characterized in that the clenbuterol or the clenbuterol hydrochloride micro powder and the surface modified carrier are mixed, the clenbuterol or the clenbuterol hydrochloride micro powder and the surface modified carrier are roughly mixed by adopting an equivalent dilution method, and then the clenbuterol or the clenbuterol hydrochloride micro powder and the surface modified carrier are further mixed by adopting a high-shear mixer. The high shear mixing speed is 100 and 250 rpm. The mixing time is 10-60 min.
In the process of mixing the clenbuterol or the clenbuterol hydrochloride micro powder and the surface modified carrier, the clenbuterol or the clenbuterol hydrochloride micro powder is diluted in equal amount and then mixed, which is beneficial to improving the uniformity of the mixture.
The Chuangbuterol or the Chuangbuterol hydrochloride inhalation powder inhalation is filled by an HPMC capsule of # 3. The filling amount of the capsule is 15 mg/capsule.
The clenbuterol or the clenbuterol hydrochloride inhalation powder aerosol has good content uniformity, and the most preferable formula is clenbuterol hydrochloride micro powder, magnesium stearate micro powder, lactose micro powder and lactose, wherein the clenbuterol hydrochloride or clenbuterol hydrochloride inhalation powder aerosol comprises the following components in percentage by weight: 1: 5: 50: 445- -1: 5: 100: 395, FPF value is above 45%.
After the salbutamol or salbutamol hydrochloride inhalation powder inhalation is stored, the FPF value is stable. The post-storage FPF change value is less than 3%.
The clenbuterol or clenbuterol hydrochloride inhalation powder inhalation is a solid dry powder preparation which uses airflow generated by active inhalation of a patient to inhale medicine powder into the lung and exerts curative effect on the lung. The powder inhalation is characterized in that the particle size distribution, the mixing proportion and the mixing process of the active medicament, the carrier and the carrier surface modifier in the prescription are optimized to obtain the Chuangbuterol or Chuangbuterol hydrochloride powder inhalation which has the advantages of uniform medicament content, low hygroscopicity, good storage stability, excellent aerodynamic property, higher FPF value and suitability for pulmonary inhalation administration. The dry powder inhalation can be applied to capsule type, bubble cap type or storage type inhalation devices. The preparation effectively overcomes the defects of poor stability of the medicine in the aerosol, damage of the propellant to the environment, low deposition rate of the medicine in the lung, need of training a user to coordinate medicine spraying and deep inhalation actions and the like, and provides a new choice for clinical treatment of patients suffering from asthma and chronic obstructive pulmonary diseases.
The carrier is added into the powder inhalation, so that the volume and the weight of the very trace amount of the salbutamol or the salbutamol hydrochloride in the using process are increased, and the medicine is convenient to fill and use. The surface modifier is added to play a role in modifying the surface of the carrier, so that the aerodynamic property of the final aerosol powder is improved, and better deposition of drug particles in the lung is facilitated. Meanwhile, the fluidity of the powder inhalation is improved, the filling is convenient, the hygroscopicity of the medicine is reduced, and the storage of the medicine is convenient.
Description of the drawings:
FIG. 1 aerodynamic measurements of a 100rpm mixing speed for a salbutamol powder aerosol were made in example 1.
Figure 2 aerodynamic measurements of a salbutamol powder aerosol prepared at 250rpm mixing speed in example 2.
The aerodynamic measurement results of the salbutamol powder aerosol in the example of fig. 3.
FIG. 4 aerodynamic measurement results of an accelerated test of a 250rpm mixing speed 30min Chuanyterol powder aerosol in example 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
Prescription:
chuangbuterol hydrochloride 200mg
Lactose containing 10% micropowder lactose 150g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, drying and storing. The prescription dose of the clenbuterol hydrochloride micro powder and the commercial lactose carrier containing 10 percent of micro powder lactose are precisely weighed, sieved by a 60-mesh sieve, mixed, put into a wet granulator, the rotating speed is adjusted to be 100 plus or minus 10rpm, the mixing time is 10 min/time, and mixed for 6 times. After the mixing is finished, collecting the product, drying and storing. The content uniformity results are shown in table 2, which shows that the content uniformity is slightly different at different mixing times, and the aerodynamic measurement results show that the FPF value is 31.2%, and the fluidity test results show that the contact angle is 28.9 °, and the fluidity is good.
Example 2
Prescription:
chuangbuterol hydrochloride 200mg
Lactose containing 10% micropowder lactose 150g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. The clenbuterol hydrochloride micro powder with the prescription amount and the commercial lactose carrier containing 10 percent of micro powder lactose are precisely weighed, sieved by a 60-mesh sieve, mixed, put into a wet granulator, the rotating speed is adjusted to be 250 plus or minus 10rpm, the mixing time is 10 min/time, and mixed for 6 times. After the mixing is finished, collecting the product, drying and storing. The results of content uniformity are shown in Table 3, which shows that the content uniformity is slightly different at different mixing times, and the results of aerodynamic measurement show that the FPF value is 29.6%, and the results of fluidity test show that the contact angle is 29 degrees, and the fluidity is good.
Example 3
Prescription:
chuangbuterol hydrochloride 200mg
Lactose micropowder 15g
Lactose 135g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. Precisely weighing lactose micropowder of prescription dose and lactose carrier without lactose micropowder on market, sieving with 60 mesh sieve, mixing, placing into wet granulator, adjusting rotation speed to 300 + -10 rpm, mixing for 10 min/time, and mixing for 3 times. After mixing, the modified lactose carrier containing 10% lactose micropowder is obtained and stored under dry condition. The prescription dose of the clenbuterol hydrochloride micro powder and 150g of modified lactose containing 10% lactose micro powder are precisely weighed, the obtained product is sieved by a 60-mesh sieve, and then the obtained product is put into a wet granulator, the rotating speed is adjusted to be 250 +/-10 rpm, the mixing time is 10 min/time, and the obtained product is mixed for 3 times. After the mixing is finished, collecting the product, drying and storing. The aerodynamic measurement result shows that the FPF value is 25.1%, the fluidity test result shows that the contact angle is 28.1 degrees, and the fluidity is good.
Example 4
Prescription:
chuangbuterol hydrochloride 200mg
Lactose micropowder 30g
Lactose 120g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. Precisely weighing lactose micropowder of prescription dose and lactose carrier without lactose micropowder on market, sieving with 60 mesh sieve, mixing, placing into wet granulator, adjusting rotation speed to 300 + -10 rpm, mixing for 3 times, each time for 10min to obtain modified lactose containing 20% lactose micropowder, drying and storing. Precisely weighing the prescription dose of the salbutamol hydrochloride micro powder and 150.00g of modified lactose containing 20% lactose micro powder, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting, drying and storing. The results of aerodynamic measurement show that the FPF value is 29.1%, and the results of fluidity test show that the contact angle is 27.8 DEG, and the fluidity is good.
Example 5
Prescription:
chuangbuterol hydrochloride 200mg
Magnesium stearate micropowder 0.75g
Lactose 149.25g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. Pulverizing magnesium stearate by the same method, drying and storing to obtain magnesium stearate micropowder. Precisely weighing magnesium stearate micropowder and commercial lactose carrier without micropowder lactose in a prescription amount, sieving with 60 mesh sieve, mixing, feeding into a wet granulator, adjusting rotation speed to 300 + -10 rpm, mixing for 3 times, each time for 10min, preparing modified lactose containing 0.5% magnesium stearate micropowder, drying and storing. Precisely weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150g of modified lactose containing 0.5% magnesium stearate micro powder, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotating speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting, drying and storing. The aerodynamic measurement result shows that the FPF value is 38.6%, the fluidity test result shows that the contact angle is 26.4 degrees, and the fluidity is good.
Example 6
Prescription:
chuangbuterol hydrochloride 200mg
Magnesium stearate micropowder 1.5g
Lactose 148.5g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. Pulverizing magnesium stearate by the same method, drying and storing to obtain magnesium stearate micropowder. Precisely weighing magnesium stearate micropowder in a prescription amount and a commercially available lactose carrier without micropowder lactose, sieving with a 60-mesh sieve, mixing, placing into a wet granulator, adjusting the rotation speed to 300 +/-10 rpm, mixing for 3 times, each time for 10min, preparing modified lactose containing 1% magnesium stearate micropowder, drying and storing. Precisely weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150g of modified lactose containing 1% magnesium stearate micro powder, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting, drying and storing. The aerodynamic measurement result shows that the FPF value is 41.4%, the fluidity test result shows that the contact angle is 25.2 degrees, and the fluidity is good.
Example 7
Prescription:
chuangbuterol hydrochloride 200mg
Magnesium stearate micropowder 2.25g
Lactose 147.75g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting the Chuanbuterol hydrochloride micro powder, and storing under a dry condition. Pulverizing magnesium stearate by the same method, drying and storing to obtain magnesium stearate micropowder. Precisely weighing magnesium stearate micropowder in a prescription amount and a commercially available lactose carrier without micropowder lactose, sieving with a 60-mesh sieve, mixing, placing into a wet granulator, adjusting the rotation speed to 300 +/-10 rpm, mixing for 3 times, each time for 10min, preparing modified lactose containing 1.5% of magnesium stearate micropowder, drying and storing. Precisely weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150g of modified lactose containing 1.5% magnesium stearate micro powder, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotating speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting, drying and storing. The aerodynamic measurement result shows that the FPF value is 40.7%, the fluidity test result shows that the contact angle is 24.8 degrees, and the fluidity is good.
Example 8
Prescription:
the preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting the Chuanbuterol hydrochloride micro powder, and storing under a dry condition. Pulverizing magnesium stearate by the same method, drying and storing to obtain magnesium stearate micropowder. Precisely weighing magnesium stearate micropowder, lactose micropowder and commercial lactose carrier free of lactose micropowder according to the prescription amount, sieving with a 60-mesh sieve, mixing, feeding into a wet granulator, adjusting the rotation speed to 300 +/-10 rpm, mixing for 3 times, each time for 10min, preparing modified lactose containing 1% of magnesium stearate micropowder and 10% of lactose micropowder, drying and storing. Accurately weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150.00g of modified lactose, sieving by a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting the product, drying and storing. The aerodynamic measurement result shows that the FPF value is 47.8%, the fluidity test result shows that the contact angle is 26.2 degrees, and the fluidity is good.
Example 9
Prescription:
chuangbuterol 200mg
Magnesium stearate micropowder 1.50g
Lactose 148.50g
The preparation method comprises the following steps: taking the albuterol and the magnesium stearate, roughly mixing according to the proportion of the prescription, and crushing by using a jet mill by using compressed nitrogen as a gas source. The feed pressure was 7.0bar and the comminution pressure was 6.0 bar. Collecting the product which is the co-pulverized micro powder of the salbutamol and the magnesium stearate, measuring the particle size, drying and storing. Precisely weighing the co-pulverized micro powder of the salbutamol and the magnesium stearate and the lactose carrier which is sold on the market and does not contain micro powder lactose, sieving by a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotating speed to be 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting the product after the mixing is finished, drying and storing. The results of aerodynamic measurement show that the FPF value is 30.5%, and the results of fluidity test show that the contact angle is 27.5 degrees, and the fluidity is good.
Example 10
Prescription:
100mg of Chuangbuterol hydrochloride
Lactose containing 10% lactose micropowder 150.00g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, drying and storing. The clenbuterol hydrochloride micro powder with the prescription amount and the commercial lactose carrier containing 10 percent of micro powder lactose are precisely weighed, sieved by a 60-mesh sieve, mixed, put into a wet granulator, the rotating speed is adjusted to be 250 plus or minus 10rpm, the mixing time is 10 min/time, and mixed for 3 times. After the mixing is finished, collecting the product, drying and storing. The aerodynamic measurement result shows that the FPF value is 29.3%, the fluidity test result shows that the contact angle is 28.6 degrees, and the fluidity is good.
Example 11
Prescription:
chuangbuterol hydrochloride 300mg
Lactose containing 10% lactose micropowder 150.00g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, drying and storing. The clenbuterol hydrochloride micro powder with the prescription amount and the commercial lactose carrier containing 10 percent of micro powder lactose are precisely weighed, sieved by a 60-mesh sieve, mixed, put into a wet granulator, the rotating speed is adjusted to be 250 plus or minus 10rpm, the mixing time is 10 min/time, and mixed for 3 times. After the mixing is finished, collecting the product, drying and storing. The aerodynamic measurement result shows that the FPF value is 32.6%, the fluidity test result shows that the contact angle is 28.2 degrees, and the fluidity is good.
Example 12
Prescription:
chuangbuterol hydrochloride 200mg
Leucine micropowder 1.50g
Lactose 148.50g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. The feed pressure was 7.0bar and the comminution pressure was 6.0 bar. Collecting the product which is the clenbuterol hydrochloride micro powder, measuring the particle size, drying and storing. Pulverizing leucine by the same method, drying, and storing. The leucine micro powder and the lactose carrier without micro powder lactose are precisely weighed according to the prescription amount, screened by a 60-mesh sieve, put into a wet granulator, the rotating speed is adjusted to be 300 plus or minus 10rpm, the mixing time is 10 min/time, and the mixture is mixed for 3 times. After mixing, collecting the product which is modified lactose containing 1% leucine micropowder, drying and storing. The prescription dose of the clenbuterol hydrochloride micro powder and 150.00g of modified lactose containing 1% leucine micro powder are precisely weighed, sieved by a 60-mesh sieve, put into a wet granulator, the rotating speed is adjusted to be 250 plus or minus 10rpm, the mixing time is 10 min/time, and the mixture is mixed for 3 times. After the mixing is finished, collecting the product, drying and storing. The results of aerodynamic measurement show that the FPF value is 29.1%, and the results of fluidity test show that the contact angle is 27.9 DEG, and the fluidity is good.
Example 13
Prescription:
chuangbuterol hydrochloride 200mg
Magnesium stearate micropowder 1.5g
Lactose 148.5g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. Precisely weighing magnesium stearate and lactose carrier according to the prescription amount, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 300 +/-10 rpm, mixing for 3 times, 10min each time, preparing modified lactose containing 1% of magnesium stearate, drying and storing. Precisely weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150g of modified lactose containing 1% of magnesium stearate, sieving with a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting, drying and storing. The results of aerodynamic measurement show that the FPF value is 29.6%, and the results of fluidity test show that the contact angle is 25.9 DEG, and the fluidity is good.
Example 14
Prescription:
the preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting the Chuanbuterol hydrochloride micro powder, and storing under a dry condition. Pulverizing magnesium stearate by the same method, drying and storing to obtain magnesium stearate micropowder. Precisely weighing magnesium stearate micropowder, lactose micropowder and commercial lactose carrier free of lactose micropowder according to the prescription amount, sieving with a 60-mesh sieve, mixing, feeding into a wet granulator, adjusting the rotation speed to 300 +/-10 rpm, mixing for 3 times, each time for 10min, preparing modified lactose containing 1% of magnesium stearate micropowder and 10% of lactose micropowder, drying and storing. Accurately weighing the prescription dose of the clenbuterol hydrochloride micro powder and 150.00g of modified lactose, sieving by a 60-mesh sieve, mixing, putting into a wet granulator, adjusting the rotation speed to 250 +/-10 rpm, mixing for 3 times, each time for 10min, collecting the product, drying and storing. The results of aerodynamic measurement show that the FPF value is 45.9%, and the results of fluidity test show that the contact angle is 25.4 DEG, and the fluidity is good.
Comparative example
Prescription:
chuangbuterol hydrochloride 200mg
Lactose 150.00g
The preparation method comprises the following steps: taking the clenbuterol hydrochloride, taking compressed nitrogen as a gas source, and crushing by adopting a jet mill. Feeding pressure of 7.0bar, crushing pressure of 6.0bar, crushing, collecting to obtain the Chuangbuterol hydrochloride micro powder, and storing under a dry condition. The clenbuterol hydrochloride micro powder and lactose with the prescription amount are precisely weighed, and are put into a wet granulator after being sieved by a 60-mesh sieve, the rotating speed is adjusted to be 250 plus or minus 10rpm, the mixing time is 10 min/time, and the mixture is mixed for 3 times. After the mixing is finished, collecting the product, drying and storing. The results of the aerodynamic measurement showed that the FPF value was 17.5% and the results of the flowability measurement showed that the contact angle was 35.3 °.
Test example 1
The particle size of each component in the dry powder inhalation preparation has a significant effect on the properties of the preparation. The particle size of each composition was determined by dry laser diffraction method (neopataxane laser granulometer, germany). With the ROLOS module, R1/R3 lens, mode of operation ref 5s start 1% stop 5s tb 1.
Table 1 shows the results of particle size determination of the raw and auxiliary materials, i.e. the intermediate, wherein after jet milling, the salbutamol or the salbutamol and the surface modifier are subjected to jet milling, spray drying or supercritical fluid technology treatment to form particles with a particle size suitable for pulmonary inhalation administration, so that the particles can be used for further preparation of dry powder inhalation preparations. The particle size of various surface modifier micro powder is equivalent to that of the Chuangbuterol micro powder, which is beneficial to playing the surface modification effect on the lactose carrier.
Test example 2
And (3) determining the content uniformity of the aerosol powder by a high performance liquid chromatography. After the powder and aerosol mixing is finished, six sampling positions are selected in a wet granulator, about 100mg of samples are removed respectively, the samples are precisely weighed and then put into a 25mL volumetric flask, water is added for dissolving, constant volume shaking is carried out uniformly, and the concentration of the samples is analyzed by a high performance liquid chromatography.
Tables 2 and 3 show the content measurement results of the aerosols of examples 1 and 2 at various time points, respectively, and the content uniformity has no significant difference with different mixing times at the respective mixing speeds.
Test example 3
Due to the physiological structure of the lungs, and the specificity of pulmonary administration, a pharmaceutical powder needs to have specific aerodynamic properties in order to be effectively deposited in the lungs. The deposition amount of the drug powder in the lung directly affects the curative effect of the drug. According to the regulation of Chinese pharmacopoeia in 2015, the fog drop (particle) distribution of the effective part is used as an index for screening to evaluate the reasonability of process parameters. The invention utilizes a new generation of pharmaceutical impactor (NGI) to determine the aerodynamic behavior of the preparation. And the results are used as the basis for prescription screening.
FIG. 1 shows the results of aerodynamic measurements of drug and lactose carriers in a powder inhalation of salbutamol hydrochloride at 100rpm for different mixing times. The aerodynamic performance of the medicine in the powder inhalation is improved along with the prolonging of the mixing time.
FIG. 2 shows the results of aerodynamic measurements of drug and lactose carriers in a powder inhalation of salbutamol hydrochloride at 250rpm for different mixing times. The deposition of drug particles at each level of the NGI varies with mixing time. The aerodynamic behaviour is best when mixed for more than 30 min.
The aerodynamic performance of the powder spray is improved by adding a surface modifier into the carrier. In the comparative example, the powder spray was prepared using unmodified lactose as a carrier, and aerodynamic properties were measured to compare the use of the modifier.
Figure 3 and table 4 compare the aerodynamic performance of the dry powder aerosol of each example.
Examples 3 and 4, the aerodynamic properties of the powder aerosol were improved by adding 10% and 20% lactose micropowder to the lactose carrier, and the powder aerosol with 20% lactose micropowder content had a higher FPF value. However, since lactose fine powder has a high surface energy and is easily agglomerated, 20% of the fine powder content in the actual production process causes problems of non-uniform content and segregation of the drug from the carrier.
Examples 5, 6 and 7, the aerodynamic properties of the powder cloud were improved by adding 0.5%, 1% and 1.5% magnesium stearate micropowder to the lactose carrier, and the powder cloud with a magnesium stearate content of 1% had a higher FPF value.
In examples 8 and 14, 10% of lactose micropowder, 1% of magnesium stearate micropowder and 20% of lactose micropowder are used, and 2% of magnesium stearate micropowder is used to modify the lactose carrier at the same time, when the weight ratio of the magnesium stearate micropowder to the lactose micropowder is: 1: 20-1: when 10, the aerodynamic behavior is better, and the deposition of the drug in the lung is more favorable.
The co-pulverized fine powder of salbutamol and magnesium stearate prepared by the co-pulverization method in example 9 has improved aerodynamic behavior, probably because the drug is co-pulverized with magnesium stearate, the energy of the drug contacting the lactose carrier is changed, and the drug particles are more easily detached from the lactose surface.
In examples 10 and 11, different amounts of salbutamol hydrochloride were added to the formulations, with the FPF increasing with increasing amounts of salbutamol hydrochloride added.
In example 12, 1% leucine was used to modify lactose and produce a powder aerosol, which improved the aerodynamic properties.
In example 13, the powder cloud was modified with 1% magnesium stearate to improve the aerodynamic performance of the powder cloud, but the modification was weaker than that of the powder cloud in example 6, in which 1% magnesium stearate powder was added. The micronization treatment of the magnesium stearate is illustrated, which is beneficial to the magnesium stearate to exert the modification effect of the lactose carrier.
Test example 4
The powder repose angle is measured by adopting a fixed funnel method, a funnel is fixed above coordinate paper (the paper is placed on a horizontal table) at a certain height, materials are added from the funnel until the top of a formed stacking cone is just contacted with the bottom of the funnel, the diameter of the cone is measured, and the repose angle is calculated by taking the ratio of the height of the bottom of the funnel to the radius of the cone as a tangent value.
Table 4 shows the fluidity results of the comparative examples and each example. By adding lactose micropowder, magnesium stearate micropowder and leucine micropowder, the flowability of the powder spray is improved, and the flowability is better and better along with the increase of the addition amount.
Test example 5
Drying and storing the raw material medicine and the intermediate, putting the powder to be dried and stored into an aluminum foil bag, adding allochroic silica gel into the aluminum foil bag as a drying agent, sealing, and placing in a dryer containing the allochroic silica gel for room temperature storage.
Test example 6
The powder spray is subjected to an accelerated test under the storage conditions that: storing at 40 deg.C and 75% humidity for 7 days; storing at 40 deg.C and 75% humidity for 14 days; storing at 40 deg.C and 75% humidity for 30 days; storing at 40 deg.C and 75% humidity for 60 days; the storage was carried out at 40 ℃ and 75% humidity for 90 days.
FIG. 4 and Table 5 show the results of accelerated test measurement of the powder cloud of example 2 with a mixing time of 30 min. The result shows that the FPF value of the salbutamol hydrochloride in the powder inhalation is not obviously reduced, which indicates that the powder inhalation is relatively stable under the conditions of the temperature of 40 ℃ and the humidity of 75 percent.
TABLE 1 particle size of raw and auxiliary materials and intermediates
TABLE 2 sample point contents (%)% of Chuanybuterol hydrochloride powder aerosol prepared at 100rpm in example 1
Table 3 the content (%) of each sample point of the salbutamol hydrochloride powder aerosol was prepared at a mixing speed of 250rpm in example 2.
TABLE 4 aerodynamic vs. flowability comparison
Table 5 aerodynamic measurement results of the 250rpm mixing speed 30min albuterol hydrochloride aerosol acceleration test in example 2.
The results show that the aerodynamic behavior of the drug in each example is improved compared to the comparative examples by modification treatment of the lactose carrier. After different surface modifiers are added, the FPF value of the salbutamol hydrochloride powder inhalation is improved, preferably the following proportion is selected, and the weight ratio of the lactose micropowder to the lactose is as follows: 1: 4- -1: 9; the weight ratio of the magnesium stearate micropowder to the lactose is as follows: 1: 199- -3: 197; the weight ratio of leucine to lactose was: 1: 199- -3: 197; the weight ratio of the magnesium stearate micropowder, the lactose micropowder and the lactose is as follows: 1: 20: 378.8-1: 10: 28.9, more preferably 1: 10: 89-1: 20: 79.
Claims (10)
1. the albuterol inhalation powder inhalation is characterized by comprising active ingredients and a surface modified carrier, wherein the components in percentage by weight are as follows: 0.05-0.25% of active ingredient, 99.75-99.95% of surface modified carrier, wherein the active ingredient is the salbutamol, the surface modified carrier is the carrier which is surface modified by surface modifier, and the weight ratio of the carrier surface modifier to the carrier is as follows: 1: 399- -25: 75, preferably: 1: 199- -11: 39.
2. the salbutamol inhalation aerosol formulation of claim 1, wherein the salbutamol is salbutamol or salbutamol hydrochloride.
3. The albuterol inhalation powder of claim 1, wherein the surface modifier comprises one or more of magnesium stearate, lactose, and leucine in the form of fine powder.
4. The albuterol inhalation powder formulation according to claim 1, wherein the carrier is one or more of physiologically acceptable sugar, polyol, and amino acid, and is selected from lactose, sucrose, glucose, fructose, maltose, trehalose, mannitol, xylitol, sorbitol, leucine, alanine, tryptophan, valine, isoleucine, glycine, phenylalanine, proline, serine, tyrosine, cysteine, methionine, glutamic acid, threonine, aspartic acid, glutamine, lysine, and arginine.
5. The albuterol inhalation powder of claim 1, wherein the surface-modified carrier comprises one or more of magnesium stearate, lactose and leucine as a surface modifier, and one or more of lactose, mannitol and leucine as a carrier.
6. The albuterol inhalation powder of claim 5, wherein the surface-modified lactose is lactose modified with lactose micropowder, lactose modified with stearic acid micropowder, magnesium stearate micropowder and lactose micropowder, wherein the weight ratio of lactose micropowder to lactose is: 1: 4- -1: 9; the weight ratio of the magnesium stearate micropowder to the lactose is 1: 199- -3: 197; the weight ratio of the leucine micropowder to the lactose is 1: 199- -3: 197; the weight ratio of the magnesium stearate micropowder, the lactose micropowder and the lactose is as follows: 1: 10: 89-1: 20: 79.
7. the albuterol inhalation powder of any of claims 1-6, wherein the surface modifier micropowder has a median particle size of less than 5 μm, and 90% of the carrier surface modifier micropowder has a particle size of less than 10 μm.
8. The method for preparing the albuterol inhalation powder cloud agent according to claim 1, wherein the albuterol or albuterol hydrochloride micropowder is prepared;
(1) preparing the Chuanbuterol or the Chuanbuterol hydrochloride micro powder;
(2) preparing a surface modified carrier;
(3) the clenbuterol or the clenbuterol hydrochloride micro powder is mixed with the surface modified carrier.
9. The method according to claim 8, wherein in the step (2), the carrier and the surface modifier for carrier or the fine powder of the surface modifier are subjected to a high shear mixing treatment using a mixer granulator.
10. Use of a salbutamol inhalation powder formulation according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease.
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| CN101342155B (en) * | 2007-07-11 | 2012-01-04 | 天津帝士力投资控股集团有限公司 | (R,R)-formoterol inhalation dust cloud agent and preparation method thereof |
| CN112451509B (en) * | 2020-12-19 | 2023-03-07 | 沈阳药科大学 | Chuangbuterol powder inhalation and preparation method thereof |
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| CN1179097A (en) * | 1995-01-31 | 1998-04-15 | 协调药物发展有限公司 | Carrier particles for use in dry powder inhalers |
| CN1424909A (en) * | 2000-04-17 | 2003-06-18 | 维克多瑞有限公司 | Formulations for use in inhaler devices |
| CN101106975A (en) * | 2004-11-23 | 2008-01-16 | 维克特拉有限公司 | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
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