Dronedarone pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicine, and particularly discloses a dronedarone pharmaceutical composition and a preparation method and application thereof.The pharmaceutical composition comprises active ingredients, a carrier and a surfactant, the active ingredients comprise dronedarone and / or pharmaceutically acceptable salt thereof, the carrier comprises a pharmaceutically acceptable high-molecular polymer, and the surfactant comprises a surfactant. The surfactant comprises oleoyl polyoxyethylene glyceride and / or polyoxyethylene hydrogenated castor oil. The specific surfactant is combined with the dronedarone and / or the pharmaceutically acceptable salt thereof, so that the multi-medium dissolution of the medicine can be remarkably improved, the bioavailability is further improved, and the in-vivo variation is reduced; and the pharmaceutical composition has good stability.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and particularly relates to a dronedarone pharmaceutical composition, a preparation method and an application thereof, and specifically relates to a dronedarone solid dispersion, a preparation method and an application thereof. Background Art

[0002] Dronedarone hydrochloride is used to treat sinus rhythm patients with a history of paroxysmal or persistent atrial fibrillation to reduce the risk of hospitalization for atrial fibrillation (AF). The chemical name is: N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride, the molecular formula is C 31 H 44 N2O5S·HCl, the structural formula is as follows:

[0003]

[0004] Dronedarone hydrochloride exhibits properties of all four Vaughan-Williams classes of antiarrhythmic drugs, but the extent to which each property contributes to dronedarone's clinical effects is unclear.

[0005] It is reported that the absolute bioavailability of dronedarone is very low, about 4%, when administered on an empty stomach due to first-pass metabolism. When dronedarone is taken with a high-fat diet, the absolute bioavailability increases to about 15%. The marketed specification is 400 mg (C 31 H 44 N2O5S), its specifications are high and its bioavailability is low. At the same time, dronedarone hydrochloride is a highly variable drug.

[0006] Commercial dronedarone preparations contain poloxamer to improve intestinal drug solubility. However, this method has limited solubilization effect and the product has high variability. Therefore, it is necessary to find a method to improve the solubility of dronedarone hydrochloride to improve its bioavailability and reduce the variability of in vivo pharmacokinetic parameters.

[0007] In the prior art, a Chinese invention patent (publication number: CN117482055A) discloses a method for preparing low-dose dronedarone hydrochloride tablets, wherein the core particles are dronedarone hydrochloride API blended with a polymer and silica. Experimental reproduction shows that the dissolution levels of dronedarone hydrochloride in different media involved in this technical solution vary greatly, and it is impossible to simultaneously improve the dissolution of dronedarone hydrochloride in multiple media, and it may be impossible to significantly reduce the variability of in vivo pharmacokinetic parameters.

[0008] Therefore, it is urgent to develop a dronedarone pharmaceutical composition with stable quality, high bioavailability and significantly reduced in vivo variability to better meet clinical needs. Summary of the invention

[0009] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a dronedarone pharmaceutical composition and a preparation method and application thereof, wherein the pharmaceutical composition can significantly improve the dissolution rate of dronedarone in a multi-media, thereby significantly improving its bioavailability, and reducing the variability of pharmacokinetic parameters in vivo. At the same time, the dronedarone pharmaceutical composition of the present invention has good stability.

[0010] In order to solve the above technical problems, the first aspect of the present invention provides a pharmaceutical composition comprising the following components:

[0011] An active ingredient, the active ingredient comprising dronedarone and / or a pharmaceutically acceptable salt thereof;

[0012] A carrier, the carrier comprising a pharmaceutically acceptable high molecular polymer; and

[0013] A surfactant comprising oleoyl polyoxyethylene glyceride and / or polyoxyethylene hydrogenated castor oil.

[0014] In some embodiments of the present invention, the pharmaceutically acceptable salt includes hydrochloride, citrate, maleate or tartrate, preferably hydrochloride.

[0015] In some embodiments of the present invention, the polyoxyethylene hydrogenated castor oil is selected from polyoxyethylene 40 hydrogenated castor oil and / or polyoxyethylene 60 hydrogenated castor oil.

[0016] In some embodiments of the present invention, the surfactant is oleoyl polyoxyethylene glyceride.

[0017] In some embodiments of the present invention, the mass ratio of the active ingredient to the surfactant is (3-16):1, for example, it can be: 4.26:1, 5.32:1, 6.08:1, 7.11:1, 8.53:1, 10.64:1 or 14.16:1, preferably (4.26-8.53):1, and further preferably (4.26-7.11):1.

[0018] In some embodiments of the present invention, the high molecular polymer is selected from at least one of povidone, copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene, acrylic resin, polyvinyl acetate and polyethylene glycol.

[0019] In some embodiments of the present invention, examples of the povidone include, but are not limited to, povidone K12, povidone K15, povidone K17, povidone K25, povidone K30, povidone K29 / 32, povidone K60, and povidone K120, preferably povidone K29 / 32 and / or povidone K12.

[0020] In some embodiments of the present invention, examples of the copovidone include, but are not limited to, copovidone VA64 and copovidone S-630, preferably copovidone S-630.

[0021] In some embodiments of the present invention, the high molecular polymer is selected from copovidone and / or polyvinyl alcohol.

[0022] In some embodiments of the present invention, the hydropropyl methylcellulose is classified by viscosity including but not limited to E3, E5, E6, E15, E50LV, preferably hydropropyl methylcellulose E3.

[0023] In some embodiments of the present invention, examples of the polyethylene glycol include, but are not limited to, PEG4000, PEG6000, and PEG8000, preferably PEG4000 or PEG6000.

[0024] In some embodiments of the present invention, the mass ratio of the active ingredient to the carrier is 1:(0.25-3), for example, it can be: 1:0.25, 1:0.50, 1:0.75, 1:1, 1:2, 1:2.5 or 1:3, preferably 1:(0.75-2.5), and further preferably 1:(1-2.5). Within this range, the amount of excipients used in the pharmaceutical composition promotes the dissolution of the drug in multiple media, and the size of the subsequent pharmaceutical composition is more suitable for oral administration and has stronger drugability.

[0025] In some embodiments of the present invention, the pharmaceutical composition further comprises an antioxidant and / or an adjuvant.

[0026] In some embodiments of the present invention, the antioxidant is selected from at least one of butylated hydroxyanisole, dibutylated hydroxytoluene and vitamin E polyethylene glycol succinate, preferably butylated hydroxyanisole. The use of the antioxidant can improve the stability of the pharmaceutical composition.

[0027] In some embodiments of the present invention, the mass ratio of the active ingredient to the antioxidant is 23.67:(0.01-0.4).

[0028] In some embodiments of the present invention, the auxiliary agent includes at least one of a filler, a disintegrant and a lubricant.

[0029] In some embodiments of the present invention, the filler is selected from at least one of microcrystalline cellulose, lactose, calcium hydrogen phosphate and silicon dioxide, preferably microcrystalline cellulose.

[0030] In some embodiments of the present invention, the filler comprises silicon dioxide and / or microcrystalline cellulose.

[0031] In some embodiments of the present invention, the filler is silicon dioxide and microcrystalline cellulose.

[0032] In some embodiments of the present invention, the mass ratio of silicon dioxide to microcrystalline cellulose is 1:(0.1-9), preferably 1:(0.18-8.77).

[0033] In some embodiments of the present invention, the mass ratio of the active ingredient to the filler is 1:(0.2-6), preferably 1:(0.3-5), more preferably 1:(0.3-3), and even more preferably 1:(0.38-2.08).

[0034] In some embodiments of the present invention, the disintegrant is selected from at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably cross-linked polyvinylpyrrolidone.

[0035] In some embodiments of the present invention, the mass ratio of the active ingredient to the disintegrant is 1:(0.01-1.5), preferably 1:(0.05-1.2), and further preferably 1:(0.05-0.4).

[0036] In some embodiments of the present invention, the lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, polyethylene glycol, talc, hydrogenated vegetable oil, and micro-powdered silica gel, preferably magnesium stearate.

[0037] In some embodiments of the present invention, the average molecular weight of the polyethylene glycol is 4000-6000.

[0038] In some embodiments of the present invention, the particle size distribution of the pharmaceutical composition is D 90 Between 211-408 μm, and D 50 Between 112-303μm.

[0039] In some embodiments of the present invention, the particle size distribution of the pharmaceutical composition is D 90 Between 250-400 μm, and D 50 Between 150-300μm.

[0040] In some embodiments of the present invention, the active ingredient exists in a molecular, colloidal, microcrystalline or amorphous state.

[0041] The second aspect of the present invention provides a method for preparing the above-mentioned pharmaceutical composition, the preparation method comprising vacuum drying, spray drying, hot melt extrusion, wet granulation or fluidized bed granulation, preferably fluidized bed granulation. The particles prepared by the fluidized bed one-step granulation method have a narrow particle size distribution range, uniform particles, no stickiness between particles, good compressibility, and high industrial feasibility.

[0042] In some embodiments of the present invention, the fluidized bed granulation method comprises the following steps:

[0043] (1) dissolving a carrier and a surfactant in a solvent to obtain a first mixed solution;

[0044] (2) dissolving the active ingredient in the first mixed solution to obtain a second mixed solution;

[0045] (3) Spraying the second mixed solution onto the surface of a fluidized bed granulation substrate using a fluidized bed granulation process to obtain the pharmaceutical composition.

[0046] In some embodiments of the present invention, the fluidized bed granulation substrate is selected from at least one of microcrystalline cellulose, lactose, calcium hydrogen phosphate and silicon dioxide.

[0047] In some embodiments of the present invention, the fluidized bed granulation substrate is silicon dioxide and microcrystalline cellulose, and the mass ratio of silicon dioxide to microcrystalline cellulose is 1:(0.10-6.00), preferably 1:(0.18-5.90), and further preferably 1:(0.18-5.66). Within this range, the amount of excipients used in the pharmaceutical composition can ensure the feasibility and drugability of the formulation process, and ensure that the size of the subsequent pharmaceutical composition is more suitable for oral administration.

[0048] In some embodiments of the present invention, the mass ratio of the active ingredient to the fluidized bed granulation substrate is 1:(0.1-3.5), preferably 1:(0.2-2), more preferably 1:(0.2-1.5), and even more preferably 1:(0.25-1.04).

[0049] In some embodiments of the present invention, the solvent is an alcohol solvent or an aqueous solution thereof.

[0050] In some embodiments of the present invention, the solvent is a C1-C3 alcohol or an aqueous solution thereof, preferably an ethanol aqueous solution.

[0051] The third aspect of the present invention provides a pharmaceutical preparation, comprising the above-mentioned pharmaceutical composition, or comprising the pharmaceutical composition prepared by the above-mentioned preparation method.

[0052] In some embodiments of the present invention, the pharmaceutical preparation further comprises a pharmaceutically acceptable excipient.

[0053] In some embodiments of the present invention, the pharmaceutical preparation is a capsule, a dry suspension, a granule, a fine granule or a tablet.

[0054] Compared with the prior art, the above technical solution of the present invention has at least the following technical effects or advantages:

[0055] Dronedarone hydrochloride belongs to BCS class II or IV drugs, with low solubility. The original drug has little solubilization effect by adding poloxamer, and has a high coefficient of variation in vivo. The dronedarone composition prepared by the prior art has large differences in multi-media dissolution and cannot reduce in vivo variation. It was unexpectedly found in the study that the present invention uses a specific surfactant in combination with dronedarone and / or its pharmaceutically acceptable salt, which can significantly improve the multi-media dissolution of the drug, further improve the bioavailability and reduce in vivo variation; and the pharmaceutical composition has good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 The X-ray diffraction pattern of the solid dispersion particles of formulation 38.

[0057] Figure 2 The dissolution test results of the drug preparations of DA071, Comparative Examples 1-2 and Prescription 38 in the medium 0.1M HCl;

[0058] Figure 3 The dissolution test results of the drug preparations of DA071, Comparative Examples 1-2 and Prescription 38 in a medium pH 4.5 solution;

[0059] Figure 4 These are the dissolution test results of the drug preparations of DA071, Comparative Examples 1-2 and Prescription 38 in a medium pH 6.8 solution. DETAILED DESCRIPTION

[0060] The present invention is described in detail below in conjunction with the examples, so that the technical personnel of the relevant technical field can understand the present invention. It is necessary to point out here that the examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. The non-essential improvements and adjustments made to the present invention by the skilled person in the relevant field according to the above invention content should still belong to the scope of protection of the present invention. At the same time, the raw materials mentioned below that are not described in detail are all commercially available products; the process steps or preparation methods that are not mentioned in detail are all process steps or preparation methods known to those skilled in the art.

[0061] The detection methods of the release, particle size, X-ray spectra and stability-related substances in the following embodiments, comparative examples and reference examples are as follows:

[0062] 1. Release test method: According to the release test method (the second method of Part IV 0931 of the 2020 edition of the Chinese Pharmacopoeia), the multi-medium is 0.1 mol / L hydrochloric acid (0.1MHCl), pH 4.5, and pH 6.8 solution. After sampling, the release test is carried out using high performance liquid chromatography, and the dissolution results are expressed as the mean (N=3).

[0063] 2. Particle size detection method: Determine according to the particle size and particle size distribution determination method (Method 3 of Part IV 0982 of the 2020 edition of the Chinese Pharmacopoeia).

[0064] 3. X-ray spectrum detection method: X-ray powder diffraction instrument, Shimadzu XRD-6100 X-ray powder diffractometer; radiation source Cu (1.54060A); generator (Target) mA: 10 mA; starting 2θ: 3°, scanning range: 3°-60°, scanning step 0.02°, scanning speed 2° / min.

[0065] 4. Stability-related substances detection method: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition, Part IV, 0512).

[0066] Reference ratio

[0067] Dronedarone hydrochloride tablets (400 mg; batch number: DA071; Sanofi), the dissolution characteristics of which in multiple media are shown in Table 1.

[0068] Table 1:

[0069]

[0070]

[0071] As shown in Table 1, the cumulative release of the original tablet in 0.1M HCl medium is only 5%. Therefore, in the research process, the present invention uses 0.1M HCl medium to screen the formulation process, and then conducts multi-media dissolution comparison after obtaining the target formulation process.

[0072] Comparative Example 1

[0073] Referring to the dronedarone hydrochloride tablets disclosed in the Chinese invention patent (publication number: CN117482055A), the components thereof are shown in Table 2.

[0074] Table 2:

[0075] Components Mass (mg) / tablet Proportion (%) Dronedarone Hydrochloride 213 32.8 Copolyvinylpyrrolidone VA64 213 32.8 Silica 1 4 0.6 lactose 149.15 22.9 Crospovidone 65 10.0 Silicon dioxide 2 (lubricant) 2.6 0.4 Magnesium Stearate 3.25 0.5 Total 650 100

[0076] The preparation method of dronedarone hydrochloride tablets of comparative example 1 comprises the following steps:

[0077] The raw material of dronedarone hydrochloride is mixed with copolyvidone and silicon dioxide in proportion, and the mixture is extruded in a twin-screw extruder. The extrusion process parameters are: feed rate 25rpm, screw speed 300rpm, temperature 25℃ in zone 1, 90℃ in zone 2, 155℃ in zones 3-6, and 150℃ in zones 7-9. After the extrudate is cooled, it is crushed into suitable particles using a mobile granulator and a hammer mill. Fillers, disintegrants, and lubricants are added to the obtained particles, and they are directly tableted after being mixed evenly.

[0078] The dissolution test results of the dronedarone hydrochloride tablets prepared in Comparative Example 1 are shown in Table 3.

[0079] Table 3:

[0080]

[0081]

[0082] As shown in Table 3, the dissolution of dronedarone hydrochloride tablets prepared in Comparative Example 1 in 0.1M HCl at 120 min was about 3 times higher than that of reference example DA071, the dissolution in pH 4.5 medium was equivalent to that of the reference example, and the dissolution in pH 6.8 medium was about 13 times higher than that of the reference example.

[0083] Comparative Example 2

[0084] The formulation of dronedarone hydrochloride non-solid dispersion is shown in Table 4.

[0085] Table 4:

[0086] effect Element 200mg specification (%, based on dronedarone) Active ingredients Dronedarone Hydrochloride 23.67 Carrier Copolyvinylpyrrolidone S-630 18.93 Carrier Polyvinyl alcohol 4.73 Surfactants Oleoyl polyoxyethylene glycerides 3.33 Antioxidants Butylated Hydroxyanisole 0.03 Fillers Silicon dioxide 3.89 Fillers Microcrystalline Cellulose 7.22 Fillers Microcrystalline Cellulose 26.89 Disintegrants Crospovidone 7.86 Lubricants Magnesium Stearate 3.44 Coating powder Obaday Tablet weight gain 3%

[0087] The preparation method of dronedarone hydrochloride tablets of comparative example 2 comprises the following steps:

[0088] First, weigh the prescribed amount of dronedarone hydrochloride, copovidone S-630, polyvinyl alcohol, oleoyl polyoxyethylene glyceride, butylated hydroxyanisole, silicon dioxide, and microcrystalline cellulose and mix them evenly to prepare mixed granules 1.

[0089] The mixed granules 1 prepared above were mixed with the prescribed amount of microcrystalline cellulose and cross-linked polyvinylpyrrolidone to obtain mixed granules 2; magnesium stearate was mixed with about 3 times the amount of mixed granules 2 and passed through a 40-mesh sieve, and then mixed with the remaining mixed granules 2. The powder was directly compressed into tablets and coated with Opadry coating powder.

[0090] The dissolution results of the dronedarone hydrochloride tablets of the reference example and comparative examples 1-2 are shown in Tables 5-7.

[0091] Table 5:

[0092]

[0093] Table 6:

[0094]

[0095] Table 7:

[0096]

[0097] As shown in Tables 5-7, in 0.1M HCl medium, the dissolution of Comparative Example 1 is increased by about 3 times and 1 times compared with DA071 and Comparative Example 2, respectively; in pH 4.5 medium, the dissolution of Comparative Example 1 is equivalent to that of DA071, and the dissolution is increased by about 0.6 times compared with Comparative Example 2; in pH 6.8 medium, the dissolution of Comparative Example 1 is increased by about 13 times and 3.5 times compared with DA071 and Comparative Example 2, respectively. Therefore, Comparative Example 2 does not have an obvious solubilization effect.

[0098] Example 1: Screening of surfactants

[0099] The surfactants used in the dronedarone pharmaceutical compositions of prescriptions 1-7 are respectively polyethylene glycol (32) stearate, diethylene glycol monoethyl ether, propylene glycol monolaurate, caprylic capric macrogol glyceride, dicaprylic capric propylene glycol ester, polyoxyethylene 40 hydrogenated castor oil, and oleoyl polyoxyethylene glyceride. The specific components are shown in Table 8.

[0100] Table 8:

[0101]

[0102]

[0103] The preparation method of the dronedarone pharmaceutical preparation of prescription 1-7 comprises the following steps:

[0104] First, weigh the prescribed amount of povidone K15 and surfactant, add them to the ethanol aqueous solution in turn, stir until completely dissolved, slowly add the prescribed amount of dronedarone hydrochloride, and after the drug is dissolved to be transparent, place it in a vacuum drying oven for drying, set the temperature at 40-60°C, and the vacuum degree is: -0.5 bar to -1.0 bar, to obtain solid dispersion particles, and then mix them with the prescribed amount of microcrystalline cellulose and cross-linked povidone to obtain mixed particles; magnesium stearate and about 3 times the amount of mixed particles are mixed and passed through a 40-mesh sieve, and then mixed with the remaining mixed particles to obtain the total mixed particles and then filled into the capsule shell.

[0105] The dissolution test results of the dronedarone pharmaceutical preparations of Formulations 1-7 are shown in Table 9.

[0106] Table 9:

[0107]

[0108]

[0109] As shown in Table 9, the dissolution of Comparative Example 1 is improved by about 3 times compared with DA071, and it is unexpectedly found in the process of screening a large number of surfactants that by adding surfactants polyoxyethylene 40 hydrogenated castor oil and oleoyl polyoxyethylene glyceride, Prescriptions 6 and 7 can significantly increase the dissolution of dronedarone hydrochloride compared with Comparative Example 1. Among them: after adding surfactant polyoxyethylene 40 hydrogenated castor oil to Prescription 6, the dissolution can be increased by more than 10 times; after adding oleoyl polyoxyethylene glyceride to Prescription 7, the dissolution can be increased by about 16 times. Therefore, the addition of polyoxyethylene 40 hydrogenated castor oil or oleoyl polyoxyethylene glyceride to the prescription is more likely to improve the bioavailability of the preparation than Comparative Example 1.

[0110] Example 2: Screening of vectors

[0111] The carriers used in the dronedarone pharmaceutical compositions of prescriptions 8-13 are respectively hydroxypropyl methylcellulose acetate succinate, povidone K15, hydroxypropyl methylcellulose E3, copovidone S-630, polyvinyl alcohol and PEG 4000. The specific components are shown in Table 10.

[0112] Table 10:

[0113]

[0114]

[0115] The preparation method of the dronedarone pharmaceutical preparation of prescription 8-13 comprises the following steps:

[0116] First, weigh the prescribed amount of carrier and surfactant, add them to the ethanol aqueous solution in sequence, stir until completely dissolved, slowly add the prescribed amount of dronedarone hydrochloride, and prepare the adhesive after the drug is dissolved until transparent; use the fluidized bed granulation process to spray the adhesive on the microcrystalline cellulose (set the inlet air temperature at 40-80°C and the inlet air volume at 20-100m 3 / h, spraying speed of 3-10g / min) to prepare solid dispersion particles, and then mix with the prescribed amount of cross-linked polyvinylpyrrolidone to obtain mixed particles; magnesium stearate and about 3 times the amount of the mixed particles are mixed and passed through a 40-mesh sieve, and then mixed with the remaining mixed particles to obtain the total mixed particles and then filled into the capsule shell.

[0117] The dissolution test results of the dronedarone pharmaceutical preparations of prescriptions 8-13 are shown in Table 11.

[0118] Table 11:

[0119]

[0120] As shown in Table 11, the dissolution of Comparative Example 1 is improved by about 3 times compared with DA071, and it is unexpectedly found in the process of a large number of carrier screening experiments that after adding hypromellose acetate succinate, the dissolution of dronedarone hydrochloride in Prescription 8 is not improved compared with Comparative Example 1, and after adding povidone, hypromellose, polyvinyl alcohol, and polyethylene glycol, Prescriptions 9-13 can significantly improve the dissolution of dronedarone hydrochloride compared with Comparative Example 1, among which the dissolution of Prescriptions 9-13 can be improved by about 3 times. Therefore, the addition of a hydrophilic carrier to the prescription is more likely to improve the bioavailability of the preparation than Comparative Example 1.

[0121] Example 3: Optimal mass ratio of active ingredient to carrier

[0122] The mass ratio of the active ingredient to the carrier in the dronedarone pharmaceutical composition of prescriptions 14-21 is between 1:(0.25-3), and the specific components are shown in Table 12.

[0123] Table 12:

[0124]

[0125] The preparation method of the dronedarone pharmaceutical preparation of prescription 14-21 comprises the following steps:

[0126] First, weigh the prescribed amount of copovidone S-630, polyvinyl alcohol, and oleoyl polyoxyethylene glyceride, add them into the ethanol aqueous solution in sequence, and stir until they are completely dissolved; slowly add the prescribed amount of dronedarone hydrochloride, and after the drug is dissolved until transparent, use the solvent-vacuum drying method to prepare solid dispersion particles, mix them with microcrystalline cellulose, and fill them into the capsule shell.

[0127] The dissolution test results of dronedarone pharmaceutical preparations of prescriptions 14-21 are shown in Table 13.

[0128] Table 13:

[0129]

[0130] As shown in Table 13, the dissolution of Comparative Example 1 is increased by about 3 times compared with DA071, and by controlling the mass ratio of the active ingredient to the carrier within the range of 1:(0.25-3), Prescriptions 14-21 can significantly increase the dissolution of dronedarone hydrochloride compared with Comparative Example 1, and the dissolution is increased by about 0.6 times or more than that of Comparative Example 1, and as the mass ratio of the active ingredient to the carrier is increased, the dissolution amount also increases, the dissolution increases by about 0.6 times or more (Prescriptions 14-21), the dissolution increases by about 3 times (Prescriptions 17-21), and even by about 3.5 times (Prescription 21). Considering the feasibility and industrialization of comprehensive formulation molding, the preferred mass ratio of the active ingredient to the carrier of the present invention is 1:(0.25-3), more preferably 1:(0.75-2.5), and further preferably 1:(1-2.5).

[0131] Example 4: Optimal mass ratio of surfactant to active ingredient

[0132] The mass ratio of surfactant to active ingredient in the dronedarone pharmaceutical compositions of prescriptions 22-28 is between 1:(4.26-14.16), and the specific components are shown in Table 14.

[0133] Table 14:

[0134]

[0135] The preparation method of the dronedarone pharmaceutical preparation of prescriptions 22-28 comprises the following steps:

[0136] First, weigh the prescribed amount of copovidone S-630, polyvinyl alcohol, and oleoyl polyoxyethylene glyceride, add them into the ethanol aqueous solution in sequence, and stir until they are completely dissolved; slowly add the prescribed amount of dronedarone hydrochloride, and after the drug is dissolved until transparent, use the solvent-vacuum drying method to prepare solid dispersion particles, mix them with microcrystalline cellulose, and fill them into the capsule shell.

[0137] The dissolution test results of dronedarone pharmaceutical preparations of prescriptions 22-28 are shown in Table 15.

[0138] Table 15:

[0139]

[0140]

[0141] As shown in Table 15, the dissolution of Comparative Example 1 is increased by about 3 times compared with DA071. During the test, it was found that when the mass ratio of surfactant to active ingredient was in the range of 1:(10.64-14.16), Prescriptions 22 and 23 did not significantly increase the dissolution of dronedarone hydrochloride compared with Comparative Example 1; when the mass ratio of surfactant to active ingredient was in the range of 1:(4.26-8.53), Prescriptions 24-28 were able to significantly increase the dissolution of dronedarone hydrochloride compared with Comparative Example 1. As the ratio of drug to surfactant was increased, the dissolution amount also increased, and the dissolution increased by more than 0.5 times (Prescriptions 24-28), more than about 2 times (Prescriptions 25-28), and even more than 3.6 times (Prescription 28). Considering the feasibility of comprehensive industrialization, the mass ratio of surfactant to active ingredient is preferably 1:(3-16), more preferably 1:(4.26-8.53), and further preferably 1:(4.26-7.11).

[0142] Example 5: Screening of fluidized bed substrates

[0143] Prescriptions 29-33 use fluidized bed granulation method to prepare dronedarone solid dispersions. The fluidized bed substrates used are silicon dioxide and microcrystalline cellulose, or mannitol and microcrystalline cellulose, respectively. The specific components are shown in Table 16.

[0144] Table 16:

[0145]

[0146] The preparation method of the dronedarone drug solid dispersion of prescription 29-33 comprises the following steps:

[0147] First, the prescribed amount of polyvinyl alcohol, copovidone S-630, and oleoyl polyoxyethylene glyceride are weighed, and they are added to the ethanol aqueous solution in sequence, and stirred until completely dissolved, and then the prescribed amount of dronedarone hydrochloride is slowly added, and the adhesive is prepared after the drug is dissolved to be transparent; the adhesive is sprayed on the fluidized bed substrate by a fluidized bed granulation process (the inlet air temperature is set at 40-80°C, the inlet air volume is set at 20-100m 3 / h, spraying rate 3-10g / min) to obtain solid dispersion particles.

[0148] The granulation results showed that the oily feeling of prescription 29 was not strong, and the oily feeling of prescription 30 (without silicon dioxide) was higher than that of prescription 29. The granules were easy to stick together, which affected the mixing uniformity of the granules and could not enter the next step of preparation. The substrate dosage of prescriptions 29, 31-33 was acceptable, the prepared mixture had good uniformity, and the tableting did not produce sticking. Therefore, silicon dioxide and microcrystalline cellulose were selected as substrates and the ratio was screened. The mass ratio of silicon dioxide to microcrystalline cellulose was 1: (0.18-5.66).

[0149] The particle size distribution of fluidized bed granulation particles of prescription 33 is shown in Table 17.

[0150] Table 17:

[0151] Particle size (unit: μm) Interval distribution % 0-75 3.3 75-125 8.1 125-150 5.2 150-180 7.8 180-250 18.3 250-355 43.5 355-850 13.8 >850 0

[0152] It can be seen from Table 17 that the particles produced by the fluidized bed one-step granulation method have a narrow particle size distribution range, uniform particles, no stickiness between particles, good compressibility, and high industrial feasibility.

[0153] Example 6: Investigation of dissolution and compressibility of dronedarone hydrochloride solid dispersions with different particle sizes

[0154] The particle size distribution of the dronedarone solid dispersion of formulations 34-37 is D 90 Between 211-450 μm, and D 50 Between 112-327μm, the specific particle size and composition are shown in Table 18.

[0155] Table 18:

[0156]

[0157]

[0158] The preparation method of the dronedarone pharmaceutical preparation of prescriptions 34-37 comprises the following steps:

[0159] The preparation process is the same as that of Example 5. The same batch of dronedarone hydrochloride solid dispersion is granulated by a granulator (the granulation speed and / or the granulation screen aperture are adjusted) to obtain particles with different particle size distributions, and then mixed evenly with fillers, disintegrants, and lubricants, respectively, tableted, and coated.

[0160] Among them: the parameters of tableting are shown in Table 19.

[0161] Table 19:

[0162]

[0163] As shown in Tables 18-19, when pressed into tablets of the same hardness, dronedarone hydrochloride solid dispersion D 90 Particle size is in the range of 211-408 μm (D 50 In the range of 112-303μm), the compressibility is better than D 90 Particle size 450 μm (D 50 Particle size 327μm) is good, preferably D 90 Particle size is in the range of 211-408 μm (D 50 The solid dispersion of dronedarone hydrochloride (in the range of 112-303 μm) is tableted, but considering that the smaller the particle size, the larger the angle of repose, in order to avoid poor fluidity of the tableting particles, D 90 The particle size is in the range of 248-408 μm (D 50 The solid dispersion particles of dronedarone hydrochloride (in the range of 146-303 μm) were tableted, i.e., D 90 In the range of 250-400 μm, D 50 In the range of 150-300μm.

[0164] The dissolution test results of dronedarone pharmaceutical preparations of formulations 34-37 are shown in Table 20.

[0165] Table 20:

[0166]

[0167]

[0168] As shown in Table 20, the dissolution rate of dronedarone hydrochloride solid dispersions with different particle sizes in 120 min is similar, which is about 3.2 times higher than that of Comparative Example 1. The larger the particle size, the slower the dissolution rate. 90 The particle size is in the range of 248-408 μm (D 50 Dronedarone hydrochloride solid dispersion particles (in the range of 146-303 μm), namely D 90 In the range of 250-400 μm, D 50 In the range of 150-300μm.

[0169] Example 7: Preferred pharmaceutical preparations

[0170] Prescription 38 Taking into account all the factors considered in Examples 1-6, the components of the preferred dronedarone hydrochloride pharmaceutical preparation are shown in Table 21.

[0171] Table 21:

[0172]

[0173] The preparation method of the dronedarone hydrochloride pharmaceutical preparation of prescription 38 comprises the following steps:

[0174] First, the prescribed amount of copovidone S-630, polyvinyl alcohol, oleoyl polyoxyethylene glyceride, and butylated hydroxyanisole are weighed, and the mixture is added to an ethanol aqueous solution in sequence, and stirred until completely dissolved, and then the prescribed amount of dronedarone hydrochloride is slowly added, and the adhesive is prepared after the drug is dissolved to be transparent; the adhesive is sprayed on a mixture of silicon dioxide and microcrystalline cellulose by a fluidized bed granulation process (the inlet air temperature is set at 40-80° C., and the inlet air volume is set at 20-100 m 3 / h, spray rate 3-10g / min) to obtain solid dispersion particles. Its X-ray diffraction pattern is as follows Figure 1 As shown by Figure 1 It can be seen that dronedarone hydrochloride in the solid dispersion is in an amorphous state.

[0175] The prepared solid dispersion particles are mixed with the prescribed amount of microcrystalline cellulose and cross-linked polyvinylpyrrolidone to obtain mixed particles; magnesium stearate is mixed with about 3 times the amount of the mixed particles and passed through a 40-mesh sieve, and then mixed with the remaining mixed particles. The powder is directly compressed into tablets and coated with Opadry coating powder.

[0176] The dissolution test results of dronedarone hydrochloride drug preparation of prescription 38 are as follows Figure 2-4 As shown in Tables 22-24.

[0177] Table 22:

[0178]

[0179] Table 23:

[0180]

[0181] Table 24:

[0182]

[0183]

[0184] Depend on Figure 2-4 As shown in Tables 22-24, in the pH 4.5 medium, the dissolution of DA071, Comparative Example 1, and Prescription 38 at 120 min is comparable. In the 0.1M HCl and pH 6.8 media, the dissolution of Comparative Example 1 is at least about 3 times higher than that of DA071, while the dissolution of Prescription 38 is significantly higher than that of Comparative Example 1, and the dissolution is significantly increased by at least about 1 times, wherein the dissolution of 0.1M HCl is about 3.4 times higher than that of Comparative Example 1, and the dissolution of pH 6.8 is about 1.2 times higher than that of Comparative Example 1; Comparative Example 2 (non-solid dispersion) and Prescription 38 (solid dispersion) have significant differences in multi-media dissolution before and after the preparation of solid dispersions. The results show that the same prescription prepared as a solid dispersion has the advantage of significantly improving multi-media dissolution. Therefore, Prescription 38 (solid dispersion) shows that dissolution is pH-independent compared to dronedarone hydrochloride tablets, and is expected to improve the in vivo bioavailability more than Comparative Example 1, while reducing the variability of in vivo pharmacokinetic parameters.

[0185] The results of the accelerated dissolution stability test (40°C / 75%RH) of the dronedarone hydrochloride pharmaceutical preparation of Formulation 38 are shown in Table 25.

[0186] Table 25:

[0187]

[0188] As shown in Table 25, there was no significant change in the hydrochloric acid dissolution of prescription 38 after 6 months of accelerated treatment compared with 0 days.

[0189] The results of the accelerated test of the content of related substances in the dronedarone hydrochloride pharmaceutical preparation of prescription 38 are shown in Table 26.

[0190] Table 26:

[0191]

[0192]

[0193] As shown in Table 26, there was no significant change in the related substances of prescription 38 after 6 months acceleration compared with 0 days.

[0194] In summary, the dronedarone hydrochloride solid dispersion of the present invention and the pharmaceutical preparation prepared therefrom have high dissolution, thus having good bioavailability, and the dissolution is not pH-dependent, which is more likely to improve bioavailability and reduce the variability of in vivo pharmacokinetic parameters.

[0195] For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, without having to go through creative labor. Therefore, simple improvements made to the present invention by those skilled in the art based on the disclosure of the present invention should be within the protection scope of the present invention. The above embodiments are preferred embodiments of the present invention, and all processes similar to the present invention and equivalent changes made should belong to the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the following components: An active ingredient, the active ingredient comprising dronedarone and / or a pharmaceutically acceptable salt thereof; A carrier, the carrier comprising a pharmaceutically acceptable high molecular polymer; and A surfactant comprising oleoyl polyoxyethylene glyceride and / or polyoxyethylene hydrogenated castor oil.

2. The pharmaceutical composition according to claim 1, characterized in that The high molecular polymer is selected from at least one of povidone, copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene, acrylic resin, polyvinyl acetate and polyethylene glycol.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The mass ratio of the active ingredient to the carrier is 1:(0.25-3); and / or the mass ratio of the active ingredient to the surfactant is (3-16):

1.

4. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises an antioxidant and / or an adjuvant.

5. The pharmaceutical composition according to claim 4, characterized in that The antioxidant is selected from at least one of butylated hydroxyanisole, dibutyl hydroxytoluene and vitamin E polyethylene glycol succinate; and / or the mass ratio of the active ingredient to the antioxidant is 23.67:(0.01-0.4); and / or the auxiliary agent includes at least one of a filler, a disintegrant and a lubricant.

6. The pharmaceutical composition according to claim 1, characterized in that The particle size distribution of the pharmaceutical composition is D 90 Between 211-408 μm, and D 50 Between 112-303μm.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The preparation method includes vacuum drying, spray drying, hot melt extrusion, wet granulation or fluidized bed granulation.

8. The method for preparing the pharmaceutical composition according to claim 7, characterized in that: The fluidized bed granulation method comprises the following steps: (1) dissolving a carrier and a surfactant in a solvent to obtain a first mixed solution; (2) dissolving the active ingredient in the first mixed solution to obtain a second mixed solution; (3) Spraying the second mixed solution onto the surface of a fluidized bed granulation substrate using a fluidized bed granulation process to obtain the pharmaceutical composition.

9. The method for preparing the pharmaceutical composition according to claim 8, characterized in that: The fluidized bed granulation substrate is selected from at least one of microcrystalline cellulose, lactose, calcium hydrogen phosphate and silicon dioxide; and / or the mass ratio of the active ingredient to the fluidized bed granulation substrate is 1:(0.1-3.5).

10. A pharmaceutical preparation, characterized in that A pharmaceutical composition comprising any one of claims 1 to 6, or a pharmaceutical composition prepared by the preparation method according to any one of claims 7 to 9.

Images