Drug combination microspheres, preparation method thereof and raw material composition thereof

Abstract

The present invention discloses drug combination microspheres, a preparation method, and a raw material composition. The raw material composition of the drug microspheres of the present invention comprises the following components: formoterol fumarate, mometasone furoate, and a solvent. The drug combination microspheres of the present invention have a reduced bulk density and significantly reduce the residue of the prepared powder inhaler in the inhalation device and capsule shell, which is beneficial for increasing lung deposition and has good drug development prospects.

Description

Technical Field

[0001] The present invention relates to a drug combination microsphere, a preparation method thereof and a raw material composition thereof. Background Art

[0002] The treatment of chronic respiratory diseases such as asthma requires the preparation of particles with an appropriate aerodynamic size. It is currently believed that drug particles with an aerodynamic size of 1-5 μm achieve maximum lung deposition. Researchers worldwide are currently focusing on the preparation of loose, porous inhalable microspheres. This is because, in addition to reducing the geometric diameter of the particles, the aerodynamic size can also be reduced by reducing particle density. Spherical particles exhibit less drag than particles of other shapes, allowing them to more easily pass through the airways and reach deep into the lungs, thereby exerting their therapeutic effects.

[0003] The methods for preparing inhalation microspheres usually include thermal spray drying and freeze drying. When using the spray freeze drying method, it is first necessary to prepare a drug-containing solution. The ideal solvent should be able to dissolve multiple drugs with different properties at the same time and be easy to solidify and sublime.

[0004] The existing method for preparing mometasone furoate monohydrate is as follows: the mometasone furoate raw material is completely dissolved in an organic aqueous solution mixed with water and an organic solvent by heating to form a nearly saturated solution of mometasone furoate, water and organic solvent at a high temperature, and the product is further precipitated by further cooling. The product is crystalline.

[0005] The prior art has not reported any pharmaceutical microspheres containing mometasone furoate and formoterol fumarate hydrate. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the drawbacks of existing micronized mometasone furoate and formoterol fumarate, such as high bulk density or low lung deposition of the resulting powder inhalers. To this end, the present invention provides drug combination microspheres, a preparation method, and a raw material composition. The drug combination microspheres of the present invention have a reduced bulk density, significantly reduce residues of the prepared powder inhaler inhaler devices and capsule shells, and increase lung deposition, making them suitable as raw materials for preparing microspheres in inhalation preparations.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a raw material composition for drug microspheres, which comprises the following components: formoterol fumarate (FF), mometasone furoate (MF) and a solvent;

[0009] The weight ratio of the mometasone furoate to the formoterol fumarate is (2-25):1;

[0010] The total concentration of the mometasone furoate and the formoterol fumarate is ≥14 mg / ml, and the total concentration is the mass-to-volume ratio of the total mass of the mometasone furoate and the formoterol fumarate to the volume of the solvent;

[0011] The solvent is a mixed solvent of water and dioxane, and the volume ratio of the dioxane to the water is ≥2.1:1.

[0012] In the present invention, the formoterol fumarate is preferably formoterol fumarate hydrate, such as formoterol fumarate dihydrate.

[0013] In the present invention, the weight ratio of the mometasone furoate to the formoterol fumarate is preferably (2.3-24.3):1, such as 2.3:1, 7.0:1, 9.1:1, 13.0:1, 18.5:1, 20:1 or 24.3:1.

[0014] In the present invention, the total concentration of the mometasone furoate and the formoterol fumarate is preferably 14.7 mg / mL-63.9 mg / mL, for example, 14.7 mg / mL, 31.5 mg / mL, 33.7 mg / mL, 34.9 mg / mL, 45.0 mg / mL, 51.5 mg / mL or 63.9 mg / mL.

[0015] In the present invention, the concentration of the mometasone furoate is preferably 10.3-61.3 mg / mL, for example, 10.3 mg / mL, 29.5 mg / mL, 30 mg / mL, 31.4 mg / mL, 41.7 mg / mL, 48.8 mg / mL or 61.3 mg / mL. The concentration of the mometasone furoate is the mass volume ratio of the mometasone furoate to the solvent.

[0016] In the present invention, the concentration of the formoterol fumarate is preferably 1.5-4.4 mg / mL, for example 1.5 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 3.2 mg / mL, 3.5 mg / mL, 4.2 mg / mL or 4.4 mg / mL, and the concentration of the formoterol fumarate is the mass volume ratio of the formoterol fumarate to the solvent.

[0017] In the present invention, the mass ratio of the total mass of the mometasone furoate and the formoterol fumarate to the solvent is preferably (1.4%-6%):1, for example, 1.4%:1, 3.26%:1, 3.37%:1, 4.3%:1, 4.9%:1 or 6%:1.

[0018] In the present invention, the volume ratio of the dioxane to the water is preferably (2.1-4):1, for example, 2.1:1, 2.6:1, 2.8:1, 3.2:1, 3.6:1 or 4:1.

[0019] In a preferred embodiment of the present invention, the raw material composition is composed of the following components: the aforementioned formoterol fumarate, the aforementioned mometasone furoate and the aforementioned solvent.

[0020] The present invention also provides a method for preparing drug microspheres, which comprises the following steps: subjecting the above raw material composition to a spray freeze-drying method to obtain the drug microspheres.

[0021] The conditions and operations in the spray freeze drying method may be conventional conditions and operations in the art. The present invention particularly prefers the following conditions and operations:

[0022] The gas-liquid ratio in the spray freeze drying method is preferably 1 (MPa:ml / min):1-100 (MPa:ml / min), for example 1:50 (MPa:ml / min).

[0023] The freeze-drying time in the spray freeze-drying method is preferably 18 h to 36 h, for example 36 h.

[0024] In some embodiments, the method for preparing the drug microspheres preferably comprises the following steps:

[0025] Step 1: adding the formoterol fumarate and the mometasone furoate to a mixed solvent of water and dioxane to obtain a mixed solution A;

[0026] Step 2: The mixed solution A is subjected to a spray freeze-drying method to obtain the drug microspheres.

[0027] In step 1, the mixed solution A is preferably ultrasonically mixed before spray freeze drying. The ultrasonic mixing time is preferably 5-20 minutes. The ultrasonic mixing frequency is preferably 40 kHz.

[0028] The present invention also provides a drug microsphere comprising the following components: formoterol fumarate and mometasone furoate;

[0029] The weight ratio of the mometasone furoate (MF) to the formoterol fumarate (FF) is (2-25):1.

[0030] The weight ratio of the mometasone furoate to the formoterol fumarate is preferably (2.3-24.3):1, such as 2.3:1, 7.0:1, 9.1:1, 13.0:1, 18.5:1, 20:1 or 24.3:1.

[0031] In the present invention, the diameter of the drug microspheres can be a conventional diameter size in microsphere preparations, preferably 200-500 nm.

[0032] In the present invention, the drug microspheres may or may not include a solvent, and the solvent is preferably dioxane and / or water.

[0033] The amount of the solvent can be the amount of solvent remaining when the drug microspheres are prepared using conventional methods in the art.

[0034] In the present invention, the drug microspheres are preferably prepared by the above-mentioned method for preparing drug microspheres.

[0035] In the present invention, the drug microspheres are composed of the following components:

[0036] Group a: the above-mentioned formoterol fumarate and the above-mentioned mometasone furoate;

[0037] Group b: the above-mentioned formoterol fumarate, the above-mentioned mometasone furoate and the above-mentioned solvent.

[0038] The present invention also provides a use of the solvent in preparing the drug microspheres; the drug microspheres are composite microspheres of formoterol fumarate and mometasone furoate.

[0039] In the present invention, "microspheres" refer to the spherical structure formed after the drug is processed, and the particle size is 1-250 μm.

[0040] In the present invention, "solid content" refers to the percentage of the total mass of solid matter in the mixed solution used for spray freeze drying to the total mass of the mixed solution.

[0041] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0042] The reagents and raw materials used in the present invention are commercially available.

[0043] The positive progress of the present invention is that compared with micronized drugs, the drug combination microspheres of the present invention have the following advantages:

[0044] (1) The drug combination microspheres of the present invention can be used as raw materials for preparing inhalation preparations, and their bulk density is lower;

[0045] (2) The powder inhaler prepared from the drug combination microspheres of the present invention has less residue in the inhalation device and capsule shell, which is beneficial to increase the lung deposition amount;

[0046] (3) The drug combination microspheres of the present invention can have a solid content concentration as high as 3% while meeting the clinical dosage ratio, providing a screening space for product development;

[0047] (4) The drug components in the drug combination microspheres of the present invention are more evenly mixed, and the synchronization of the dual drug is higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is an electron microscope image of the drug microspheres of Example 1.

[0049] Figure 2 This is an electron microscope image of the drug microspheres of Example 2.

[0050] Figure 3 This is the electron microscope image of the product of Comparative Example 1.

[0051] Figure 4 The suspension states of the aerosol containing the drug microspheres of Example 1 at 0s, 10s and 20s.

[0052] Figure 5 The suspension state of the aerosol containing micronized formoterol fumarate and mometasone furoate at 0s, 10s and 20s.

[0053] Figure 6 Electron microscopic images of micronized mometasone furoate particles and particle dispersion.

[0054] Figure 7 Electron microscopic images of micronized formoterol fumarate particles and particle dispersion.

[0055] Figure 8 This is an electron microscope image of the drug microsphere particles and particle dispersion in Example 1.

[0056] Figure 9 This is the X-ray powder diffraction pattern of micronized mometasone furoate.

[0057] Figure 10 The X-ray powder diffraction pattern of micronized formoterol fumarate.

[0058] Figure 11 This is the X-ray powder diffraction pattern of the drug microspheres of Example 1.

[0059] Figure 12 This is the electron microscope image of the product of Comparative Example 3. DETAILED DESCRIPTION

[0060] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0061] Example 1

[0062] First, prepare 50 ml of an 80% (volume percentage) dioxane aqueous solution. Next, weigh 1.5 g of mometasone furoate and 0.075 g of formoterol fumarate dihydrate into the 50 ml dioxane aqueous solution and dissolve them under 40 kHz ultrasonic frequency for 5-20 minutes to produce a mixed solution of mometasone furoate and formoterol fumarate. The concentration of mometasone furoate is 30 mg / ml, and the concentration of formoterol fumarate dihydrate is 1.5 mg / ml. Solids content = 3%.

[0063] The mixed solution was rapidly cooled into liquid nitrogen at a gas-liquid ratio of 1:100 (MPa:ml / min) to freeze into small ice balls. After lyophilization for 36 hours, loose and porous drug absorption microspheres were obtained. The diameter of the microspheres was 200-500nm. The SEM images are shown in Figure 2. Figure 1 shown.

[0064] Examples 2-7

[0065] According to the concentrations of dioxane, water, mometasone furoate and fortropol fumarate dihydrate in Table 1, drug microspheres were prepared according to the steps of Example 1.

[0066] The electron microscope image of Example 2 is as follows Figure 2 shown.

[0067] Table 1

[0068]

[0069] As can be seen from the table above, the total concentration of the drug-containing solution (formoterol fumarate dihydrate and mometasone furoate) is higher than 14.6 mg / ml (solids content is 1.44%), which can form drug microspheres. It can be seen that the requirements for preparing the microspheres of the present invention can only be met when the conditions of the dual drug complex solution are at a specific drug concentration and a specific ratio of dioxane water.

[0070] Continuing to increase the solid content can still form microspheres. Therefore, electron microscopy was performed on microspheres with a solid content of 1.44%. During the spray freeze drying process to prepare drug microspheres, electron microscopy was performed on microspheres with a solid content of 3.05% (Example 1). Microspheres can be formed under the electron microscope.

[0071] Comparative Examples 1-11

[0072] According to the concentrations of the solvent, mometasone furoate and fortrol fumarate dihydrate in Table 2, the corresponding product was prepared according to the steps of Example 1. The obtained product was characterized by electron microscopy. No microspheres could be formed under the electron microscope. Specifically, Figure 3 .

[0073] Table 2

[0074]

[0075]

[0076] Since no spherical particles formed under electron microscopy at a solids content of 0.86%, this indicates that the solid material was unable to support the microsphere structure and collapsed during the freeze-drying process. Therefore, in the subsequent search for a good solvent, it was assumed that microspheres could not form when the solids content was < 0.8%, and electron microscopy was not performed.

[0077] Effect embodiment

[0078] 1. Bulk density

[0079] According to the aerodynamic particle size formula [1] : where d ae is the aerodynamic particle size, d geo is the geometric diameter, ρ p is the density of drug particles, and X is the shape factor. According to the above formula, the aerodynamic particle size is not only proportional to the geometric particle size, but also related to the density of drug particles.

[0080] Table 3 Relationship between solid state and bulk density of different APIs

[0081]

[0082] Conclusion: When the particle size is basically the same, the bulk density of formoterol fumarate and mometasone furoate microspheres prepared by spray freeze drying is lower than that of micronized mometasone furoate crystals and micronized formoterol fumarate.

[0083] 2. Suspended state

[0084] Formoterol fumarate and mometasone furoate microspheres (Example 1) were prepared into aerosol (the suspension medium was hydrofluorocarbon (HFA 134a)) with a concentration of 2.42 mg / ml. The suspension state at different times (0, 10s, 20s) was observed. Figure 4 .

[0085] Micronized formoterol fumarate and mometasone furoate (mass ratio of the two is 1.1:23) were used to prepare aerosol (suspending medium is hydrofluoroalkane (HFA 134a)), with a total drug concentration of 2.42 mg / ml. The suspension state at different times (0, 10s, 20s) was observed. Figure 5 .

[0086] Conclusion: After preparing two different solid state APIs into aerosols, the suspension state was changed by changing the density. Compared with the untreated micronized formoterol fumarate and mometasone furoate drugs, the suspension state of formoterol fumarate and mometasone furoate microspheres was significantly improved at the same time.

[0087] This indicates that the drug microspheres prepared by the present invention have a smaller bulk density than untreated drug raw materials and can be used as the main drug component of certain inhalation preparations such as aerosols and powder inhalers.

[0088] 3. Crystal form changes the properties of drugs

[0089] The particle structures of the solid states of different raw materials and the microspheres prepared by the present invention were observed under an electron microscope.

[0090] As shown in the electron microscope image, micronized mometasone furoate ( Figure 6 )、Micronized Formoterol Fumarate ( Figure 7 ) and the formoterol fumarate, mometasone furoate microspheres prepared by the present invention (Example 1, Figure 8 ( Figure 8 and Figure 1 Both are electron microscope images of the microspheres in Example 1, the only difference between the two is the magnification).

[0091] The solid state of different raw materials and the microspheres prepared by the present invention were subjected to X-ray powder diffraction (PXRD) detection, specifically Figure 9 ( Figure 9 is micronized mometasone furoate), Figure 10 ( Figure 10 for micronized formoterol fumarate) and Figure 11 ( Figure 11 (microspheres in Example 1)

[0092] Conclusion: PXRD patterns indicate that both micronized mometasone furoate and micronized formoterol fumarate are crystalline, while the formoterol fumarate and mometasone furoate prepared by spray freeze drying are amorphous. Crystalline form can alter drug properties; the microspheres prepared in this invention can improve the solubility of certain poorly soluble drugs. Furthermore, changes in crystal form can affect their absorption in the body, providing new insights into the development of certain immediate-release and sustained-release formulations.

[0093] 4. The percentage of solid state of the API in different parts of the powder aerosol

[0094] Determination method: According to the 2020 edition of the Chinese Pharmacopoeia Part IV 0951 Aerodynamic characteristics of fine particles of inhalation preparations, the aerodynamic characteristics of the pressure quantitative aerosol are tested using NGI, and the content of each layer is detected by high performance liquid chromatography. The content of each layer is added together to obtain the total amount detected, and the content of each layer is divided by the total amount to obtain the deposition percentage.

[0095] The formoterol fumarate and mometasone furoate microspheres prepared in Example 1 were placed in a powder inhaler device (the name of the powder inhaler device is aerolizer) or a capsule shell, and micronized formoterol fumarate and mometasone furoate (the mass ratio of the two was 1.1:23) were placed in a powder inhaler device (the name of the powder inhaler device is aerolizer) or a capsule shell, and the deposition percentages of the drug solids at different locations were tested. The results are shown in Table 4:

[0096] Table 4

[0097]

[0098] Conclusion: A comparison of the inhalation device deposition percentages of the two solid APIs revealed that the micronized formoterol fumarate / mometasone furoate powder inhaler adhered more readily to the inhalation device and capsule shell than the formoterol fumarate / mometasone furoate inhalation microsphere powder inhaler prepared by the method of the present invention. This resulted in excessive loss of active drug within the device, significantly reducing the amount of active drug deposited in the lungs. The prepared drug microsphere composite powder inhaler, on the other hand, exhibited reduced residue in the inhalation device and capsule shell, resulting in increased lung deposition.

[0099] The 1,4-dioxane aqueous solution of the present invention obtained through screening and having a specific ratio can be used for reprocessing the raw materials of the dual combination of mometasone furoate and formoterol fumarate medicine, and the obtained characteristic microspheres have outstanding advantages in certain preparation fields.

[0100] Without adding excipients, there are fewer ways to reprocess two drug raw materials with greatly different properties, which is more difficult. The present invention uses the screening of solvents, process considerations and characterization of microsphere properties, and the three are interconnected to obtain spherical structure drugs with unique properties. The multiple considerations of the prescription and preparation process in this process make the drug combination microspheres obtained by the invention have a low bulk density. The prepared powder inhaler greatly reduces the residue in the inhalation device and capsule shell, and increases the lung deposition amount. Under the premise of meeting the clinical dosage ratio, the solid content concentration can be as high as 3%, which provides a screening space for product development. The prepared drug combination microspheres make the mixing of the two drugs more uniform, improve the synchronization of the dual drug, and have good drug development prospects.

Claims

1. A raw material composition for pharmaceutical microspheres, characterized in that: The raw material composition consists of the following components: formoterol fumarate, mometasone furoate and a solvent; The weight ratio of the mometasone furoate to the formoterol fumarate is (2-25):1; The total concentration of the mometasone furoate and the formoterol fumarate is 14 mg / mL-63.9 mg / mL; The solvent is a mixed solvent of water and dioxane, and the volume ratio of the dioxane to the water is (2.1-4):

1.

2. The raw material composition of pharmaceutical microspheres according to claim 1, characterized in that: The raw material composition satisfies one or more of the following conditions: (1) The formoterol fumarate is formoterol fumarate hydrate; (2) The weight ratio of the mometasone furoate to the formoterol fumarate is (2.3-24.3):1; (3) The total concentration of the mometasone furoate and formoterol fumarate is 14.6 mg / mL-63.8 mg / mL.

3. The raw material composition of pharmaceutical microspheres according to claim 2, characterized in that: The weight ratio of the mometasone furoate to the formoterol fumarate is 2.3:1, 7.0:1, 9.1:1, 13.0:1, 18.5:1, 20:1 or 24.3:

1.

4. The raw material composition of pharmaceutical microspheres according to claim 2, characterized in that: The total concentration of the mometasone furoate and the formoterol fumarate is 14.7 mg / mL, 31.5 mg / mL, 33.7 mg / mL, 34.9 mg / mL, 45.0 mg / mL or 51.5 mg / mL.

5. The raw material composition of pharmaceutical microspheres according to claim 2, characterized in that: The raw material composition satisfies one or more of the following conditions: (1) The formoterol fumarate is formoterol fumarate dihydrate; (2) The concentration of mometasone furoate is 10.3-61.3 mg / mL; (3) The concentration of the formoterol fumarate is 1.5-4.4 mg / mL; (4) The volume ratio of the dioxane to the water is 2.1:1, 2.6:1, 2.8:1, 3.2:1, 3.6:1 or 4:

1.

6. The raw material composition of pharmaceutical microspheres according to claim 5, characterized in that: The concentration of mometasone furoate is 10.3 mg / mL, 29.5 mg / mL, 30 mg / mL, 31.4 mg / mL, 41.7 mg / mL, 48.8 mg / mL or 61.3 mg / mL.

7. The raw material composition of pharmaceutical microspheres according to claim 5, characterized in that: The concentration of the formoterol fumarate is 1.5 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 3.2 mg / mL, 3.5 mg / mL, 4.2 mg / mL or 4.4 mg / mL.

8. A method for preparing drug microspheres, characterized in that: The method comprises the following steps: subjecting the raw material composition according to any one of claims 1 to 7 to a spray freeze-drying method to obtain the drug microspheres.

9. The method for preparing pharmaceutical microspheres according to claim 8, wherein: The method for preparing the drug microspheres satisfies one or more of the following conditions: (1) The spray freeze drying method has a gas-liquid ratio in MPa:ml / min of 1:1-100; (2) The freeze-drying time in the spray freeze-drying method is 18h-36h; (3) The preparation method of the drug microspheres comprises the following steps: Step 1: adding the formoterol fumarate and the mometasone furoate to a mixed solvent of water and dioxane to obtain a mixed solution A; Step 2: The mixed solution A is subjected to a spray freeze-drying method to obtain the drug microspheres.

10. The method for preparing pharmaceutical microspheres according to claim 9, wherein: The gas-liquid ratio in the spray freeze drying method is 1:50 in terms of MPa:ml / min.

11. The method for preparing pharmaceutical microspheres according to claim 9, wherein: The freeze-drying time in the spray freeze-drying method is 36 hours.

12. The method for preparing pharmaceutical microspheres according to claim 9, wherein: In the step 1, the mixed solution A is ultrasonically mixed before spray freeze drying.

13. The method for preparing pharmaceutical microspheres according to claim 12, wherein: The ultrasonic time is 5-20 minutes.

14. The method for preparing pharmaceutical microspheres according to claim 12, wherein: The frequency of the ultrasound is 40 kHz.

15. A drug microsphere, characterized in that: The drug microspheres are prepared by the preparation method of drug microspheres according to any one of claims 8 to 14.

16. The pharmaceutical microspheres according to claim 15, characterized in that: The drug microspheres meet one or more of the following conditions: (1) The weight ratio of the mometasone furoate to the formoterol fumarate is (2.3-24):1; (2) The diameter of the drug microspheres is 200-500 nm.

17. The pharmaceutical microspheres according to claim 16, wherein The weight ratio of the mometasone furoate to the formoterol fumarate is 2.3:1, 7:1, 9.1:1, 13.0:1, 18.5:1 or 20:

1.

18. Use of the raw material composition of the pharmaceutical microspheres according to any one of claims 1 to 7 in the preparation of pharmaceutical microspheres, wherein: The drug microspheres are composite microspheres of formoterol fumarate and mometasone furoate.

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