A solid dispersion and its formulation

Abstract

This invention relates to a solid dispersion and its formulation, wherein the solid dispersion contains the active ingredient rivaroxaban and a carrier, and the solid dispersion exhibits good stability, rapid dissolution rate, and the ability to improve the solubility of the active ingredient. The carrier is defined as described in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a solid dispersion and its preparation, as well as a method for preparing the preparation and its therapeutic use in cardiovascular diseases. Background Technology

[0002] Rivaroxaban, chemical name: 5-chloro-nitro-({(5S)-2-oxo-3-[-4-(3-oxo-4-morpholinyl)phenyl]-1,3-azolidin-5-yl}methyl)-2-thiophene-carboxamide, chemical structural formula is as follows:

[0003]

[0004] It was jointly developed by Bayer Pharmaceuticals and Johnson & Johnson. It was first launched in Canada in September 2008 and approved by the FDA on July 1, 2011. It is available in oral tablets (2.5mg, 10mg, 15mg, and 20mg strengths). The formulation in the FDA instructions is: croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

[0005] Solid dispersions (SDs) are dispersion systems in which drugs are uniformly dispersed in a carrier in highly dispersed states such as molecules, amorphous, or microcrystalline, forming a solid form. As an intermediate in pharmaceutical formulations, solid dispersions can increase the dissolution rate and bioavailability of poorly soluble drugs, delay drug release, increase drug stability, and solidify liquid drugs.

[0006] Patent document CN101128205A discloses an amorphous material produced by hot melt extrusion, containing rivaroxaban, hydroxypropyl cellulose (HPC), or polyvinylpyrrolidone (PVP), and may include a softener sugar alcohol, such as xylitol, to lower the hot melt extrusion temperature. Simultaneously, a high-viscosity carrier material is used to obtain a solid dispersion with sustained-release properties. In the prior art, no rivaroxaban solid dispersion exhibiting rapid-release behavior has been reported and successfully commercialized. Summary of the Invention

[0007] This invention provides a rapidly dissolving rivaroxaban solid dispersion containing the active ingredient rivaroxaban and a carrier. The carrier has a viscosity of less than 100 mPa·s in a 2% aqueous solution at 20°C; preferably, the carrier has a viscosity of less than 50 mPa·s; more preferably, the carrier has a viscosity of 0.1~50 mPa·s.

[0008] In this invention, suitable carriers include: hydroxypropyl methylcellulose acetate succinate, soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), hydroxypropyl methylcellulose, hydroxypropyl cellulose, copovidone, and povidone.

[0009] In a preferred embodiment of the present invention, the carrier is hydroxypropyl methylcellulose acetate succinate, soluplus, hydroxypropyl methylcellulose, or copovidone.

[0010] In a preferred embodiment of the present invention, the carrier is a copolyvinylpyrrolidone. The copolyvinylpyrrolidone is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, such as Kollidon VA64 manufactured by BASF or Plasdone S-630 manufactured by Ashland.

[0011] This invention has found that increasing the content of the carrier in a solid dispersion helps to improve the solubility and dissolution rate of rivaroxaban. Therefore, in the solid dispersion of this invention, the amount of the carrier relative to the total weight of the solid dispersion is 50% or more; in a preferred embodiment of this invention, the weight percentage of the carrier in the solid dispersion is 70% or more; more preferably, the content of the carrier is 75% or more.

[0012] The solid dispersion described above can be prepared by conventional methods in the art, such as hot melt extrusion, co-precipitation, co-evaporation, solvent-melt method, or spray drying; preferably, the solid dispersion is prepared by solvent evaporation, hot melt extrusion, or spray drying.

[0013] In a preferred embodiment of the present invention, the solid dispersion is composed of rivaroxaban and a carrier, wherein the carrier is copovidone; and the percentage content of the carrier in the solid dispersion is above 70%.

[0014] In a preferred embodiment of the present invention, the solid dispersion is composed of rivaroxaban and a carrier, wherein the carrier is copovidone; and the percentage content of the carrier in the solid dispersion is above 75%.

[0015] In a preferred embodiment of the present invention, the content of rivaroxaban in the solid dispersion is 0.1% to 30%.

[0016] In a preferred embodiment of the present invention, the content of rivaroxaban in the solid dispersion is 0.1% to 25%.

[0017] In a preferred embodiment of the present invention, the content of rivaroxaban in the solid dispersion is 4-6 mg per unit formulation; preferably, the content of rivaroxaban in the unit formulation is 5 mg.

[0018] In another aspect, the present invention provides a sustained-release formulation comprising a solid dispersion, a sustained-release material, and a pharmaceutically acceptable excipient.

[0019] In a preferred embodiment of the present invention, the sustained-release formulation comprises a solid dispersion, a sustained-release material, and a pharmaceutically acceptable excipient, wherein the solid dispersion contains rivaroxaban and a carrier selected from copovidone.

[0020] This invention discovers that when the viscosity of the sustained-release material is below 1000 mPa·s, such as when the sustained-release material is selected from hydroxypropyl methylcellulose (15cp), hydroxypropyl methylcellulose (5cp), hydroxypropyl cellulose (HPC-L type), hydroxypropyl cellulose (HPC-M type), etc., it exhibits burst release in in vitro dissolution tests after 2 hours. Unexpectedly, this invention also discovers that increasing the viscosity of the sustained-release material can achieve the desired dissolution. The sustained-release material has a viscosity of 1,000 mPa·s to 150,000 mPa·s; preferred sustained-release materials have a viscosity of 1,000 mPa·s to 100,000 mPa·s; and further preferred sustained-release materials have a viscosity of 3,000 mPa·s to 100,000 mPa·s.

[0021] Suitable sustained-release materials are selected from one or more of cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, sodium alginate, calcium alginate, guar gum, chitosan, crospovidone, or glyceryl behenate. The cellulose derivatives include hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and hydroxypropyl methyl cellulose.

[0022] In a preferred embodiment of the present invention, the sustained-release material is selected from one or more of hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polyvinylpyrrolidone, sodium alginate, calcium alginate, guar gum, chitosan, crospovidone, or glyceryl behenate.

[0023] In a preferred embodiment of the present invention, the sustained-release material is selected from cellulose derivatives, and the cellulose derivatives have a viscosity of 1,000 mPa·s to 150,000 mPa·s; more preferably, the viscosity is 1,000 mPa·s to 100,000 mPa·s; and even more preferably, the viscosity is 3,000 mPa·s to 100,000 mPa·s.

[0024] Suitable cellulose derivatives include: hydroxypropyl methylcellulose K4M (viscosity 4,000 mPa·s), hydroxypropyl methylcellulose E4M (viscosity 4,000 mPa·s), hydroxypropyl methylcellulose K15M (viscosity 15,000 mPa·s), hydroxypropyl methylcellulose K35M (viscosity 35,000 mPa·s), hydroxypropyl methylcellulose K100M (viscosity 100,000 mPa·s), etc.

[0025] In this invention, the sustained-release material can be one or a combination of two or more, and a suitable viscosity can be obtained by mixing single or different types of sustained-release materials or different models of sustained-release materials. The weight percentage of the sustained-release material in the sustained-release formulation is 5-70%; preferably, it is 10-60%.

[0026] The sustained-release formulation may be a tablet, pill, granule or capsule, with tablets being the preferred sustained-release formulation.

[0027] In the sustained-release formulation of the present invention, suitable pharmaceutically acceptable excipients include, but are not limited to, fillers, surfactants, and lubricants; the excipients may be one or a combination of two or more; the amount of the excipients in the sustained-release formulation may be a conventional proportion in the art.

[0028] Suitable fillers include one or a combination of two or more of lactose or lactose hydrate, starch, mannitol, sorbitol, xylitol, erythritol, sucrose, calcium bicarbonate, dextrin, and microcrystalline cellulose. In this invention, the filler accounts for 5% to 90% of the weight of the sustained-release formulation; preferably, it accounts for 10% to 85%.

[0029] Suitable surfactants include one or a combination of two or more of sodium dodecyl sulfate, sodium stearate, calcium stearate, sodium dodecylbenzene sulfonate, polyethylene glycol, and sodium carboxymethyl cellulose. The surfactant accounts for 0.1% to 10% of the weight of the sustained-release formulation; preferably, it accounts for 0.5% to 8% by weight.

[0030] Suitable lubricants include one or a combination of two or more of the following: stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearate fumarate, silica, polyethylene glycol, magnesium palmitate, and calcium palmitate. The weight ratio of the lubricant in the sustained-release formulation is 0.01% to 5%; preferably 0.05% to 3% by weight.

[0031] In a preferred embodiment of the present invention, the sustained-release formulation comprises a solid dispersion, a sustained-release material, a filler, a surfactant, and a lubricant.

[0032] In another aspect, the present invention provides a method for preparing a solid dispersion, comprising the following steps:

[0033] 1) Mix rivaroxaban with the carrier material;

[0034] 2) The mixture obtained in step 1) is then obtained by hot melt extrusion and pulverization.

[0035] In another aspect, the present invention provides a method for preparing a sustained-release formulation, comprising the following steps:

[0036] 1) Mix rivaroxaban with the carrier material;

[0037] 2) The mixture obtained in step 1) is then subjected to hot melt extrusion and pulverization;

[0038] 3) Mix the obtained solid dispersion with slow-release materials, fillers, surfactants, lubricants and other excipients;

[0039] 4) Prepare the mixture from step 3) into a formulation, such as by compressing it into tablets.

[0040] In another aspect, the present invention provides the use of the rivaroxaban solid dispersion or the sustained-release formulation in the preparation of a medicament for treating cardiovascular diseases, wherein the cardiovascular diseases are selected from myocardial infarction, angina pectoris, thrombosis, etc.

[0041] Rivaroxaban has low water solubility, and its solubility is pH-independent. Preparing it as an amorphous solid dispersion is a common solubilization method. However, rivaroxaban has a melting point of approximately 230°C (which has properties such as...). Figure 1 As shown in the DSC diagram, rivaroxaban decomposes and produces impurities. When preparing solid dispersions using hot melt extrusion, high melting temperatures lead to increased impurities, while low melting temperatures prevent rivaroxaban from becoming completely amorphous. Existing technologies use softeners such as sugar alcohols to lower the melting temperature, but this often prevents rivaroxaban from becoming completely amorphous, and softeners tend to increase the impurity content in the formulation. This invention provides a solid dispersion containing rivaroxaban that achieves good stability through the selection of a carrier, enabling complete amorphization at higher hot melt extrusion temperatures without the need for softeners, significantly improving the solubility of rivaroxaban, and maintaining low impurity content over a wider temperature range. Attached Figure Description

[0042] Figure 1 Rivarzaban DSC chart;

[0043] Figure 2 XRPD diagram of rivaroxaban solid dispersion (carrier: hydroxypropyl cellulose);

[0044] Figure 3 DSC diagram of rivaroxaban solid dispersion;

[0045] Figure 4 XRPD diagram of rivaroxaban solid dispersion (carrier VA64);

[0046] Figure 5 Dissolution behavior of rivaroxaban with different carrier ratios. Detailed Implementation

[0047] This invention is illustrated by specific embodiments, and not by further limiting the scope of the invention. The "viscosity" or "viscosity" of this invention is determined at 20°C in a 2% aqueous solution; in this invention, "API" refers to rivaroxaban.

[0048] Example 1: Carrier Material Testing

[0049] Methods for preparing amorphous solid dispersions:

[0050] 1) Weigh the prescribed amount of rivaroxaban and carrier excipients, and pass them through a 30-mesh sieve;

[0051] 2) Mixing: Mix the sieved raw and auxiliary materials for 100 revolutions;

[0052] 3) Hot melt extrusion: The above total mixture sample is hot melt extruded at 200℃ with a feeding speed of 5~20rpm and a torque of 4~6Ncm.

[0053] 4) Crushing: Crush the above sample in a crusher for 5 seconds and pass it through a 30-mesh sieve.

[0054] Following the methods described above, solid dispersions of rivaroxaban were prepared with different types of carrier materials:

[0055]

[0056] After hot melt extrusion, the sample appears as follows (dark color usually indicates a high impurity content; opaque usually indicates the presence of crystalline forms):

[0057]

[0058] In different carriers, the hot melt extrusions of copovidone are light in color and transparent, indicating that copovidone has better stability than other carrier materials.

[0059] Example 2

[0060] The extrudates at different hot-melt extrusion temperatures were measured to determine the degree of amorphization and the impurity content at different temperatures. The extrudates were prepared according to the following method:

[0061] 1. Weigh the prescribed amount of raw and auxiliary materials and pass them through a 30-mesh sieve;

[0062] 2. Mixing: Mix the sieved raw and auxiliary materials together at 500 rpm;

[0063] 3. Hot melt extrusion: The above total mixture sample is hot melt extruded at 170℃, 180℃, 200℃, and 210℃, with a feeding speed of 5~20rpm and a torque of 4~6Ncm.

[0064] 4. Grinding: Grind the above sample in a grinder for 5 seconds and pass it through a 30-mesh sieve.

[0065] Determine the percentage (%) of impurities at different temperatures:

[0066]

[0067] "NA" indicates that it has not been tested.

[0068] The Soluplus carrier degrades at 180°C, while the copovidone VA64 maintains good stability over a wide temperature range, which is advantageous in terms of process. Soluplus requires higher extrusion temperatures (e.g., 210°C) to obtain transparent extrudates, while copovidone VA64 can produce transparent samples at 200°C.

[0069] Hydroxypropyl cellulose extrudate at 200°C exhibits the following properties: Figure 2 The XRPD diagram shown indicates that the dispersion contains partial crystal forms; the extrudate of copovidone VA64 at 200°C exhibits the following characteristics: Figure 3 The DSC diagram shown and Figure 4 The XRPD plot shown indicates that it is amorphous.

[0070] Example 3: Solubility and Dissolution Behavior Test

[0071] The solubility of the solid dispersion was tested in a solution with pH=1.0, and the results are as follows:

[0072]

[0073] The " / " indicates that it is almost insoluble. The experimental results show that when copovidone VA 64 is selected as the carrier, the solubility of rivaroxaban can be increased by up to 3 times, and the dissolution rate of rivaroxaban can be significantly increased.

[0074] A comparison of rivaroxaban copolyvinyl VA 64 at three different ratios (ratios of 1:3, 1:4, and 1:6, dissolution conditions: rivaroxaban 15mg, 0.1N HCl, 300ml, 50rpm, slurry method) was performed, and the dissolution curves are shown below. Figure 5 As shown, the results indicate that there is no significant difference in the dissolution behavior of rivaroxaban and VA64 when the ratio is 1:3 to 1:6, which also explains that there is no precipitation phenomenon after the solid dispersion is dissolved.

[0075] Example 4: Stability of solid dispersions

[0076] Different proportions of rivaroxaban and copovidone Kollidon ® Preparation of solid dispersions using VA 64:

[0077]

[0078] Preparation method:

[0079] 1) Weigh the prescribed amount of raw and auxiliary materials and pass them through a 30-mesh sieve;

[0080] 2) Mixing: Mix the sieved raw and auxiliary materials together at 500 rpm;

[0081] 3) Hot melt extrusion: The above total mixture sample is hot melt extruded at 200℃, with a feeding speed of 5~20rpm and a torque of 4~6Ncm.

[0082] 4) Crushing: Crush the above sample in a crusher for 5 seconds and pass it through a 30-mesh sieve.

[0083] Stability was tested using the following method:

[0084]

[0085] The results of related substance analysis on the solid dispersion are as follows:

[0086]

[0087] "NA" indicates that it was not tested. Rivaroxaban and copovidone VA 64 formed a solid dispersion that showed good stability at different ratios, and the impurity content did not increase significantly during long-term storage.

[0088] Example 5 Preparation of sustained-release formulation

[0089] Formulation preparation method:

[0090] 1) Weigh according to the prescription amount, mix the solid dispersion and excipients and then pass through a 30-mesh sieve.

[0091] 2) Premix all excipients and solid dispersions except magnesium stearate for 100 rpm, then add magnesium stearate and mix for 40 rpm.

[0092] 3) Tableting: The die used is φ9.5*R11.5, and the pressure is ~2500lbs.

[0093] Prepare the following tablets using the method described above:

[0094]

[0095] Dissolution test

[0096] Using pH 6.8 PBS as the dissolution medium (900 ml, 100 rpm, slurry method), dissolution tests were performed on the above-mentioned samples with different formulations. The results are as follows:

[0097]

[0098] Based on the dissolution data, it can be determined that the formulation of the present invention has a good sustained-release effect.

[0099] Example 6 Stability Test

[0100] The stability of the tablets was investigated using the following method:

[0101]

[0102] Stability results

[0103]

[0104] The sustained-release formulation of this invention has good stability.

[0105] The above description of the embodiments is only for the purpose of helping to understand the core idea of ​​the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the solid dispersion and solid formulations containing the present invention without departing from the principle of the present invention, but these improvements and modifications also fall within the scope of protection claimed in the claims of the present invention.

Claims

1. A solid dispersion containing the active ingredient rivaroxaban and a carrier, characterized in that, The carrier has a viscosity of less than 100 mPa·s in a 2% aqueous solution at 20°C.

2. The solid dispersion according to claim 1, characterized in that, The carrier is selected from hydroxypropyl methylcellulose acetate succinate, soluplus, hydroxypropyl methylcellulose, copovidone, and povidone.

3. The solid dispersion according to claim 1 or 2, characterized in that, The carrier is copolyvinylpyrrolidone.

4. The solid dispersion according to any one of claims 1-3, characterized in that, The carrier content in the solid dispersion is above 70%.

5. The solid dispersion according to any one of claims 1-4, characterized in that, The carrier content is above 75%.

6. The solid dispersion according to any one of claims 1-5, characterized in that, The solid dispersion contains the active ingredient rivaroxaban and the carrier copolyvinylpyrrolidone.

7. A sustained-release formulation comprising the solid dispersion, sustained-release material, and pharmaceutically acceptable excipients as described in any one of claims 1-6.

8. The sustained-release formulation according to claim 7, characterized in that, The excipients include fillers, surfactants, and lubricants.

9. The sustained-release formulation according to claim 7, characterized in that, The sustained-release material has a viscosity of 1,000 mPa·s to 150,000 mPa·s; preferably, it has a viscosity of 1,000 mPa·s to 100,000 mPa·s.

10. The sustained-release formulation according to claim 7, characterized in that, The sustained-release material is selected from one or more of cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, sodium alginate, calcium alginate, guar gum, chitosan, crospovidone, or glyceryl behenate.

11. The use of the solid dispersion according to any one of claims 1-6 or the sustained-release formulation according to any one of claims 7-10 in the preparation of a medicament for treating cardiovascular-related diseases.

12. The application according to claim 11, characterized in that, The cardiovascular-related diseases mentioned are selected from myocardial infarction, angina pectoris, and thrombosis.

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