CN113559086A - Inhalant containing chloroquine therapeutic agent and preparation method thereof - Google Patents
Inhalant containing chloroquine therapeutic agent and preparation method thereof Download PDFInfo
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Abstract
The invention provides a chloroquine inhalant and a preparation method thereof, belonging to the field of pharmaceutical preparations. The inhalant contains chloroquine phosphate or hydroxychloroquine sulfate, stabilizer and diluent, and has high use efficiency, and can be used for preventing new epidemic situation, such as new coronavirus pneumonia, with rapid action. The inhalation powder inhalation has better stability, has the functions of masking the taste, enhancing the stability and protecting organism biomembranes for chloroquine phosphate or hydroxychloroquine sulfate after being wrapped by the stabilizing agent, has strong targeting effect through lung absorption, can also effectively avoid the first pass effect caused by the liver during oral administration, and improves the bioavailability.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to an inhalant containing chloroquine therapeutic agents and a preparation method thereof.
Background
Chloroquine Phosphate (Chloroquinone Phosphate) is an antimalarial drug, is prepared by structural optimization and modification of the oldest antimalarial drug quinine (cinchona cream), and has the chemical name of 7-chloro-4- [ [ [4- (diethylamino) -1-methylbutyl]Amino group]Quinoline phosphate (1: 2) with the molecular formula C18H26ClN3·2H3PO4And the molecular weight is 515.87.
Hydroxychloroquine sulfate (hydroxychloroquine sulfate) is an antimalarial drug, is a weak base like chloroquine, and can exert its effects by concentrating parasite acidic vesicles and inhibiting the polymerization of heme, as well as by interacting with DNA to inhibit certain enzymes. The chemical name is 2- [ [ [4- [ (7-chloro-4-quinolyl) amino]Pentyl radical]Ethylamino group]Ethanol sulfate (1: 1) with molecular formula of C18H26ClN3O.H2SO4And the molecular weight is 433.95.
The chloroquine phosphate is an oral preparation at present sold at home and abroad, the oral preparation is convenient to use, but has slow effect, low utilization rate, long treatment course and serious reaction possibility when the dosage is large, and is accompanied by adverse reactions such as dizziness, headache, dim eyesight, anorexia, nausea, vomiting, abdominal pain, diarrhea, skin pruritus, rash, even exfoliative dermatitis, tinnitus, dysphoria and the like, and common people are toxic to eyes.
Disclosure of Invention
The invention provides an inhalant containing chloroquine therapeutic agent and a preparation method thereof aiming at the existing technical problems.
The purpose of the invention can be realized by the following technical scheme:
an inhalant containing a chloroquine therapeutic agent, which comprises the following components:
1-30 parts of therapeutic agent
0.1-30 parts of stabilizer
1-20 parts of a diluent;
wherein: the therapeutic agent is chloroquine phosphate or hydroxychloroquine sulfate.
In some preferred embodiments: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 1-20 parts, 1-20 parts and 2-15 parts in sequence.
In some more preferred embodiments: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 5-15 parts, 1-20 parts and 1-10 parts in sequence.
The technical scheme of the invention is as follows: the stabilizer is at least one of arginine, threonine, aspartic acid, glutamic acid, leucine and isoleucine.
Preferably, the method comprises the following steps: the stabilizer is at least one of leucine, arginine and threonine.
The technical scheme of the invention is as follows: the diluent is at least one of lactose, trehalose, sucrose, mannitol and xylitol.
Preferably, the method comprises the following steps: the diluent is at least one of mannitol, lactose and xylitol.
A preparation method of the inhalant containing the chloroquine therapeutic agent comprises the following steps:
(1) dissolving a stabilizer and a diluent in water for injection, adding a therapeutic agent, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain dry powder containing the chloroquine therapeutic agent;
(3) and filling the dry powder containing the chloroquine therapeutic agent into a plant capsule, and sealing by using a capsule packaging machine.
The method comprises the following steps: air inlet temperature: 118 +/-2 ℃; the material temperature is 50-80 ℃, the atomization pressure is 150-200 kPa, the liquid inlet speed is 10-15 mL/min, and the solid-liquid content of the mixed liquid is 10-30 mg/mL.
The technical scheme of the invention is as follows: the pressure is gauge pressure.
An inhalant containing a chloroquine therapeutic agent, which comprises the following components:
1-30 parts of therapeutic agent
0.1-30 parts of stabilizer
1-20 parts of a diluent;
wherein: the therapeutic agent is chloroquine phosphate or hydroxychloroquine sulfate.
Optionally: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 1-20 parts, 1-20 parts and 2-15 parts in sequence. Or: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 5-15 parts, 1-20 parts and 1-10 parts in sequence.
Optionally: the stabilizer is at least one of arginine, threonine, aspartic acid, glutamic acid, leucine and isoleucine. Or: the stabilizer is at least one of leucine, arginine and threonine.
Optionally: the diluent is at least one of lactose, trehalose, sucrose, mannitol and xylitol. Or: the diluent is at least one of mannitol, lactose and xylitol.
The technical scheme of the invention is as follows: the inhalant containing the chloroquine therapeutic agent is a powder inhalant containing the chloroquine therapeutic agent.
The invention has the beneficial effects that:
the inventive chloroquine phosphate or hydroxychloroquine sulfate inhalant can improve the use efficiency, and has prevention effect, such as new epidemic situation-novel coronavirus pneumonia, and can quickly take effect. The inhalation powder inhalation has better stability, has the functions of masking the taste, enhancing the stability and protecting organism biomembranes for chloroquine phosphate or hydroxychloroquine sulfate after being wrapped by the stabilizing agent, has strong targeting effect through lung absorption, can also effectively avoid the first pass effect caused by the liver during oral administration, and improves the bioavailability.
Detailed Description
The invention is further illustrated by the following examples, without limiting the scope of the invention:
example 1:
a chloroquine phosphate powder inhalation for inhalation comprises
The preparation process comprises the following steps:
(1) dissolving leucine in water for injection, adding chloroquine phosphate and mannitol, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain chloroquine phosphate inhalation powder;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried chloroquine phosphate dry powder into a 3# HPMC plant capsule, and sealing by using a capsule packaging machine.
Example 2:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving leucine in water for injection, adding hydroxychloroquine sulfate and mannitol, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
Example 3:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving leucine in water for injection, adding hydroxychloroquine sulfate and lactose, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
Example 4:
the preparation process comprises the following steps:
(1) dissolving arginine in water for injection, adding chloroquine phosphate and lactose, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain chloroquine phosphate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried chloroquine phosphate dry powder into a 3# HPMC plant capsule, and sealing by using a capsule packaging machine.
Example 5:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving arginine in water for injection, adding hydroxychloroquine sulfate and mannitol, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
Example 6:
a chloroquine phosphate powder inhalation for inhalation comprises
The preparation process comprises the following steps:
(1) dissolving threonine in water for injection, adding chloroquine phosphate and mannitol, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain chloroquine phosphate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried chloroquine phosphate dry powder into a 3# HPMC plant capsule, and sealing by using a capsule packaging machine.
Example 7:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving leucine in water for injection, adding hydroxychloroquine sulfate and xylitol, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
Comparative example 1:
a chloroquine phosphate powder inhalation for inhalation comprises
The preparation process comprises the following steps:
(1) dissolving leucine and mannitol in water for injection, adding chloroquine phosphate, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain chloroquine phosphate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried chloroquine phosphate dry powder into a 3# HPMC plant capsule, and sealing by using a capsule packaging machine.
Comparative example 2:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving leucine and mannitol in water for injection, adding hydroxychloroquine sulfate, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
Comparative example 3:
a chloroquine phosphate powder inhalation for inhalation comprises
The preparation process comprises the following steps:
(1) dissolving leucine and mannitol in water for injection, adding chloroquine phosphate, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain chloroquine phosphate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried chloroquine phosphate dry powder into a 3# HPMC plant capsule, and sealing by using a capsule packaging machine.
Comparative example 4:
the hydroxychloroquine sulfate powder inhalation for inhalation comprises the following components
The preparation process comprises the following steps:
(1) dissolving leucine and mannitol in water for injection, adding hydroxychloroquine sulfate, and stirring to form a uniform solution;
(2) spray drying the solution by adopting a spray drying technology to obtain hydroxychloroquine sulfate powder mist inhalant;
wherein the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 60 ℃, the atomization pressure is 170kPa, the liquid inlet speed is 12.0mL/min, and the solid-liquid content of the mixed liquid is 15 mg/mL.
(3) And filling the dried hydroxychloroquine sulfate dry powder into 3# HPMC plant capsules, and sealing by using a capsule packaging machine.
The test method of the deethylation impurity is a liquid phase HPLC method, and the test conditions are as follows:
a chromatographic column: c18 (4.6X 250mm5 μm);
mobile phase: acetonitrile-potassium dihydrogen phosphate solution (pH 3.5 adjusted with phosphoric acid)
Flow rate: 1.0mL min-1；
Detection wavelength: 250 nm;
sample introduction amount: 10 uL;
column temperature: at 25 ℃.
As can be seen from the above table 1, the illumination stability of the embodiments 1 to 7 is obviously superior to that of the comparative example, the generation of impurities under the illumination condition can be obviously reduced after the chloroquine phosphate or the hydroxychloroquine sulfate is coated by the stabilizer, and the impurities are smaller than those in the comparative example under the conditions of high temperature and high humidity.
TABLE 2 study of chloroquine phosphate or hydroxychloroquine sulfate powder aerosol powder Properties
| Name (R) | Angle of repose | Coefficient of compression (% | FPF(％) | Average particle diameter |
| Example 1 | 25.6° | 22.4 | 35.1 | 8.1μm |
| Example 2 | 28.7° | 23.6 | 34.2 | 8.5μm |
| Example 3 | 29.1° | 25.5 | 36.7 | 8.4μm |
| Example 4 | 30.5° | 28.1 | 38.8 | 7.7μm |
| Example 5 | 32.1° | 30.2 | 40.2 | 8.2μm |
| Example 6 | 33.4° | 32.1 | 39.4 | 9.3μm |
| Example 7 | 35.1 | 34.3 | 36.4 | 8.9μm |
| Comparative example 1 | 26.7 | 32.6 | 3.6 | 7.2μm |
| Comparative example 2 | 25.5 | 34.5 | 4.1 | 7.8μm |
| Comparative example 3 | 25.2 | 31.3 | 2.1 | 8.7μm |
| Comparative example 4 | 24.8 | 32.1 | 1.9 | 5.7μm |
From the above table 2, it can be seen that, under the prescription of the stabilizer and the diluent in a proper proportion, the powder obtained by spray drying has a smaller angle of repose, good fluidity and a proper bulk density, and can meet the production requirements, but when the angle is not within the range, the average particle size and the FPF do not meet the requirements of pulmonary administration.
Tissue distribution test of chloroquine phosphate or hydroxychloroquine sulfate powder aerosol for inhalation in lung
The relative bioavailability of pulmonary administration was studied by examining the blood concentration time profiles of the drugs in vivo after oral and pulmonary administration.
Experimental method 10 clean-grade rats, randomly divided into 2 groups: powder spray group and oral group. After fasting for 12h, the doses were administered separately. The powder inhalation group is inserted into the trachea through an oral visual trachea, the chloroquine phosphate or hydroxychloroquine sulfate powder inhalation is insufflated into the lung of a rat, and the dosage is 60mg/kg of chloroquine phosphate or hydroxychloroquine sulfate. The oral group is prepared by dissolving chloroquine phosphate or hydroxychloroquine sulfate in water, and performing intragastric administration at a dose of 30mg/kg chloroquine phosphate or hydroxychloroquine sulfate. Blood was collected from rat fundus vein at 15,30,60,120, 240,360,480min after administration, and plasma was collected by centrifugation. And (3) measuring the chloroquine content in the blood plasma.
Table 3 shows the pharmacokinetic treatment results of the non-atrioventricular model on chloroquine phosphate or hydroxychloroquine sulfate aerosols in rats. From the pharmacokinetic results, it is known that chloroquine phosphate or hydroxychloroquine sulfate is rapidly absorbed in the lung. Compared with an oral solid preparation, when the chloroquine phosphate or the hydroxychloroquine sulfate is administered in the form of a powder inhalation, the bioavailability of the chloroquine phosphate or the hydroxychloroquine sulfate is 48%, which indicates that when the chloroquine phosphate or the hydroxychloroquine sulfate is administered in the form of a powder inhalation, the part absorbed into blood circulation is lower than that of oral administration, because the powder inhalation must reach an alveolar part to enter the blood circulation across a qi-blood barrier to be absorbed when being administered in a lung, and a considerable part of the drug is deposited in a respiratory tract, so that the concentrations of the drug and the active metabolite thereof in the respiratory system are improved, and meanwhile, the respiratory system is also the main part attacked by influenza viruses, so the chloroquine phosphate or the hydroxychloroquine sulfate powder inhalation is more in line with the treatment requirement of influenza.
TABLE 3 pharmacokinetic parameters of chloroquine phosphate or hydroxychloroquine sulfate powder aerosols in rats
Claims (9)
1. An inhalant containing a chloroquine-based therapeutic agent, characterized in that: the composition of the inhalant is as follows:
1-30 parts of therapeutic agent
0.1-30 parts of stabilizer
1-20 parts of diluent
Wherein: the therapeutic agent is chloroquine phosphate or hydroxychloroquine sulfate.
2. The inhalant containing a chloroquine-based therapeutic agent according to claim 1, wherein: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 1-20 parts, 1-20 parts and 2-15 parts in sequence.
3. The inhalant containing a chloroquine-based therapeutic agent according to claim 1, wherein: the weight parts of the therapeutic agent, the stabilizing agent and the diluent are 5-15 parts, 1-20 parts and 1-10 parts in sequence.
4. The inhalant containing a chloroquine-based therapeutic agent according to any one of claims 1 to 3, wherein: the stabilizer is at least one of arginine, threonine, aspartic acid, glutamic acid, leucine and isoleucine.
5. The inhalant containing a chloroquine-based therapeutic agent according to any one of claims 4, wherein: the stabilizer is at least one of leucine, arginine and threonine.
6. The inhalant containing a chloroquine-based therapeutic agent according to any one of claims 1 to 3, wherein: the diluent is at least one of lactose, trehalose, sucrose, mannitol and xylitol.
7. The inhalant containing a chloroquine-based therapeutic agent according to any one of claims 6, wherein: the diluent is at least one of mannitol, lactose and xylitol.
8. A method for producing an inhalant containing a chloroquine-based therapeutic agent according to any one of claims 1 to 7, which comprises: the method comprises the following steps:
(1) dissolving a stabilizer and a diluent in water for injection, adding a therapeutic agent, and stirring to form a uniform solution;
(2) and (3) carrying out spray drying on the solution by adopting a spray drying technology to obtain the dry powder containing the chloroquine therapeutic agent.
9. The method of claim 8, wherein: the process conditions of spray drying are as follows: air inlet temperature: 118 +/-2 ℃; the material temperature is 50-80 ℃, the atomization pressure is 150-200 kPa, the liquid inlet speed is 10-15 mL/min, and the solid-liquid content of the mixed liquid is 10-30 mg/mL.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319010A1 (en) * | 2005-11-09 | 2008-12-25 | St. Jude Children's Research Hospital | Use of Chloroquine to Treat Metabolic Syndrome |
| CN102225058A (en) * | 2011-06-22 | 2011-10-26 | 中国药科大学 | Oseltamivir phosphate dry powder inhalations and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319010A1 (en) * | 2005-11-09 | 2008-12-25 | St. Jude Children's Research Hospital | Use of Chloroquine to Treat Metabolic Syndrome |
| CN102225058A (en) * | 2011-06-22 | 2011-10-26 | 中国药科大学 | Oseltamivir phosphate dry powder inhalations and preparation method thereof |
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