CN117771222B - Leifenacin inhalation spray and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses a raffinancin inhalation spray and a preparation method thereof, wherein the spray comprises active ingredient Lei Fen cina or a trihydrate or pharmaceutically acceptable salt thereof, an osmotic pressure regulator, a pH regulator, a bacteriostat, a stabilizer and a solvent; when the antibacterial agent is trichlorobutanol, the pH regulator is citric acid-sodium citrate, and the stabilizer is PVP to prepare Lei Fen-fold inhalation spray, the stability of the preparation can be obviously improved, and the lung deposition rate is very good; in addition, the stability is improved and the lung deposition rate is further improved by reasonably heating the stabilizer, the raw materials and the bacteriostatic agent solution in the preparation process, and the prepared preparation has good delivery dose uniformity and can ensure the stability of FPF under the acceleration condition.

Description

Leifenacin inhalation spray and preparation method thereof

[ Field of technology ]

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a raffinancin inhalation spray and a preparation method thereof.

[ Background Art ]

Lei Fen Naxin is a long-acting muscarinic antagonist of the formula shown in formula 1, and is administered mainly by inhalation to significantly improve pulmonary function, reduce clinical symptoms of COPD, and prevent further exacerbation of the lesions, and in 2018 FDA approved Lei Fen Naxin for maintenance therapy in patients with Chronic Obstructive Pulmonary Disease (COPD).

The existing marketed formulation is Lei Fen nacin solution for inhalation, developed by the company Ireland THERAVANCE biopharmaceutical company in combination with Mylan pharmaceuticals in the United states, approved for marketing by the FDA in the United states at month 11 in 2018 under the trade name Yupelri. The clinical application generally requires that the atomization time is controlled within 10 minutes. The deposition rate of the inhaled solution agent in the lung is very low and is about 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 (FPF, mass percent of fine particles with aerodynamic particle size smaller than 5 μm) of the inhalation spray is higher than that of inhalation solution, the administration time is short, the inhalation spray is convenient to carry, the clinical administration requirement can be well met, the administration volume of the inhalation spray is small each time, and the concentration of liquid medicine is higher than that of the inhalation liquid preparation.

The Lei Fen-cine inhalation spray developed at present is found that raw materials are separated out in the test process under the condition of low temperature or after a sample is subjected to intense oscillation for a certain time, so that the stability of the preparation is seriously affected.

[ Invention ]

In order to solve the problems, the invention provides Lei Fen-cine inhalation spray with good stability and high lung deposition rate and a preparation method thereof.

Based on the above purpose, the application adopts the following technical scheme: an inhaled spray of raffinacin comprises Lei Fen cina or its trihydrate or its pharmaceutically acceptable salt, osmotic pressure regulator, pH regulator, antibacterial agent, stabilizer and solvent.

Preferably, the Lei Fen narsin is inhaled into the spray, the active ingredient content is 0.04% -0.8%, the bacteriostatic agent content is 0.2% -0.5% and the stabilizer content is 0.2% -0.5% in terms of mass-volume ratio.

Preferably, the osmotic pressure regulator is sodium chloride, and the content of the osmotic pressure regulator in the spray is 0.9% in terms of mass-volume ratio; the solvent is water for injection.

Preferably, the bacteriostatic agent is chlorobutanol.

Preferably, the stabilizer is PVP.

Preferably, the pH adjuster is selected from citric acid and salts thereof.

Preferably, the pH of the Lei Fen that is inhaled spray is 4.0-6.0.

Further preferably, the Lei Fen narsin inhalation spray contains 0.05-0.25% of citric acid and 0.38% of citrate in terms of mass-volume ratio.

Further, the dosage ratio of the antibacterial agent chlorbutanol to the stabilizer PVP in the Lei Fen-narasin inhalation spray is 1:1.

Preferably, the stabilizer PVP is selected from PVPK12 and PVPK15.

The invention also provides a preparation method of the raffinancin inhalation spray, which specifically comprises the following steps:

(1) Adding the prescription amount of sodium chloride into water for injection, and stirring until the sodium chloride is completely dissolved;

(2) Adding a pH regulator into the solution to regulate the pH of the solution to 4.0-6.0;

(3) Adding a prescription amount of bacteriostatic agent, lei Fen cina trihydrate and a stabilizing agent into the solution prepared in the step (2), heating while stirring, and continuing to keep the temperature and stirring after heating to a certain temperature;

(4) Cooling to normal temperature, adding the rest injection water, and fixing volume to required volume;

(5) Sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Preferably, the temperature of the water for injection in step (1) is 20 to 30 ℃.

Preferably, in the step (3), the temperature is raised to 70-80 ℃, the heat preservation and stirring time is 20-30 min, the impurity is increased due to the excessively high temperature, and the FPF cannot be obviously improved due to the excessively low temperature.

Compared with the prior art, the invention has the following beneficial effects:

Experiments show that the stability of the Lei Fen narcissus inhaled spray can be improved by directly adding the stabilizing agent into the Lei Fen narcissus inhaled spray, but the lung deposition rate of the preparation is reduced; the inventor finds that when the Lei Fen nafine inhalation spray is prepared by using the trichloro-tert-butanol, the citric acid-sodium citrate and the PVP in a reasonable dosage, the stability of the preparation can be obviously improved, and the lung deposition rate is very good.

The inventor of the present invention has found that by reasonably heating the stabilizer, the raw material and the bacteriostatic agent solution during the preparation process, the stability is improved, and the lung deposition rate is further improved, and in addition, the prepared preparation has good delivery dose uniformity and can ensure the stability of FPF under the acceleration condition, and the method is simple, easy to operate and suitable for large-scale production.

[ Detailed description ] of the invention

The invention is illustrated by the following specific examples, but is in no way limited thereto, in order to make the objects, technical solutions and advantages of the invention more apparent. The following description of the preferred embodiments of the invention is merely illustrative of the invention and should not be taken as limiting the invention, it being understood that any modifications, equivalents, and improvements made within the spirit and principles of the invention are intended to be included within the scope of the invention.

The FPF detection method in the following examples refers to the four 0951 inhalation formulation fine particle aerodynamic properties determination method rule under-item device 2 (Anderson cascade impactor, ACI) determination of chinese pharmacopoeia 2020 edition;

delivery Dose Uniformity (DDU): the method for measuring the uniformity of the delivered dose of the inhalation preparation of the four general rules 0111 of the 2020 edition of Chinese pharmacopoeia is adopted for detection.

The detection method of the related substances comprises the following steps:

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) and is obtained by suction filtration and ultrasound; 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.

Elution gradient:

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

The preparation process of the Lei Fen narsin inhalation spray (the specific prescription of which is the prescription 1 in the table below) developed at present is as follows: adding the prescription amount of sodium chloride into 900ml of water for injection at 20-30 ℃ and stirring until the sodium chloride is completely dissolved; adding a pH regulator (acetic acid-sodium acetate) to enable the pH to be 4.0-6.0; adding Lei Fen nacin trihydrate with a prescription amount, and stirring for dissolution; adding bacteriostatic agent (benzyl alcohol); adding the rest injection water, and mixing at constant volume; sterilizing the medicinal liquid with 0.22 μm filter, packaging into ampoule bottle, sealing, and packaging.

In experiments, the stability is found to be poor, raw materials are often separated out under the low-temperature condition, and in order to improve the stability, a certain amount of stabilizer is added into a prescription, as shown in the following table from prescription 2 to prescription 5:

TABLE 1

As can be seen from the data in the above table, the formulation is relatively stable after the stabilizer is added to the formulation, and crystallization phenomenon does not occur, but the FPF of the formulation is significantly reduced after the stabilizer is added.

The types of the auxiliary agents are adjusted as follows;

TABLE 2

From the above table, when the bacteriostatic agent is chlorobutanol, the pH regulator is citric acid and sodium citrate, the stabilizer is PVPK12, and only three are used simultaneously, the FPF of the prepared preparation is the highest.

Based on the above, the inventors have made a great deal of research, and have unexpectedly found that, when raw materials, a bacteriostatic agent and a stabilizing agent are subjected to heat treatment in the preparation process, the preparation stability is ensured, and meanwhile, the FPF of the preparation can be remarkably improved, so that the technical scheme of the invention is obtained, and specific embodiments are as follows:

Example 1

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 20 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 70 ℃ while stirring, and continuing to keep the temperature and stirring for 30min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Example 2

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 20 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 70 ℃ while stirring, and continuing to keep the temperature and stirring for 30min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Example 3

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 25 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 75 ℃ while stirring, and continuing to keep the temperature and stirring for 25min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Example 4

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 30 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 80 ℃ while stirring, and continuing to keep the temperature and stirring for 30min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Example 5

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 30 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 70 ℃ while stirring, and continuing to keep the temperature and stirring for 20min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Example 6

Prescription:

The preparation method comprises the following steps:

Adding prescription amount of sodium chloride into 900mL of water for injection at 30 ℃ and stirring until the sodium chloride is completely dissolved; adding citric acid-sodium citrate buffer solution, and regulating the pH value of the solution to 4.0-6.0; then adding the antibacterial agent, lei Fen cina trihydrate and the stabilizer with the prescription amount into the solution, heating to 75 ℃ while stirring, and continuing to keep the temperature and stirring for 20min; cooling to normal temperature, adding water for injection, and fixing volume to required volume; sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

Test examples

The inhalation sprays prepared in examples 1 to 5 were subjected to pulmonary deposition rate (FPF) and related substance detection, and further subjected to acceleration treatment (40 ℃, RH 75%) for 6 months, and their FPF stability, delivered dose uniformity and total impurity content after acceleration were measured, and the results are shown in the following table;

TABLE 3 Table 3

As shown in the table above, the FPF of the inhalation sprays prepared in the examples 1-6 of the invention are above 69%, the raw materials are not separated out when the inhalation sprays are placed at low temperature, the total impurity content in the preparation is below 0.15%, and the preparation performance is stable; after the acceleration treatment, the FPF of formulation 1 was significantly reduced and the delivered dose uniformity was poor, while the FPF of the formulations prepared in examples 1-6 varied little and the delivered dose uniformity was good. The spray provided by the invention has the advantages that the dosage of the chlorobutanol is 0.2-0.5%, the dosage of the PVPK12 is 0.2-0.5%, the dosage of the citric acid is 0.05-0.25%, the dosage of the sodium citrate is 0.38%, the temperature rise temperature in the preparation process is 70-80 ℃, and the heat preservation and stirring time is 20-30 min, so that all performances of the prepared spray are good; when the dosage ratio of the bacteriostatic agent to the stabilizing agent is 1:1, the prepared spray has the best performance.

Comparative examples 1 to 4

The preparation process is the same as in example 1, except that the stabilizer is used in different amounts, specifically as follows:

TABLE 4 Table 4

As can be seen from the comparison of the data in the above tables and Table 3, when the amount of the stabilizer is too low, the preparation is unstable and the raw materials are separated out when the preparation is placed at low temperature; when the stabilizer is used in an excessively high amount, the FPF is significantly reduced, although the stability of the preparation can be improved and no raw materials are precipitated.

In addition, because the dosage of the effective components is too high, the dissolution in the process is difficult, the long time is required, and a large amount of raw materials are separated out after dissolution and cooling; when the dosage of the bacteriostatic agent is too low, the bacteriostatic effect cannot be achieved, and when the dosage of the bacteriostatic agent is too high, potential safety hazards exist, and the requirements are not met, so that the application does not need to examine the effective components and the dosage of the bacteriostatic agent outside the scope of the application.

Comparative examples 5 to 8

The prescriptions of comparative examples 5 to 8 are the same as the prescription 10 in table 2, except that the heating temperature and the heat-preserving stirring time in the preparation process are different, and specifically the following are adopted:

TABLE 5

As is clear from the table, by heating the stabilizer, the raw material and the bacteriostatic agent, the FPF can be improved, and comparing with examples 1 to 6, the heating temperature is 70 to 80 ℃, the stirring time is 20 to 30 minutes, the effect is better, and the impurity content can be increased due to the overhigh temperature; when the temperature is too low, the FPF cannot be obviously improved, and in addition, the stirring and heating time is too short, the FPF cannot be obviously improved.

Comparative examples 11 to 13

The difference from example 3 is that the stabilizer type is different, specifically as follows;

TABLE 6

Stable formulation number	Comparative example 11	Comparative example 12	Comparative example 13
				PVP	K15	K17	K25
FPF	69.5	62.4	53.9
				Standing at 5+ -3deg.C for 10 days	Non-devitrification	Non-devitrification	Non-devitrification

From the above tables and Table 3, it can be seen that the performance of the spray is best when PVP is used as the stabilizer for PVP, and PVPK12 and PVPK15 are used as the model.

The above examples illustrate only a few embodiments of the present invention, which are described in detail and are not to be construed as limiting the scope of the invention, and it should be noted that modifications and improvements can be made by those skilled in the art without departing from the spirit of the invention, which are within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (6)

1. An inhaled spray of raffinacin, which is characterized by comprising active ingredient Lei Fen cina or its trihydrate or its pharmaceutically acceptable salt, osmotic pressure regulator, pH regulator, bacteriostat, stabilizer and solvent; in the inhalation spray, the mass volume ratio of the active ingredients is 0.04% -0.8%, the bacteriostat content is 0.2% -0.5%, and the stabilizer content is 0.2% -0.5%;

The bacteriostatic agent is chlorbutanol;

the stabilizer is PVP; the model of the stabilizer PVP is selected from one of PVPK12 and PVPK 15;

The pH regulator is citric acid and sodium citrate;

the raw materials, the bacteriostat and the stabilizer are heated in the preparation process.

2. The Lei Fen narsin inhalation spray of claim 1 wherein the osmotic pressure regulator is sodium chloride and the content of the spray is 0.9% by mass volume; the solvent is water for injection.

3. The Lei Fen narasin inhalation spray according to claim 1, wherein the mass to volume ratio of the bacteriostatic agent to the stabilizing agent is 1:1.

4. The Lei Fen narcissus inhalation spray of claim 1, wherein the pH of the Lei Fen narcissus spray is 4.0 to 6.0.

5. The method for preparing Lei Fen nacin inhalation spray of any one of claims 1-4, which is characterized by comprising the following steps:

(1) Adding the prescription amount of sodium chloride into water for injection, and stirring until the sodium chloride is completely dissolved;

(2) Adding a pH regulator into the solution, and regulating the pH of the solution to 4.0-6.0;

(3) Adding a prescription amount of a bacteriostatic agent, lei Fen cina trihydrate and a stabilizing agent into the solution prepared in the step (2), heating while stirring, and continuing to keep the temperature and stirring after the temperature rises to a certain value;

(4) Cooling to normal temperature, adding the rest injection water, and fixing volume to required volume;

(5) Sterilizing the liquid medicine with 0.22 μm filter, packaging, and sealing.

6. The preparation method according to claim 5, wherein in the step (3), the temperature is raised to 70-80 ℃, and the heat preservation and stirring time is 20-30 min.