PREPARATION OF A PHARMACEUTICAL COMPOSITION OF OLODATEROL AND BUDESONIDE

Abstract

The present invention is directed to a liquid pharmaceutical formulation and a method for administering the pharmaceutical formulation by nebulizing the pharmaceutical formulation with an inhaler. The propellant-free pharmaceutical formulation comprises: (a) active substances selected from budesonide and olodaterol; (b) a solvent; (c) a pharmacologically acceptable solubilizing agent; (d) a pharmacologically acceptable preservative, and (e) a pharmacologically acceptable stabilizer.

Claims

1. A liquid, propellant-free pharmaceutical formulation comprising: (a) budesonide and olodaterol; (b) a solvent; and (c) a pharmacologically acceptable solubilizing agent; wherein the solubilizing agent is selected from the group consisting of a cyclodextrin derivative or a salt thereof, and combinations thereof. wherein the pharmaceutical formulation has a pH ranging from about 2.0 to about 6.0.

2. The pharmaceutical formulation according to claim 1, wherein budesonide is present in an amount ranging from about 1 mcg/ml to about 100 mcg/ml.

3. The pharmaceutical formulation according to claim 1, wherein the olodaterol is present in an amount ranging from about 2 mcg/ml to about 500 mcg/ml.

4. The pharmaceutical formulation according to claim 1, wherein the solvent is a water substantially free of other solvents.

5. The pharmaceutical formulation according to claim 1, wherein the solubilizing agent is sulfobutylether β-cyclodextrin sodium.

6. The pharmaceutical formulation according to claim 5, wherein the solubilizing agent is present in an amount ranging from about 1 g/100 ml to about 40 g/100 ml.

7. The pharmaceutical formulation according to claim 5, wherein the solubilizing agent is present in an amount ranging from about 0.04 g/4 ml to about 1.6 g/4 ml.

8. The pharmaceutical formulation according to claim 1, further comprising a pharmacologically acceptable preservative selected from the group consisting of benzalkonium chloride, benzoic acid, and sodium benzoate.

9. The pharmaceutical formulation according to claim 8, wherein the pharmacologically acceptable preservative is present in an amount ranging from about 0.08 mg/4 ml to about 12 mg/4 ml.

10. The pharmaceutical formulation according to claim 8, wherein the pharmacologically acceptable preservative is benzalkonium chloride in an amount of about 0.4 mg/4 ml.

11. The pharmaceutical formulation according to claim 1, further comprising a stabilizer selected from the group consisting of edetic acid (EDTA), edetate disodium, edetate disodium dihydrate, and citric acid, and wherein the stabilizer is present in an amount ranging from about 0.04 mg/4 ml to about 20 mg/4 ml.

12. The pharmaceutical formulation according to claim 1, further comprising sodium chloride in an amount ranging from about 0.1 g/100 ml to about 0.9 g/100 ml.

13. A method for administering the pharmaceutical formulation according to claim 1, comprising nebulizing a defined amount of the pharmaceutical formulation with an inhaler by using pressure to force the pharmaceutical formulation through a nozzle to form an inhalable aerosol.

14. The method according to claim 13, wherein the defined amount of the pharmaceutical formulation is less than about 8 microliters of the pharmaceutical formulation.

15. The method according to claim 13, wherein the average particle size of the aerosol is less than about 15 micron.

16. A method of treating asthma or COPD in a patient, comprising administering to the patient the pharmaceutical formulation according to claim 1.

17. The method of claim 16, wherein the pharmaceutical formulation is administered at a therapeutically effective dose of budesonide ranging from about 1 μg to about 100 μg and a therapeutically effective dose of olodaterol ranging from about 5 μg to about 500 μg.

18. The pharmaceutical formulation according to claim 1, wherein budesonide is present in an amount of about 500 μg/mL.

19. The liquid, propellant-free pharmaceutical formulation of claim 1 comprising: an aqueous solution of: (a) budesonide in an amount of about 1 μg/mL to about 1000 m/mL; (b) olodaterol in an amount of about 2 μg/mL to about 500 m/mL; (c) sulfobutyl ether β-cyclodextrin sodium in an amount of about 1 g/mL to about 40 g/100 ml; (d) sodium chloride in an amount of about 0.1 g/100 mL to about 0.9 g/100 mL; and (e) citric acid in an amount sufficient to adjust the pH to about 4.0.

20. The liquid, propellant-free pharmaceutical formulation of claim 1 comprising: an aqueous solution of: (a) budesonide in an amount of about 1 μg/mL to about 1000 μg/mL; (b) olodaterol in an amount of about 2 μg/mL to about 500 μg/mL; (c) sulfobutyl ether β-cyclodextrin sodium in an amount of about 1 g/mL to about 40 g/100 mL; (d) sodium chloride in an amount of about 0.1 g/100 mL to about 0.9 g/100 mL; and (e) hydrochloric acid in an amount sufficient to adjust the pH to about 5.0.

21. The liquid, propellant-free pharmaceutical formulation of claim 1 comprising: an aqueous solution of: (a) budesonide in an amount of about 50.9 mg/100 mL; (b) olodaterol in an amount of about 1.8 mg/100 mL; (c) sulfobutyl ether β-cyclodextrin sodium in an amount of about 9.6 mg/mL; and (d) citric acid in an amount sufficient to adjust the pH to about 4.0

22. The liquid, propellant-free pharmaceutical formulation of claim 1 comprising: an aqueous solution of: (a) budesonide in an amount of about 50.9 mg/100 mL; (b) olodaterol in an amount of about 1.8 mg/100 mL; (c) sulfobutyl ether β-cyclodextrin sodium in an amount of about 9.6 mg/mL; and (d) hydrochloric acid in an amount sufficient to adjust the pH to about 5.0

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIGS. 1, 2, and 3 depict various nebulizers or components of a nebulizer. FIG. 1 depicts an ultrasonic nebulizer, FIG. 2 depicts a jet nebulizer, and FIG. 3 depicts the pressure vibration element and micropores of a mesh nebulizer.

EXAMPLES

[0068] Materials and reagents: [0069] 50% benzalkonium chloride aqueous solution purchased from Merck. [0070] Edetate disodium dihydrate purchased from Merck. [0071] Sodium hydroxide purchased from Titan reagents. [0072] Hydrochloric acid purchased from Titan reagents. [0073] Citric acid (CA) purchased from Merck. [0074] Sodium chloride purchased from Merck. [0075] Sulfobutylether β-cyclodextrin purchased from Zhiyuan Bio-tech Co., Ltd., China. [0076] Budesonide and olodaterol purchased from SBECD purchased from Zhiyuan Bio-tech Co., Ltd., China.

Example 1

[0077] The formulation and preparation of a solution for administration by nebulization inhalation (samples 1-4) is as follows: [0078] 1. Weigh the prescribed amount of SBECD in a beaker and add the prescribed amount of water to make the weight up to 104.70 g. [0079] 2. After stirring to dissolve SBECD, use CA to adjust the pH to about 4.00. [0080] 3. After adjusting the pH, add the prescribed amount of BD according to Table 1, and stir overnight in the dark to dissolve. [0081] 4. After the BD is dissolved, add the prescribed amount of OH according to Table 1, and filter after dissolving. [0082] 5. Divide the above samples into four parts, adjust the pH of each sample to 5.5, 5.0, 4.5, and 4.0, respectively, with CA solution. Designate the samples as Sample 1, Sample 2, Sample 3, and Sample 4, respectively.

TABLE-US-00001 TABLE 1 Ingredient of Samples 1-4 Ingredients Sample 1 Sample 2 Sample 3 Sample 4 Budesonide(BD) 53.33 mg 53.33 mg 53.33 mg 53.33 mg Olodaterol 1.842 mg 1.842 mg 1.842 mg 1.842 mg hydrochloride (OH) Sulfobutyl ether β- 10.00 g 10.00 g 10.00 g 10.00 g Cyclodextrin sodium (SBECD) Citric acid (CA) Adjusted to pH Adjusted to pH Adjusted to pH Adjusted to pH 5.5 5.0 4.5 4.0 Purified water Added to Added to Added to Added to 104.70 g 104.70 g 104.70 g 104.70 g

Example 2

[0083] The thermal stability of samples 1˜4 of example 1 at 60° C. is provided below:

[0084] Impurity detection method: [0085] Mobile phase A: accurately weigh 3.17 g of sodium dihydrogen phosphate, add 1 L of pure water to dissolve, adjust the pH of the solution to 3.20 with phosphoric acid. Mobile Phase B: Acetonitrile. [0086] Instrument ID: HPLC. [0087] Column ID: YMC-Triart C18 250*4.6 5 μm. [0088] Detection wavelength: 230 nm. [0089] Flow rate: 1.0 mL/min. [0090] Running time: 35 min.

TABLE-US-00002 Time Mobile phase A % Mobile Phase B % 0 70 30 7 70 30 8 60 40 32 60 40 33 70 30 35 70 30

[0091] The test results are shown below.

TABLE-US-00003 TABLE 2 Thermal Stability of Samples 1-4 of Example 1at 60° C. (Condition: 60° C. ± 2° C./RH 75%) Sample 1 Sample 2 Sample 3 Sample 4 Ingredients pH 5.5 pH 5.0 pH 4.5 pH 4.0 0 day Character Colorless clear liquid Content μg/ml OH 17.87 18 17.94 17.98 BD 538.52 541.57 539.53 544.6 Total impurities % OH NA 0.09 0.08 0.07 BD NA NA NA NA 60° C. character Colorless clear liquid 7 days Content μg/ml OH 17.33 16.98 17.13 17.22 BD 514.01 518.38 520.44 519.77 Total impurities % OH 2.6 2.16 2.94 2.17 BD 1.22 0.58 0.49 0.6 60° C. Character Colorless clear liquid 14 days Content μg/ml OH 17.09 17.3 17.64 16.48 BD 498.22 532.95 543.68 487.37 Total impurities % OH 2.62 7.17 4.08 3.13 BD 2.62 1.92 0.89 1.05

[0092] CA citric acid solution was used to adjust the pH. It was found that OH was relatively stable at pH 5.5 and pH 4.0, and BD was relatively stable at pH 4.0 and 4.5. Therefore, a formulation is relatively stable when adjusted to a pH of about 4.0 with citric acid.

Example 3

[0093] The formulation and preparation of a solution for administration by nebulization inhalation (samples 5-8) is as follows: [0094] 1: Weigh the prescribed amount of SBECD into an empty beaker, add 93 g of pure water to dissolve, and adjust the pH to the target value with hydrochloric acid after dissolving. [0095] 2: Weigh the prescribed amount of BD into the above solution and stir in the dark until dissolved. [0096] 3: After dissolving, add OH into the above-solution until dissolved. [0097] 4: Adjust the pH of each sample to 5.0, 4.5, 4.0, and 3.5, respectively, with hydrochloric acid. Designate the samples as Sample 5, Sample 6, Sample 7, and Sample 8, respectively. [0098] 5: Add purified water to a final volume of 104.7 g. [0099] 6: Divide each Sample into parts and store at 40° C. and 60° C. for 5 days and 10 days. At each time point detect impurities.

TABLE-US-00004 TABLE 3 Ingredients of Samples 5-8 Ingredients Sample 5 Sample 6 Sample 7 Sample 8 Budesonide (BD) 53.33 mg 53.33 mg 53.33 mg 53.33 mg Olodaterol 1.842 mg 1.842 mg 1.842 mg 1.842 mg hydrochloride (OH) Sulfobutyl ether β- 10.00 g 10.00 g 10.00 g 10.00 g cyclodextrin sodium (SBECD) HCl Adjusted to pH Adjusted to pH Adjusted to pH Adjusted to pH 5.0 4.5 4.0 3.5 Purified water Added to Added to Added to Added to 104.70 g 104.70 g 104.70 g 104.70 g

TABLE-US-00005 TABLE 4 Thermal Stability of Samples 5-8 of Example 3 at 40° C. (Condition: 40° C. ± 2° C./RH 75%) Sample 5 Sample 6 Sample 7 Sample 8 Ingredients pH 5.0 pH 4.5 pH 4.0 pH 3.5 0 day Character Colorless clear liquid Total impurities % OH NA NA NA NA BD 0.63 0.64 0.63 0.64 40° C. Character Colorless clear liquid 5 days Total impurities % OH 0.11 0.05 0.14 0.25 BD 0.97 0.98 0.98 0.98 40° C. Character Colorless clear liquid 10 days Total impurities % OH 0.14 0.41 1.03 1.79 BD 1.36 1.09 1.12 1.14

TABLE-US-00006 TABLE 5 Thermal Stability of Samples 5-8 of Example 3 at 60° C. (Condition: 60° C. ± 2° C./RH 75%) Sample 5 Sample 6 Sample 7 Sample 8 Ingredients pH 5.0 pH 4.5 pH 4.0 pH 3.5 0 day Character Colorless clear liquid Total impurities % OH 0.19 0.19 0.19 0.29 BD 0.63 0.64 0.63 0.64 60° C. Character Colorless clear liquid 5 days Total impurities % OH 0.59 0.62 0.94 1.71 BD 1.47 1.44 1.53 1.72 60° C. Character Colorless clear liquid 10 days Total impurities % OH 2.86 4.23 8.2 15.75 BD 1.8 1.66 1.68 1.92

[0100] A hydrochloric acid solution was used to adjust the pH. The total impurities after storage are as shown in the above table. At each different pH, each active ingredient exhibited different degrees of degradation. When using hydrochloric acid to adjust the pH, pH 5.0 exhibits the best stability at 60° C.±2° C./RH 75%

Example 4

[0101] Solubility study to investigate the solubilizing effect of SBECD and Tween 80 on BD, and to investigate the solubility of BD at different concentrations.

[0102] To investigation the solubility of BD under different concentrations of SBECD: Weigh 0.1 g, 0.3 g, 0.5 g, and 1.0 g of BD into a 10 ml EP tube, add 10 ml of pure water, shake until it is completely dissolved, add excess BD (about 500 mg/100 mL), and wrap the EP tube in tin foil to protect from light. After being protected from light, place the EP tube on a shaker and shake for 24 hours.

[0103] To investigation of the solubility of BD under different concentrations of Tween 80: Weigh 0.002 g, 0.001 g, 0.0005 g, 0.1 g, 0.3 g, 0.5 g, and 1.0 g of BD into a weighing bottle, transfer the BD to a 10 ml EP tube by rinsing the weighing bottle with sufficient water to provide 10 ml in the EP tube, add excess BD (about 500 mg/100 mL), and wrap the EP tube in tin foil to protect it from light. After being protected from light, place the EP tube on a shaker and shake for 24 hours, then centrifuge to get the supernatant.

TABLE-US-00007 TABLE 6 Solubility of BD in Solutions Having Different Concentrations of SBECD and Different Concentrations of Tween 80 SBECD BD Solubility Tween 80 BD Solubility concentration (mg/100 ml) concentration (mg/100 ml) 1% 16.91 1% 16.54 3% 40.28 3% 38.88 5% 61.91 5% 64.84 10%  81.3 10%  118.79  5 mg/100 ml 0.224 10 mg/100 ml 0.256 20 mg/100 ml 0.292

[0104] According to the above results, it can see that SBECD and Tween 80 have similar solubilization effects on BD. Tween-80 is within acceptable limits. According to the US pharmacopoeia, the concentration of Tween-80 should not exceed 20 mg/100 ml in an inhalation suspension. The solubility of BD in Tween-80 concentrations of 20 mg/100 ml is only 2.92 μg/ml. Unable to meet the requirements. A BD solubility of about 500 μg/ml is needed.

Example 5

[0105] Aerodynamic Particle Size Distribution:

[0106] The aerodynamic particle size distribution of Sample 2 of Example 1 was determined using a Next Generation Pharmaceutical Impactor (NGI).

[0107] The device used to form the aerosol was a PARI E-flow device, purchased from PARI. The device was held close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 15 L/minute and was operated under ambient temperature and a relative humidity (RH) of 90%.

[0108] The solution of sample 2 was discharged into the NGI. Fractions of the dose were deposited at different stages of the NGI, in accordance with the particle size of the fraction. Each fraction was washed from the stage and analyzed using HPLC.

[0109] The result are shown in Table 7.

TABLE-US-00008 TABLE 7 Aerodynamic Particle Size Distribution of Sample 2 OH BD Cut-off Percentage Percentage diameters Dosage content at all Dosage content at all at 15 L/min Deposited (μg) levels % (μg) levels % (μm) Device 0.58 11.58 18.28 12.08 Throat 0 0 1.2 0.79 Stage 1 0.06 1.20 2.41 1.59 14.10 Stage 2 0.11 2.20 3.03 2.00 8.61 Stage 3 0.47 9.38 13.84 9.15 5.39 Stage 4 1.63 32.53 47.77 31.57 3.30 Stage 5 1.40 27.94 40.78 26.95 2.08 Stage 6 0.57 11.38 16.93 11.19 1.36 Stage 7 0.18 3.59 5.24 3.46 0.98 MOC 0 0 0 0 Stage F 0.01 0.20 1.85 1.22 Theoretical dose (μg) 5.56 161.25 Actual test dose (μg) 5.01 151.33 Recovery rate (%) 90.11 93.85 MMAD (μm) 3.33 3.33 GSD 1.57 1.58 ISM (μg) 4.37 129.44 FPD (μg) 3.79 112.57 FPF (%) 75.65 74.39 MOC is Micro-Orifice Collector. ISM is Impactor Size Mass. FPF is Fine Particle Fraction. FPD is fine particle dose. MMAD is mass median aerodynamic diameter. GSD is Geometric Standard Deviation. Stage F is a filter, which is a DDU tube connected to the end of the NGI.

Comparative Example 1

[0110] The aerodynamic Particle Size Distribution of a budesonide suspension (Comparative Sample 1 (Pulmicort): batch number: LOT 324439; dosage: 0.5 mg; Specification: 2 ml/inhalation/time).

[0111] The budesonide suspension sample was purchased from AstraZeneca Pty Ltd.

[0112] The aerodynamic particle size distribution was determined using a Next Generation Pharmaceutical Impactor (NGI). The Sample was Pulmicort. The device used to form the aerosol was an LC-Plus, purchased from PARI in Germany. The device was held close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 30 L/minute and was operated under ambient temperature and a relative humidity (RH) of 90%.

[0113] The solution of Comparative Sample 1 was discharged into the NGI. Fractions of the dose were deposited at different stages of the NGI, in accordance with the particle size of the fraction. Each fraction was washed from the stage and analyzed using HPLC.

[0114] The result are shown in Table 8.

TABLE-US-00009 TABLE 8 Aerodynamic Particle Size Distribution of Budesonide Suspension Comparative Sample 1 (Pulmicort) BD Percentage Cut-off content at diameters at Deposited Dosage (μg) all levels % 30 L/min (μm) Device 892.42 91.86 Throat 8.38 0.86 S1 6.98 0.72 11.72 S2 16.71 1.72 6.40 S3 22.43 2.31 3.99 S4 17.25 1.78 2.30 S5 5.15 0.53 1.36 S6 2.15 0.22 0.83 S7 0 0.00 0.54 MOC 0 0.00 Theoretical dose (μg) 1000 Actual test dose (μg) 971.474 Recovery rate (%) 97.15 ISM (μg) 63.69 FPD (μg) 46.98 FPF (%) 4.84

[0115] A comparison of the NGI parameters for the budesonide suspension, Comparative Sample 1 (Pulmicort), and Sample 2 of Example 1 of the invention, shows that the effective lung deposition of Sample 2 of Example 1 is much higher than that of Comparative Example 1 (Pulmicort), indicating that the bioavailability of Sample 2 of Example 1 sprayed with the E-flow device is higher.

[0116] Because the ISM of Sample 2 of Example 1 is much higher than that of the Comparative Sample 1 (Pulmicort), in order to be consistent with the Pulmicort dose, it is considered that the effective dose of OH and BD can be reduced. Accordingly, with the formulation of the invention, the dose of OH is about 5.56 μg and the dose of BD is about 161.25 μg. Administering a lower dose can reduce the side effects of drugs on the human body.

Comparative Example 2

[0117] Aerodynamic Particle Size Distribution of a budesonide inhalation aerosol

[0118] Comparative Sample 2: a budesonide suspension for inhalation was purchased from AstraZeneca Pty Ltd.

[0119] The budesonide suspension sample (Comparative Example 2) purchased from AstraZeneca Pty Ltd. administered 160 ug/press, contained 120 press/bottle, and was for administration by 2 presses/time, twice/day.

[0120] The aerodynamic particle size distribution was determined using a Next Generation Pharmaceutical Impactor (NGI). The Sample is Comparative Sample 2. The device used to nebulize the sample was an e-flow, purchased from PARI in Germany. The device was held close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 30 L/minute and the NGI was operated under ambient temperature and a relative humidity (RH) of 90%.

[0121] The solution of Comparative sample 2 was discharged into the NGI. Fractions of the dose were deposited at different stages of the NGI, in accordance with the particle size of the fraction. Each fraction was washed from the stage and analyzed using HPLC.

[0122] The result are shown in Table 9.

TABLE-US-00010 TABLE 9 Aerodynamic Particle Size Distribution of Comparative Sample 2 Percentage Cut-off content at diameter at BD Deposited Dosage (μg) all levels % 30 L/min (μm) Device 24.79 8.09 Throat 116.32 37.95 Stage 1 4.8 1.57 11.72 Stage 2 17.41 5.68 6.40 Stage 3 64.66 21.09 3.99 Stage 4 65.59 21.40 2.30 Stage 5 12.96 4.23 1.36 Stage 6 0 0 0.83 Stage 7 0 0 0.54 MOC 0 0 Theoretical dose (μg) 320 Actual test dose (μg) 306.53 Recovery rate (%) 95.79 ISM 160.62 μg FPD 143.21 μg FPF 46.72%

[0123] The effective lung deposition of Sample 2 of Example 1 is much higher than that of Comparative Sample 2.

Example 6

[0124] 1: Weigh the prescribed amount of SBECD and NaCl into an empty beaker, add 93 g of pure water to dissolve, and adjust to the target pH with hydrochloric acid or CA according to Table 10. [0125] 2: Weigh the prescribed amount of BD into the above solution and dissolve. [0126] 3: After dissolving, add OH into the above solution and dissolve. [0127] 4: Adjust the pH of each sample to the target pH with hydrochloric acid or CA according to Table 10 and designate the samples as Sample 9 and Sample 10 respectively. [0128] 5: Add purified to a final weight of 104.70 g.

TABLE-US-00011 TABLE 10 Ingredients of Samples 9-10 Ingredients Sample 9 Sample 10 Budesonide (BD) 53.33 mg 53.33 mg Olodaterol 1.842 mg 1.842 mg hydrochloride (OH) Sulfobutyl ether β- 10.00 g 10.00 g cyclodextrin sodium (SBECD) NaCl 100 mg 100 mg Adjusted pH Adjusted to pH Adjusted to pH 5.0 with HCl 4.0 with CA Purified water Added to Added to 104.70 g 104.70 g