Medicinal composition

Abstract

The invention provides a pharmaceutical composition of a nintedanib solution for inhalation. The pharmaceutical composition comprises a first container and a second container, the first container is filled with a first solution, and the first solution contains nintedanib or pharmaceutically acceptable salt thereof and does not contain a nonionic osmotic pressure regulator; the second container is filled with a second solution, and the second solution contains an ionic osmotic pressure regulator and a nonionic osmotic pressure regulator. The medicinal composition disclosed by the invention is simple in component, stable in preparation, capable of avoiding generation of genotoxic impurities, high in safety, lower in irritation to respiratory mucosa and capable of improving the compliance of a patient.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a medicinal combination of a nintedanib solution for inhalation. BACKGROUND

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial lung disease of uncertain etiology and pathogenesis. Its clinical features are progressive scarring or fibrosis confined to the interstitial space of the lung, leading to loss of lung function and resulting in respiratory failure and death. Symptoms of idiopathic pulmonary fibrosis include dry cough, exertional dyspnea, and fatigue. In the late stage of the disease, as blood oxygen levels decrease, the skin can appear blue (cyanosis), and the tips of the fingers can become thick or clubbed. As the disease progresses, signs of pulmonary hypertension and right heart failure are also observed. Its lesions are mainly limited to the lungs, and are prone to occur in middle-aged and elderly men. The lung histopathology and / or chest high-resolution CT (HRCT) is characteristically manifested as usual interstitial pneumonia (UIP).

[0003] Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting idiopathic pulmonary fibrosis (IPF). The drug has been proven to inhibit a variety of receptor tyrosine kinases (RTKs), mainly including platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), etc., thereby blocking intracellular signal transduction, inhibiting the proliferation, migration and transformation of fibroblasts, and ultimately achieving anti-fibrosis and anti-inflammatory effects. PDGFR, FGFR and VFGFR are related to the pathogenesis of idiopathic pulmonary fibrosis. Since nintedanib can competitively bind to adenosine triphosphate of these receptors, it blocks the signals related to fibroblast proliferation, migration and transformation in IPF pathology. Therefore, nintedanib can reduce the rate of decline in lung function and slow the progression of idiopathic pulmonary fibrosis.

[0004] At present, the commonly used nintedanib esylate dosage form on the market is a capsule preparation for oral administration, but the bioavailability of this preparation is low, and it can cause a series of side effects. Considering that IPF patients need long-term medication, the low bioavailability and toxicity of oral capsule preparations and other shortcomings limit their widespread application.

[0005] Inhalation preparations can solve the problem of low bioavailability of oral capsule dosage forms, but the nintedanib solution for inhalation disclosed in the prior art still has certain defects, such as poor stability and the generation of genotoxic impurities, which is not conducive to long-term storage. Therefore, it is urgent to develop a nintedanib solution for inhalation with simple preparation composition, good stability and safety and effectiveness. SUMMARY

[0006] The present application aims to at least partially solve one of the technical problems in the related art. To this end, the present application provides a medicinal combination of a nintedanib solution for inhalation.

[0007] In a first aspect, the present application provides a medicinal combination, characterized by comprising a first container and a second container: the first container contains a first solution, the first solution contains nintedanib or a pharmaceutically acceptable salt thereof, and does not contain a non-ionic osmotic pressure regulator; the second container contains a second solution, the second solution contains an ionic osmotic pressure regulator and a non-ionic osmotic pressure regulator.

[0008] In some specific embodiments, the pharmaceutically acceptable salt of nintedanib can be selected from one or more of nintedanib esylate, nintedanib hydrochloride, nintedanib hydrobromide; preferably, the pharmaceutically acceptable salt of nintedanib is nintedanib esylate.

[0009] In the art, an osmotic pressure regulator refers to a substance used to adjust the osmotic pressure of the internal and external environment of an organism, maintain cell morphology and function, and alleviate osmotic pressure damage.

[0010] In some specific embodiments, the ionic osmotic pressure regulator is selected from one or more of sodium chloride, sodium bromide, potassium chloride, potassium bromide; preferably, the ionic osmotic pressure regulator is sodium chloride.

[0011] In some specific embodiments, the concentration of the ionic osmotic pressure regulator in the blended solution obtained by blending the first solution and the second solution is 15-40 mM, for example, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM. Preferably, it can be 15-29 mM, and more preferably, it can be 15-25 mM.

[0012] In some specific embodiments, the non-ionic osmotic pressure regulator is a polyol non-ionic osmotic pressure regulator, for example, propylene glycol, sorbitol, mannitol, polyethylene glycol, etc.; preferably, it contains at least propylene glycol (for example, propylene glycol, or a combination of propylene glycol and one or more selected from sorbitol, mannitol, and polyethylene glycol); more preferably, it is propylene glycol.

[0013] In some embodiments, the non-ionic osmotic pressure adjusting agent is present in the admixture solution at a concentration of 1-5% w / w, for example, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%. Preferably, the non-ionic osmotic pressure adjusting agent is present at a concentration of 1.5-3% w / w, more preferably 1.5-2.5% w / w.

[0014] In some embodiments, the solvent in the first solution is water; and / or the solvent in the second solution is water; preferably, the water is preferably water for injection.

[0015] In some embodiments, the first solution is an aqueous solution of nintedanib or a pharmaceutically acceptable salt thereof; preferably, an aqueous solution of nintedanib esylate, an aqueous solution of nintedanib hydrochloride or an aqueous solution of nintedanib hydrobromide; more preferably, an aqueous solution of nintedanib esylate.

[0016] In some embodiments, the second solution further comprises a pH adjusting agent; more preferably, the pH adjusting agent is hydrochloric acid.

[0017] In some embodiments, the pH of the second solution is 3.0-4.6, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6.

[0018] In some embodiments, the concentration of nintedanib (as nintedanib) in the admixture solution obtained by admixing the first solution and the second solution is 0.1-2 mg / ml, for example, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml. Preferably, the concentration of nintedanib is 0.2-1.0 mg / ml.

[0019] In some embodiments, the concentration of nintedanib (as nintedanib) in the first solution can be 0.2-5 mg / ml, for example, it can be 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, 3.0 mg / ml, 3.1 mg / ml, 3.2 mg / ml, 3.3 mg / ml, 3.4 mg / ml, 3.5 mg / ml, 3.6 mg / ml, 3.7 mg / ml, 3.8 mg / ml, 3.9 mg / ml, 4.0 mg / ml, 4.1 mg / ml, 4.2 mg / ml, 4.3 mg / ml, 4.4 mg / ml, 4.5 mg / ml, 4.6 mg / ml, 4.7 mg / ml, 4.8 mg / ml, 4.9 mg / ml, 5.0 mg / ml. Preferably, it is 0.5-2 mg / ml. In some embodiments, the concentration of sodium chloride in the second solution can be 30-58 mM; specifically, it can be 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, 41 mM, 42 mM, 43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, 50 mM, 51 mM, 52 mM, 53 mM, 54 mM, 55 mM, 56 mM, 57 mM, 58 mM, 59 mM, 60 mM. More preferably, it is 30-50 mM.

[0020] In some embodiments, the mass concentration of propylene glycol in the second solution is 2-10% w / w; specifically, it can be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%; preferably, it is 3%-5% w / w.

[0021] In some embodiments, the first solution can be 1-10 ml; in particular, it can be 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml.

[0022] In some embodiments, the second solution can be 1-10 ml; in particular, it can be 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml.

[0023] In some embodiments, the pharmaceutical combination is a pharmaceutical combination for producing a solution of nintedanib for inhalation.

[0024] In some embodiments, the first solution and the second solution are mixed immediately before use. The volume ratio of the first solution to the second solution can be 1:5-5:1; in particular, the volume ratio of the first solution to the second solution when mixed immediately before use can be 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:3, 2:5, 3:1, 3:2, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4.

[0025] In some embodiments, the first solution is an aqueous solution of nintedanib ethanesulfonate; the second solution is an aqueous solution containing sodium chloride and propylene glycol. Further, in the admixture solution obtained by mixing the first solution and the second solution, the concentration of nintedanib (calculated as nintedanib) is preferably 0.1-2.0 mg / ml (for example, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml); the concentration of sodium chloride is preferably 15-29 mM (for example: 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM. More preferably, 15-25 mM); the mass concentration of propylene glycol is preferably 1-5% w / w (for example 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%. More preferably, 1.5%-2.5% w / w).

[0026] In a second aspect, the present application provides an inhalable nintedanib solution comprising nintedanib or a pharmaceutically acceptable salt thereof, an ionic osmotic pressure regulator and a non-ionic osmotic pressure regulator; wherein the concentration of the ionic osmotic pressure regulator is 15-29 mM (e.g. 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM), the concentration of nintedanib is 0.1-2 mg / ml (e.g. 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml); the non-ionic osmotic pressure regulator is preferably an alcohol non-ionic osmotic pressure regulator (e.g. propylene glycol, mannitol or polyethylene glycol, preferably propylene glycol); the concentration of the non-ionic osmotic pressure regulator is preferably 1-5% w / w (e.g. 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%; preferably 1.5%-2.5% w / w); optionally, the concentration of nintedanib (calculated as nintedanib) is 0.1-2.0 mg / ml (e.g. 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml).

[0027] In some embodiments, the admixture solution of the first solution and the second solution has an osmolality of 240-400 mOsmol / kg.

[0028] In some embodiments, the pharmaceutical combination as described above or the inhalable nintedanib solution as described above does not contain a metal ion chelator.

[0029] In some embodiments, the pharmaceutical combination as described above or the inhalable nintedanib solution as described above does not further contain a pH buffer.

[0030] In some specific embodiments, the pharmaceutical combination of the present application or the inhalable nintedanib solution of the present application as described above can further not contain a preservative.

[0031] The numerical ranges recited herein are inclusive of the recited endpoints and all sub-ranges encompassed therein.

[0032] Compared with the prior art, the present application has the following beneficial technical effects: The pharmaceutical combination of the present application as described above, (1) uses a lower amount of ionic osmotic pressure regulator, and uses a non-ionic osmotic pressure regulator, so that the blended solution has good properties and high stability (the solution is clear within 2 hours), good osmotic pressure, and lower irritation to the respiratory mucosa, thereby improving the compliance of patients. (2) When the first solution and the second solution are stored separately, both of them show good stability under normal temperature and accelerated conditions. More importantly, the pharmaceutical combination of the present application provides the non-ionic osmotic pressure regulator (such as propylene glycol) and nintedanib separately, which can avoid the generation of sulfonate genotoxic impurities (such as: 、 、 , etc.), and has higher safety. In summary, the pharmaceutical combination of the present application and the inhalable nintedanib solution have simple components, stable preparation, can avoid the generation of genotoxic impurities, and have high safety. DETAILED DESCRIPTION For better illustrating the present application, numerous specific details are given in the following detailed description of the present application. Those skilled in the art should understand that the present application can be implemented without some specific details. The following examples are only used to illustrate the present application, but should not be understood as limiting the scope of the above-mentioned subject matter of the present application to the following examples. Any equivalent replacement in the art according to the content of the present application is within the protection scope of the present application.

[0033] Hereinafter, the specific embodiments of the present application are illustrated by way of examples, and the above-mentioned content of the present application is further elaborated, but the protection scope of the present application is not limited thereto.

[0034] Example 1: Effect of propylene glycol on the stability of the solution in the first and second solutions Experimental phenomena and conclusions: when propylene glycol and nintedanib esylate are stored in one solution, sulfonate genotoxic impurities (including: 、 、 , etc.) are easily generated at 40°C, and there are great safety problems, while the storage stability and safety of propylene glycol and nintedanib esylate are higher when they are stored separately.

[0035] Example 2: Explore the effect of sodium chloride concentration on the stability of the blended solution

[0036] Test phenomenon and conclusion: When the non-ionic osmotic pressure regulator propylene glycol is in the second solution, in order to ensure the stability of the blended solution, the concentration of sodium chloride needs to be controlled. When the concentration of sodium chloride after blending is in the range of 15-40 mM, the blended solution remains clear within 2 h, which can meet the clinical use requirements (and the blended solutions of examples 2-1 to 2-7 are extended to 3 hours and still remain clear, which has sufficient stability in use and more stability advantages. In addition, the applicant found that when the concentration of sodium chloride in the blended solution is in the range of 15-25 mM (examples 2-2 to 2-7), the number of particles containing 10 pm and above does not exceed 300, which is more suitable for the use of inhalation solution. After 2 hours of the blended solution, the related substance test was conducted, and it was found that no sulfonate genotoxic impurities were produced, and the content of nintedanib can reach more than 99% (according to the percentage of labeled amount (%)).

[0037] Example 3: Investigate the effect of different propylene glycol concentrations on the stability of the blended solution

[0038] Test phenomenon and conclusion: When the non-ionic osmotic pressure regulator propylene glycol is in the second solution, the concentration of propylene glycol in the blended solution is controlled in the range of 1.0%-5.0%, the blended solution can remain clear within 2 h, which can meet the clinical use requirements. And when the concentration of propylene glycol is in the range of 1.5%-3% (examples 3-3 to 3-4), the number of particles containing 10 pm and above, 25 pm and above does not exceed 300, which is more suitable for the use of inhalation solution. After 2 hours of the blended solution, the related substance test was conducted, and it was found that no sulfonate genotoxic impurities were produced, and the content of nintedanib can reach more than 99% (according to the percentage of labeled amount (%)).

[0039] Example 4: Investigate the effect of the concentration of the first solution on the stability of the blended solution

[0040] Test phenomena and conclusions: the first solution containing different concentrations of nintedanib ethanesulfonate and the second solution containing sodium chloride and propylene glycol are mixed, when the concentration of nintedanib in the mixed solution is in the range of 0.1 mg / mL ~ 2 mg / mL, it remains clear within 2 hours, which can meet the requirements of clinical use, and the number of particles containing 10 μm and above, 25 μm and above does not exceed 300 particles (Examples 4-1 ~ 4-10), which is more suitable for use in inhalation solution. The related substance test was carried out after 2 hours of the mixed solution, it was found that no sulfonate ester genotoxic impurities were produced, and the content of nintedanib can reach more than 99% (according to the percentage (%) of the labeled amount).

[0041] Although the embodiments of the present application have been shown and described above, it should be understood that the above-described embodiments are exemplary and should not be construed as limiting the present application, and those of ordinary skill in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. A medicinal combination, characterized in that, Includes a first container and a second container: The first container contains a first solution containing nintedanib or a pharmaceutically acceptable salt thereof, and does not contain a nonionic osmoregulator. The second container holds a second solution containing ionic and non-ionic osmotic pressure regulators.

2. The medicinal combination as described in claim 1, characterized in that, The nonionic osmotic pressure regulator is a polyol-based osmotic pressure regulator; preferably propylene glycol.

3. The medicinal combination as described in claim 1, characterized in that, In the mixed solution obtained by mixing the first solution and the second solution, the concentration of the ionic osmotic pressure regulator is 15~40mM, preferably 15~25mM.

4. The medicinal combination as described in claim 1, characterized in that, Pharmaceutically acceptable salts of nintedanib are selected from one or more of nintedanib ethanesulfonate, nintedanib hydrochloride, and nintedanib hydrobromide; preferably, nintedanib ethanesulfonate.

5. The medicinal combination as described in claim 1, characterized in that, The ionic osmotic pressure regulator is selected from one or more of sodium chloride, sodium bromide, potassium chloride, and potassium bromide; preferably, the ionic osmotic pressure regulator is sodium chloride.

6. The pharmaceutical combination as described in claim 1, characterized in that, In the mixed solution obtained by mixing the first solution and the second solution, the mass concentration of the nonionic osmotic pressure regulator is 1~5% w / w, preferably 1.5%~2.5% w / w.

7. The pharmaceutical combination as described in claim 1, characterized in that, The solvent in the first solution is water; and / or the solvent in the second solution is water; preferably, the water is water for injection.

8. The pharmaceutical combination as described in claim 1, characterized in that, The first solution is an aqueous solution of nintedanib or a pharmaceutically acceptable salt thereof, preferably an aqueous solution of nintedanib isosulfonate, nintedanib hydrochloride, or nintedanib hydrobromide; more preferably an aqueous solution of nintedanib isosulfonate.

9. The medicinal combination as described in claim 1, characterized in that, The second solution further contains a pH adjuster; the pH adjuster is preferably hydrochloric acid.

10. The medicinal combination as described in claim 1, characterized in that, The pH value of the second solution is 3.0~4.

6.

11. The medicinal combination as described in claim 1, characterized in that, In the mixed solution obtained by mixing the first solution and the second solution, the concentration of nintedanib is 0.1~2 mg / ml, preferably 0.2~1 mg / ml.

12. The pharmaceutical combination as described in claim 1, characterized in that, The first solution is an aqueous solution of nintedanib ethanesulfonate; The second solution is an aqueous solution containing sodium chloride and propylene glycol.

13. The pharmaceutical composition as described in claim 12, characterized in that, The medicinal combination satisfies one or more of the characteristics in (a) to (d): (a) The concentration of nintedanib is 0.1~2 mg / ml in the mixed solution obtained by mixing the first solution and the second solution; (b) In the mixed solution obtained by mixing the first solution and the second solution, the concentration of sodium chloride is 15~29 mM; preferably 15~25 mM; (c) In the mixed solution obtained by mixing the first solution and the second solution, the mass concentration of propylene glycol is 1~5% w / w; preferably 1.5%~3% w / w; (d) In the second solution, the mass concentration of the nonionic osmotic pressure regulator is 2 to 10% w / w; preferably 3% to 6% w / w.

14. The pharmaceutical composition according to claim 1, characterized in that, in the first solution, the concentration of nintedanib is 0.2~5 mg / ml; preferably 0.5~2 mg / ml; and in the second solution, the concentration of the ionic osmotic pressure regulator is 30~58 mM; preferably 30~50 mM.

15. The pharmaceutical combination as described in claim 1, characterized in that, The first solution and the second solution are mixed before use, and the volume ratio of the first solution to the second solution can be 1:5 to 5:

1.

16. An inhalable nintedanib solution, characterized in that, It is a mixture of the first solution and the second solution as described in any one of claims 1-21.

17. An inhalable nintedanib solution, characterized in that, It includes nintedanib or its pharmaceutically acceptable salts, ionic osmoregulators, and nonionic osmoregulators; among which... The concentration of the ionic osmotic pressure regulator is 15~29mM, preferably 15~25mM; Optionally, the concentration of nintedanib is 0.1~2.0 mg / ml, preferably 0.2~1.0 mg / ml; Optionally, the ionic osmotic pressure regulator is sodium chloride; Optionally, the nonionic osmotic pressure regulator is selected from propylene glycol; Optionally, the mass concentration of the nonionic osmotic pressure regulator is 1-5% w / w; preferably 1.5%-3% w / w. Optionally, the inhalable nintedanib solution does not contain a metal ion chelating agent.

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