A pharmaceutical composition containing budesonide and a method for preparing the same

Abstract

This invention relates to the field of pharmaceutical preparations, specifically to a pharmaceutical composition containing budesonide, a capsule formulation, and a method for preparing the same. The pharmaceutical composition of this invention contains a water-soluble acid as a stabilizer for the core of the capsule, and the ratio of the water-soluble acid to budesonide in the pharmaceutical composition is 1:12 to 1:2.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a pharmaceutical composition containing budesonide, a capsule formulation, and a method for preparing them. Background Technology

[0002] IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. It is most prevalent and prone to causing kidney failure in East Asian populations, followed by Caucasian populations, and is rare in African populations. According to Frost & Sullivan data, there are approximately 2.2 million IgA nephropathy patients in my country, with 20% (440,000) being severely ill.

[0003] IgA nephropathy patients commonly present with hematuria and proteinuria. 20% of patients progress to end-stage renal failure after 10 years, 30% develop end-stage renal failure after 20 years, and 30% may exhibit varying degrees of renal function decline.

[0004] The current standard core therapy for IgA nephropathy patients is supportive care with ACEIs / ARBs (angiotensin-converting enzyme inhibitors / angiotensin II receptor antagonists), followed by immunosuppressants and hormonal drugs. A two-year (9 months of treatment + 15 months of follow-up) phase III clinical study showed that 9 months of budesonide enteric-coated capsule treatment had significant long-term benefits (renal function protection, sustained reduction in proteinuria, and improvement in microscopic hematuria), and has a therapeutic effect in altering the course of IgA nephropathy. my country has a large number of IgA nephropathy patients, but lacks targeted treatments. Budesonide enteric-coated capsules are the first approved IgA nephropathy treatment drug in China. Patients can experience long-term benefits after 9 months of treatment, which is expected to change the current treatment landscape. However, there are currently no generic versions available in China. Developing a generic drug with the same quality and bioequivalence as the original drug has significant market and application value. The structural formula of budesonide is as follows:

[0005]

[0006] In the prior art, alkali-containing ethyl cellulose is commonly used as a sustained-release material in drug compositions containing budesonide. However, budesonide is unstable with alkaline components. To meet the requirements of formulation stability, there is an urgent need to develop a budesonide composition with good stability and a process for its preparation that is stable and suitable for industrial production. Summary of the Invention

[0007] The first aspect of the present invention provides a pharmaceutical composition containing budesonide, the pharmaceutical composition comprising a drug-containing core, an isolation layer and a sustained-release layer, wherein the drug-containing core contains budesonide and a water-soluble acid as a stabilizer, and the ratio of the water-soluble acid to budesonide in the drug-containing core is 1:12-1:2.

[0008] A second aspect of the present invention provides an enteric-coated capsule formulation comprising a pharmaceutical composition according to a first aspect of the present invention, as well as a capsule shell, a bottom coating, and an enteric coating.

[0009] A third aspect of the present invention provides a method for preparing an enteric-coated capsule formulation according to a second aspect of the present invention, comprising the following steps:

[0010] (1) A drug-containing suspension containing budesonide and water-soluble acid was used to load the core of the pellet to obtain drug-containing micro pellets;

[0011] (2) Coat the drug-containing microspheres obtained in step (1) with an adhesive to form microspheres with an isolation layer;

[0012] (3) Coat the microspheres obtained in step (2) with a sustained-release material containing ethyl cellulose;

[0013] (4) Fill the microspheres obtained in step (3) into capsules;

[0014] (5) The capsules obtained in step (4) are coated with bottom coating and enteric coating in sequence.

[0015] The pharmaceutical composition of the present invention is stable during storage, and the enteric-coated capsule formulation of the present invention has a good dissolution profile, good storage stability, and is bioequivalent to the original drug TARPEYO (trade name) in humans. The preparation method of the capsule formulation of the present invention is stable, suitable for industrial production, and the resulting product is stable during storage. Detailed Implementation

[0016] The present invention will be further illustrated below through specific embodiments. It should be understood that the embodiments of the present invention are merely provided for illustrative purposes and are not intended to limit the present invention. Improvements, modifications, substitutions, and variations of the following embodiments under the premise of the technical solutions of the present invention all fall within the protection scope of the present invention.

[0017] The first aspect of the present invention provides a pharmaceutical composition containing budesonide, the pharmaceutical composition comprising a drug-containing core, an isolation layer and a sustained-release layer, wherein the drug-containing core contains budesonide and a water-soluble acid as a stabilizer, and the ratio of the water-soluble acid to budesonide in the drug-containing core is 1:12-1:2.

[0018] In one embodiment, the ratio of water-soluble acid to budesonide in the pill core is preferably 1:10 to 1:4.

[0019] In one embodiment, the water-soluble acid is selected from one or more of citric acid, succinic acid, and fumaric acid, with citric acid being preferred.

[0020] In one embodiment, the drug-containing pellet core of the pharmaceutical composition of the present invention further comprises a solid support and a binder. In a preferred embodiment, the drug-containing pellet core consists of budesonide, a water-soluble acid, a solid support, and a binder.

[0021] In one embodiment, the solid support is a blank pellet core, selected from sucrose pellet cores and microcrystalline cellulose pellet cores, preferably sucrose pellet cores.

[0022] In one embodiment, the adhesive is selected from one or more of hydroxypropyl methylcellulose, preferably hydroxypropyl methylcellulose.

[0023] In one embodiment, the budesonide contained in the pharmaceutical composition of the present invention has a particle size of D90 ≤ 5 μm, preferably D90 ≤ 3 μm.

[0024] In some embodiments, the sustained-release material of the sustained-release layer is selected from one or more of ethyl cellulose and ethyl cellulose aqueous dispersions, preferably ethyl cellulose aqueous dispersions. In one embodiment, the sustained-release material of the sustained-release layer is an ethyl cellulose aqueous dispersion with or without alkali.

[0025] In embodiments of the present invention, an ethyl cellulose aqueous dispersion refers to an aqueous dispersion comprising ethyl cellulose and other excipients, wherein the other excipients may also comprise a solubilizer. In one embodiment, the solubilizer may be oleic acid.

[0026] In some embodiments, the pharmaceutical composition of the present invention comprises 0.5%-5% budesonide, preferably 0.8%-3% budesonide, by weight. In some embodiments, the pharmaceutical composition of the present invention comprises 0.05%-1% water-soluble acid, by weight. In some embodiments, the pharmaceutical composition of the present invention comprises 60%-90% solid support, by weight. In some embodiments, the pharmaceutical composition of the present invention comprises 1%-15% binder, by weight. In some embodiments, the pharmaceutical composition of the present invention comprises 1%-15% sustained-release material, by weight.

[0027] In some embodiments, the pharmaceutical composition of the present invention contains a water-soluble acid in both the core and the separator. In some preferred embodiments, the pharmaceutical composition of the present invention contains a water-soluble acid only in the core.

[0028] A second aspect of the present invention provides an enteric-coated capsule formulation comprising a pharmaceutical composition containing budesonide as described in the first aspect of the present invention, as well as a capsule shell, a bottom coating, and an enteric coating.

[0029] In some embodiments, the capsule shell has a material composition commonly used in the field of capsule formulations, such as hydroxypropyl methylcellulose. In some embodiments, the bottom coating has a material composition commonly used in the field of capsule formulations, such as a bottom coating material comprising hydroxypropyl methylcellulose and polyethylene glycol. In some embodiments, the enteric coating has a material composition commonly used in the field of enteric-coated capsule formulations, such as an enteric coating material comprising methyl methacrylate copolymer (1:1), methyl methacrylate copolymer (1:2), talc, and triethyl citrate.

[0030] The pharmaceutical composition containing budesonide included in the enteric-coated capsule formulation of the second aspect of the present invention has the same meaning as the pharmaceutical composition described in the first aspect of the present invention. For the sake of brevity, it will not be repeated here.

[0031] A third aspect of the present invention also provides a method for preparing an enteric-coated capsule formulation according to the second aspect of the present invention, comprising the following steps:

[0032] (1) A drug-containing suspension containing budesonide and water-soluble acid was used to load the core of the pellet to obtain drug-containing micro pellets;

[0033] (2) Coat the drug-containing microspheres obtained in step (1) with an adhesive to form microspheres with an isolation layer;

[0034] (3) Coat the microspheres obtained in step (2) with a sustained-release material containing ethyl cellulose;

[0035] (4) Fill the microspheres obtained in step (3) into capsules;

[0036] (5) The capsules obtained in step (4) are coated with bottom coating and enteric coating in sequence.

[0037] In some embodiments, in step (1) of the method of the third aspect of the present invention, the core used in the drug application step is a blank core (sometimes referred to herein as a "solid support"), selected from sucrose cores and microcrystalline cellulose cores, preferably sucrose cores.

[0038] In some embodiments, in step (1) of the method of the third aspect of the present invention, the drug-containing suspension is a suspension containing budesonide and a water-soluble acid in purified water as a solvent, wherein the content of budesonide is 3% by weight. In some embodiments, the content of the water-soluble acid is 0.6% by weight.

[0039] In some embodiments, the drug-containing suspension further comprises a binder selected from one or more of hydroxypropyl methylcellulose, preferably hydroxypropyl methylcellulose.

[0040] The pharmaceutical composition of the present invention, when stored at 40°C and 75% RH for 3 months, shows that the amount of total impurities is less than 0.5% of that of budesonide.

[0041] The inventors unexpectedly discovered that adding water-soluble acid as a stabilizer to the drug-containing capsule core resulted in samples with good stability and complete dissolution, solving the product stability problem. Furthermore, the capsule formulation of this invention is well absorbed in the human body and is bioequivalent to the original product. In addition, the preparation process of this invention is simple, has good reproducibility, and is easy to scale up for production, meeting the industrialization requirements of the product. Attached Figure Description

[0042] Figure 1 These are line graphs showing the dissolution rates of the examples and comparative formulations. Specific Implementation

[0044] In this article, "drug-containing core" refers to a core containing the active ingredient desinede.

[0045] In this document, unless otherwise stated, the content of components is described as a weight percentage.

[0046] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely provided for illustrative purposes and are not intended to limit the present invention. Simple improvements to the present invention based on the technical solutions of the present invention are all within the protection scope of the present invention.

[0047] Example 1

[0048] Budesonide enteric-coated capsule microparticle composition 1 was prepared according to Table 1 and the preparation process described below.

[0049] Table 1 Budesonide Enteric-coated Capsule / Microparticle Composition 1

[0050]

[0051] Preparation process:

[0052] (1) The core of the pellet is loaded with a drug-containing suspension containing budesonide and water-soluble acid:

[0053] Add the sucrose pellet cores (manufacturer: Calec, model: 16-18 mesh) to the fluidized bed, set the inlet air temperature to 60℃ and the inlet air volume to 25m³ / h. 3 Preheating is performed at a rate of / h, and liquid spraying begins when the material temperature reaches 50℃. The inlet air volume is set to 30m³ / h. 3 The system operates at a constant speed, with an inlet air temperature of 60℃, a material temperature of 50℃, an atomization pressure of 1.0 bar, and a pump speed of 10%. During the core loading process, the drug-containing aqueous suspension is continuously stirred. After the drug-containing suspension is sprayed, the inlet air temperature is set to 60℃, and the inlet air volume is set to 30 m³ / h.3 / h, dry for 15min, then discharge.

[0054] (2) Coat the microspheres obtained in step (1) with an adhesive to form an isolation layer:

[0055] Add the core of the medicine pill to the fluidized bed, set the inlet air temperature to 60℃ and the inlet air volume to 25m³. 3 Preheating is performed at a rate of / h, and liquid spraying begins when the material temperature reaches 50℃. The inlet air volume is set to 30m³ / h. 3 The system operates at a constant speed of 1.0 bar, with an inlet air temperature of 60°C, a material temperature of 50°C, and atomization pressure of 1.0 bar. The pump speed is 10%, and the coating solution (hydroxypropyl methylcellulose aqueous solution) is continuously stirred throughout the process. After the coating solution is sprayed, the inlet air temperature is set to 60°C, and the inlet air volume is 30 m³ / h. 3 / h, dry for 15min, then discharge.

[0056] (3) Coat the microspheres obtained in step (2) with a sustained-release material containing ethyl cellulose:

[0057] The microparticles obtained in step (2) are added to a fluidized bed, and the inlet air temperature is set to 60℃ and the inlet air volume to 25m³. 3 Preheating is performed at a rate of / h, and liquid spraying begins when the material temperature reaches 50℃. The inlet air volume is set to 30m³ / h. 3 The fluidized bed was started at 10% pump speed and inlet air temperature of 60℃. During the coating process, the material temperature was controlled at 50℃, and the coating solution was continuously stirred. After coating, the inlet air temperature was set to 60℃ and the inlet air volume to 30m³ / h. 3 / h, dry for 15min.

[0058] (4) Fill the microspheres obtained in step (3) into capsules:

[0059] Install the capsule filling mold as required, debug the capsule filling machine, and after the capsule filling machine is running normally, feed the material for trial filling. After the filling volume difference is adjusted and qualified, the filling can be carried out.

[0060] (5) Coat the capsules obtained in step (4) with a bottom layer:

[0061] Install the coating machine as required, setting the inlet air temperature to 60℃ and the inlet air volume to 100m³. 3 The atomization pressure was 1.0 bar, the fan air pressure was 1.0 bar, the coating pan speed was 15 rpm, the pump speed was 10%, and the capsule temperature was controlled at 45℃ during the coating process. The aqueous coating solution containing hydroxypropyl methylcellulose and polyethylene glycol was kept under stirring. After spraying, the inlet air temperature was set to 40℃ and the inlet air volume to 100 m³ / h. 3 / h, reduce the coating pan to 3rpm, and dry for 10min;

[0062] The resulting capsules were then subjected to enteric coating.

[0063] Install the coating machine as required, setting the inlet air temperature to 400℃ and the inlet air volume to 100m³. 3 The atomization pressure was 1.0 bar, the fan air pressure was 1.0 bar, the pot rotation speed was 15 rpm, the pump speed was 10%, and the capsule temperature was controlled at 30℃ during the coating process. The enteric coating solution (60% methacrylic acid-methyl methacrylate copolymer (1:1), 20% methacrylic acid-methyl methacrylate copolymer (1:2), 20% talc, 10% triethyl citrate) was kept under stirring. After the spraying was completed, the inlet air temperature was set to 50℃ and the inlet air volume to 100 m³ / h. 3 Dry for 30 minutes at a constant temperature (h). The final product is capsule 1.

[0064] Example 2

[0065] Budesonide enteric-coated capsule microparticle composition 2 was prepared according to Table 2 and the preparation process described in Example 1. It should be understood that Example 2 differs from Example 1 in that the preparation steps of Example 2 were formulated according to the composition of microparticle composition 2 in Table 2. Capsules 2 were finally prepared.

[0066] Table 2 Composition of Budesonide Enteric-coated Capsule Microparticle Composition 2

[0067]

[0068]

[0069] Example 3

[0070] Budesonide enteric-coated capsule microparticle composition 3 was prepared according to Table 3 and the preparation process described in Example 1. It should be understood that Example 3 differs from Example 1 in that the preparation steps of Example 3 were formulated according to the composition of microparticle composition 3 in Table 3. Capsules 3 were finally prepared.

[0071] Table 3. Composition of Budesonide Enteric-coated Capsule Microparticle Composition 3

[0072]

[0073] Comparative Example 1

[0074] Budesonide enteric-coated capsule microparticle composition 4 was prepared according to Table 4 and the preparation process described in Example 1. It should be understood that Comparative Example 1 differs from Example 1 in that the preparation steps of Comparative Example 1 were formulated according to the composition of microparticle composition 4 in Table 4. Capsules 4 were finally prepared.

[0075] Table 4. Composition of Budesonide Enteric-coated Capsule Microparticle Composition 4

[0076]

[0077]

[0078] Comparative Example 2

[0079] Budesonide enteric-coated capsule microsphere composition 5 was prepared according to Table 5 and the preparation process described in Example 1. Comparative Example 2 differs from Example 1 in that the preparation steps of Comparative Example 2 were formulated according to the composition of microsphere composition 5 in Table 4. Finally, capsule 5 was prepared.

[0080] Table 5 Composition of Budesonide Enteric-coated Capsule Microparticle Composition 5

[0081]

[0082] Experiment Example 4: Stability Test

[0083] The capsule samples prepared in the examples and comparative examples were packaged in oral solid pharmaceutical high-density polyethylene bottles and placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 3 months. Changes in related substances were detected by high-performance liquid chromatography (HPLC), and the results are shown in Table 7 below. After placement, the drug-containing capsule cores were taken from the capsules, solutions were prepared, and HPLC analysis was performed.

[0084] In this article, "total impurities" or "total impurities" refers to the sum of impurities detected other than known process impurities.

[0085] The following were detected by high performance liquid chromatography:

[0086] Table 6. Relevant parameters for high performance liquid chromatography.

[0087]

[0088]

[0089] Gradient elution method:

[0090]

[0091] Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0092] Table 7. Accelerated stability testing of capsule samples obtained from the examples and comparative examples.

[0093]

[0094] Experimental Example 5: Dissolution Determination

[0095] Dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0096] Dissolution conditions:

[0097] (1) Preparation method of acid medium

[0098] 0.1 mol / L hydrochloric acid solution: Accurately measure 9 ml of hydrochloric acid, dilute with water to 1000 ml, and mix well.

[0099] (2) Buffer medium preparation method

[0100] pH 6.8 dissolution medium: Weigh 6.805g of potassium dihydrogen phosphate, add 0.896g of sodium hydroxide, dissolve in water and dilute to 1000ml, mix well, and measure the pH value to be 6.8.

[0101] Take 12 tablets of this product and operate according to the method in acidic medium. After 120 minutes, take 7 ml of the solution, filter it through 0.45 μm, discard 5 ml of the initial filtrate, and take the subsequent filtrate as the test solution. Take the test sample under the acid dissolution test, transfer the sedimentation basket to 900 ml of the corresponding buffer medium preheated to 37°C, and take 7 ml of the solution according to the sampling time specified under the dissolution conditions (30 min, 60 min, 90 min, and 120 min respectively), filter it through 0.45 μm, discard 5 ml of the initial filtrate, and take the subsequent filtrate as the test solution, and immediately replenish the same volume of medium.

[0102] Reference solution: Weigh approximately 22 mg of budesonide reference standard accurately, place it in a 100 ml brown volumetric flask, add acetonitrile and shake to dissolve and dilute to the mark, then shake well; accurately measure 2 ml, place it in a 100 ml brown volumetric flask, dilute to the mark with the appropriate medium, and shake well.

[0103] Accurately measure 5 μl of the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount by peak area using the external standard method.

[0104] Chromatographic conditions:

[0105] Instrument: High Performance Liquid Chromatography-Ultraviolet Detector

[0106] Chromatographic column: Waters Acquity BEH C18, 2.1 mm × 50 mm, 1.7 μm

[0107] Mobile phase: Sodium acetate buffer (dissolve 2.72g of sodium acetate in 1000ml of water, shake well, and adjust the pH to 4.8 with glacial acetic acid) - acetonitrile (50:50)

[0108] Flow rate: 0.5 ml / min; Detection wavelength: 246 nm; Column temperature: 40 ℃; Injection volume: 5 μl.

[0109] The measurement results are shown in Table 8 below. Figure 1 .

[0110] Table 8 Comparison of dissolution rates of capsules prepared in the examples and comparative examples.

[0111]

Claims

1. A pharmaceutical composition comprising budesonide, which comprises a drug-containing pellet core, a separation layer and a sustained-release layer, wherein, The drug-containing pill core contains budesonide and a water-soluble acid as a stabilizer. The ratio of the water-soluble acid to budesonide in the drug-containing pill core is 1:12-1:2, preferably 1:10-1:

4.

2. The pharmaceutical composition according to claim 1, wherein the water-soluble acid is selected from one or more of citric acid, succinic acid, and fumaric acid.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the drug-containing pellet core further comprises a solid support and a binder.

4. The pharmaceutical composition according to claim 3, wherein the solid support is a blank pellet core selected from sucrose pellet core and microcrystalline cellulose pellet core, preferably sucrose pellet core.

5. The pharmaceutical composition according to any one of claims 3-4, wherein the binder is selected from one or more of hydroxypropyl methylcellulose, preferably hydroxypropyl methylcellulose.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the particle size of budesonide is D90≤5µm, preferably D90≤3µm.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the sustained-release material of the sustained-release layer is selected from one or more of ethyl cellulose and ethyl cellulose aqueous dispersion, preferably ethyl cellulose aqueous dispersion.

8. The pharmaceutical composition according to any one of claims 1-7, wherein after storage at 40°C and 75% RH for 3 months, the total amount of impurities is less than 0.5% of budesonide, by mass.

9. An enteric-coated capsule formulation comprising a pharmaceutical composition according to any one of claims 1-8, and a capsule shell, a bottom coating, and an enteric coating.

10. A method for preparing the enteric-coated capsule formulation according to claim 9, comprising the following steps: (1) A drug-containing suspension containing budesonide and water-soluble acid was used to load the core of the pellet to obtain drug-containing micro pellets; (2) Coat the drug-containing microspheres obtained in step (1) with an adhesive to form microspheres with an isolation layer; (3) Coat the microspheres obtained in step (2) with a sustained-release material containing ethyl cellulose; (4) Fill the microspheres obtained in step (3) into capsules; (5) The capsules obtained in step (4) are coated with bottom coating and enteric coating in sequence.

Images