CN117482055A - Preparation method of low-dose dronedarone hydrochloride tablet - Google Patents

Preparation method of low-dose dronedarone hydrochloride tablet Download PDF

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CN117482055A
CN117482055A CN202210882365.6A CN202210882365A CN117482055A CN 117482055 A CN117482055 A CN 117482055A CN 202210882365 A CN202210882365 A CN 202210882365A CN 117482055 A CN117482055 A CN 117482055A
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dronedarone hydrochloride
ratio
preparation
silicon dioxide
zone
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孙凯荣
高飞
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Jiangsu Litaer Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of a low-dose dronedarone hydrochloride tablet, which comprises the following steps: (1) Blending dronedarone hydrochloride bulk drug with polymer and silicon dioxide; (2) Extruding the mixture obtained in the step (1) through a double-screw hot-melt extruder; (3) Cooling the extrudate obtained in the step (2), crushing the cooled extrudate by using a cone-type granulator, and crushing the crushed extrudate by using a hammer crusher to obtain a crushed material with the D90 of 250-300 mu m and the D50 of 150-180 mu m; (4) Uniformly mixing the crushed material obtained in the step (3) with a filler, a disintegrating agent and a lubricant, and tabletting. The dronedarone hydrochloride tablet obtained by the method has high solubility, good stability, good safety and good bioavailability.

Description

Preparation method of low-dose dronedarone hydrochloride tablet
Technical Field
The invention belongs to the field of preparation of pharmaceutical preparations, and particularly relates to a preparation method of a low-dose dronedarone hydrochloride tablet.
Background
Dronedarone tablet (madarone, micarone) developed by the company senofil-amonte, france, is the only new antiarrhythmic drug available in the market for long-term rhythm control for more than ten years. Approval to market in the united states and europe was followed in 7 months and 11 months, and approval to market in domestic in 8 months 2012 for sinus rhythm patients with a history of paroxysmal or persistent atrial fibrillation, reducing the risk of hospitalization for Atrial Fibrillation (AF).
Dronedarone hydrochloride has very low solubility in aqueous media, in particular, its solubility exhibits pH dependence at room temperature, with maximum solubility in the range of pH3 to 5. Because of the dissolution characteristics, the solubility of dronedarone hydrochloride is gradually reduced after oral administration, the bioavailability is low due to precipitation of the drug in an intestinal environment with higher pH, and the solubility of the drug in the intestinal environment is increased by adding a surfactant poloxamer into a commercially available preparation. However, the method has higher requirements on the uniformity of poloxamer and larger intestinal pH race difference, resulting in higher variability of the product. It is therefore necessary to find a method that increases the dissolution rate of dronedarone hydrochloride in order to increase its bioavailability and reduce the variability.
CN102078307a discloses a preparation method of dronedarone hydrochloride tablet, which comprises micronizing dronedarone hydrochloride by solid dispersion technique, mixing with adjuvants, and making into tablet. The method uses solvent precipitation technology to deposit the drug on the surface of the inert carrier to increase the surface area, thereby improving the dissolution rate, but adopts micronization and solvent precipitation technology in the process, is more complex, and finally can cause the residual of solvent.
CN104771376a discloses another preparation method of dronedarone hydrochloride tablet, which comprises the steps of melting and granulating poloxamer and a melting framework material, mixing with dronedarone hydrochloride and other suitable auxiliary materials, granulating, and preparing into tablets. According to the method, poloxamer is uniformly attached to a molten framework material, so that although the solubility of a medicine can be increased, the stability of a sample obtained by the method is poor due to the fact that the poloxamer and dronedarone Long Xiangrong are poor.
CN114377148A discloses another preparation method of dronedarone hydrochloride tablet, which comprises forming inclusion compound from dronedarone hydrochloride and cyclodextrin, mixing with suitable auxiliary materials, granulating, and making into tablet. The medicine obtained by the process has smaller specification (only 20 mg), and the blood concentration after administration is lower and can not meet the treatment requirement.
CN103764126a discloses another preparation method of dronedarone hydrochloride, which is to subject dronedarone hydrochloride and poloxamer to hot melt granulation at 100 ℃, the solubility of the sample obtained by the method is similar to that of the conventional bulk drug, and although the method can reduce the size of the tablet, the medication compliance is provided, but the medication dosage is not reduced. In addition, the sample obtained by this method has poor stability because poloxamer and dronedarone generate nitrogen-oxygen impurities at high temperature.
Disclosure of Invention
In order to solve the problems in the prior art, the inventor provides a method for preparing a low-dose dronedarone hydrochloride tablet by using a hot-melt extrusion technology through long-term research, the dronedarone hydrochloride tablet obtained by the method obviously improves the solubility of the medicament, effectively inhibits the precipitation problem of dronedarone under the condition of a medium with higher pH value, and improves the bioavailability of the medicament absorbed in vivo. In addition, the safety risk brought by high-dose administration can be reduced on the premise of ensuring the effectiveness of the medicine. Because poloxamer surfactant is not used, the stability of the dronedarone hydrochloride tablet prepared by the technology is also obviously improved.
The technical scheme is as follows: a preparation method of a low-dose dronedarone hydrochloride tablet, which comprises the following steps:
(1) Blending dronedarone hydrochloride bulk drug with polymer and silicon dioxide;
(2) Extruding the mixture obtained in the step (1) through a double-screw hot-melt extruder, wherein the extrusion temperature of the double-screw hot-melt extruder is set to be 1 zone 20-30 ℃,2 zone 80-100 ℃,3-6 zone 150-160 ℃,7-9 zone 145-155 ℃, the screw rotating speed is 300+/-50 rpm, and the feeding speed is 20+/-5 rpm;
(3) Cooling the extrudate obtained in the step (2), crushing the cooled extrudate by using a cone-type granulator, and crushing the crushed extrudate by using a hammer crusher to obtain a crushed material with the D90 of 250-300 mu m and the D50 of 150-180 mu m;
(4) Uniformly mixing the crushed material obtained in the step (3) with a filler, a disintegrating agent and a lubricant, and tabletting; wherein, the ratio of the raw materials is 32-43%, the ratio of the polymer is 32-43%, the ratio of the silicon dioxide is 0.6-1.3%, the ratio of the disintegrating agent is 8-10%, the ratio of the lubricant is 0.5-1.0%, the ratio of the filling agent is the rest ratio, and the total ratio of each component is 100%.
Wherein the polymer of step (1) is selected from polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer (e.g. copovidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably copovidone, such as kollidon va64 or Plasdone S630.
The ratio of the raw materials is 32-43%, preferably 33%.
The polymer content is 32-43%, preferably 33%.
The ratio of the bulk drug to the polymer is preferably 1:1.
The twin-screw extruder described in step (2) was selected from Leistritz ZSE 12mm twin-screw extruders.
In the step (3), the extrudate is generally subjected to two or more crushing treatments, and the extrudate is generally subjected to multiple treatments in a hammer crushing manner in a conventional crushing process. Compared with a repeated hammer type crushing mode, the crushing mode has the advantages that the feeding speed is controllable, the crushed particles are more uniform, the crushing process is stable, and the large-scale production is easy.
The disintegrating agent in step (4) is selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone, such as Polyplasdone XL or Kollidon CL.
The lubricant in the step (4) is one or more selected from magnesium stearate, stearic acid, silicon dioxide and sodium stearyl fumarate, preferably magnesium stearate or a mixture of magnesium stearate and silicon dioxide.
The filler in the step (4) is selected from one or more of lactose, mannitol and microcrystalline cellulose, and more preferably lactose, such as Tablettose 80 or Flowlac 100.
The proportion of disintegrant is 8-10%, preferably 10%. The lubricant accounts for 0.5-1.0%. The filler is used in the remaining proportion of the preparation.
The total proportion of the raw materials, the polymer, the silicon dioxide, the disintegrating agent, the lubricant and the filler is 100 percent.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The surfactant is not used, so that nitrogen and oxygen impurities generated by the preparation and the surfactant are avoided, and the stability of the medicine is improved.
(2) The dronedarone hydrochloride is dispersed in the polymer carrier, so that the solubility of the medicine is obviously improved, the precipitation problem of dronedarone under the condition of a medium with higher pH is effectively inhibited, and the bioavailability of the medicine absorbed in vivo is improved.
(3) The low-dose dronedarone tablet prepared by the technology has the bioavailability equivalent to that of a commercially available preparation, namely, the madarone, but has reduced in-vivo variability. On the premise of ensuring the effectiveness of the medicine, the safety risk and the inter-individual difference brought by high-dose administration can be reduced.
Detailed description of the preferred embodiments
The invention will be further illustrated with reference to specific examples.
Example 1 preparation of formulation 1
Mixing dronedarone hydrochloride raw material with copovidone and silicon dioxide in proportion, extruding the mixture in a double screw extruder, and extruding technological parameters: the feed rate was 20rpm, the screw speed was 250rpm, the temperature was 20℃in zone 1, 100℃in zone 2, 150℃in zone 3-6, and 145℃in zone 7-9. The extrudate is cooled and then crushed into suitable granules using a mobile granulator and hammer mill. Adding filler, disintegrating agent and lubricant into the granule, mixing, and tabletting.
Formulation 1 was prepared according to the recipe shown in table 1 with reference to the above preparation process.
Table 1 formulation composition
Component (A) Mass (mg)/tablet Duty cycle (%)
Dronedarone hydrochloride 426 42.6
Copovidone VA64 426 42.6
Silica 1 8.0 0.8
Lactose and lactose 45 4.5
Crosslinked povidone 85 8.6
Silica 2 (Lubricant) 5.0 0.5
Magnesium stearate 5.0 0.5
Total amount of 1000 100
Example 2 preparation of formulation 2
Mixing dronedarone hydrochloride raw material with copovidone and silicon dioxide in proportion, extruding the mixture in a double screw extruder, and extruding technological parameters: the feed rate was 25rpm, the screw speed was 300rpm, the temperature was 25℃in zone 1, 90℃in zone 2, 155℃in zone 3-6, and 150℃in zone 7-9. The extrudate is cooled and then crushed into suitable granules using a mobile granulator and hammer mill. Adding filler, disintegrating agent and lubricant into the granule, mixing, and tabletting.
Formulation 2 was prepared according to the recipe shown in table 2 with reference to the above preparation process.
Table 2 formulation composition of formulation 2
Example 3 preparation of formulation 3
Mixing dronedarone hydrochloride raw material with copovidone and silicon dioxide in proportion, extruding the mixture in a double screw extruder, and extruding technological parameters: the feed rate was 30rpm, the screw speed was 350rpm, the temperature was 1 zone 30 ℃,2 zone 80 ℃,3-6 zone 160 ℃,7-9 zone 155 ℃. The extrudate is cooled and then crushed into suitable granules using a mobile granulator and hammer mill. Adding filler, disintegrating agent and lubricant into the granule, mixing, and tabletting.
Formulation 3 was prepared according to the recipe shown in table 3 with reference to the above preparation process.
Table 3 formulation composition of formulation 3
Component (A) Mass (mg)/tablet Duty cycle (%)
Dronedarone hydrochloride 213 32.8
Copovidone VA64 213 32.8
Silica dioxide 4 0.6
Lactose and lactose 151.75 23.3
Crosslinked povidone 65 10
Magnesium stearate 3.25 0.5
Total amount of 650 100
EXAMPLE 4 stability Studies
Stability studies were performed on the formulations 1 to 3 obtained in examples 1 to 3 and the commercially available formulation (Michelon), i.e., the formulations were allowed to stand at a high temperature (50 ℃) for 30 days to examine the changes of the related substances, and the HPLC detection results are shown in Table 4.
Table 4 stability study data
Wherein, the impurity 1 is nitrogen-oxygen impurity, the nitrogen-oxygen impurity increases fast after the commercial preparation is lofted, and the related substances of the preparation obtained by the method are obviously better than the commercial preparation (Michael) after the preparation is placed for 30 days at 50 ℃.
EXAMPLE 5 solubility study
The solubility of dronedarone hydrochloride and dronedarone hydrochloride in formulation 2 was measured in water and a series of pH buffer solutions representing the physiological pH range, the solubility data being shown in table 5.
TABLE 5 solubility study data (Unit: mg/ml)
Medium (D) Dronedarone hydrochloride Dronedarone hydrochloride in formulation 2
pH1.0 hydrochloric acid 0.0163 0.0595
Citrate at pH3.0 0 3.9964
phosphate at pH4.5 3.0532 5.2271
phosphate at pH6.0 0.0145 4.8036
phosphate at pH6.8 0 2.9642
Water and its preparation method 0.8333 4.0096
From the above table data, the solubility of dronedarone hydrochloride in formulation 2 was greatly increased both in water and in buffer solutions with ph=1.0 to 6.8, as compared to dronedarone hydrochloride.
EXAMPLE 6 dissolution investigation
And (3) dissolving out by using a paddle method according to the requirements of Chinese pharmacopoeia. Formulations 1-3 were placed in 1000 ml of phosphate buffer, pH4.5, and stirred at 37℃and a stirring speed of 75 rpm. After 15, 30, 45, 60, 90 minutes, 10 ml of the sample was taken out, and the dissolution rate of the active ingredient was measured by ultraviolet rays. After 90 minutes, the pH of the dissolution medium was adjusted to 5.0, 5.5 and 6.0 (to simulate the pH change of the gastrointestinal tract in vivo), and the dissolution amounts of the active ingredients in the remaining samples were measured, and the results are shown in Table 6 below.
TABLE 6 dissolution data for dronedarone hydrochloride in samples
As can be seen from the above table, formulations 1-3 substantially match the dissolution profile of the commercial formulation Michael within 90 minutes at pH 4.5. As the pH increased, dronedarone hydrochloride gradually precipitated, but formulations 1-3 had less dronedarone than the commercially available formulation, madarone.
Example 7 evaluation of bioavailability
The dose used was 60 mg/animal, irrespective of the period/state, corresponding to 6mg/kg (for dogs, 10kg of body weight was assumed) and to 400mg of the dose administered to the human (i.e. about 6mg/kg for a human weighing 70 kg).
The administration conditions were as follows:
fasted period: the animals were not fed at night prior to dosing. Water and conventional feed (SSNIFFhdH) were administered one hour and 4 hours after dosing, respectively.
Feeding period: at 10 minutes prior to dosing, the animals received a 50g high fat diet (ssniff doughfda high fat model) with an energy value of 100kcal and consisting of 15% protein, 25% carbohydrate and 50-60% fat. Water and conventional dog feed (SSNIFFhdH) were then administered one hour and 4 hours after dosing, respectively.
Pretreatment with pentagastrin was performed 0.5 hours prior to dosing. Pentagastrin (6 μg/kg,0.25 ml/kg) was administered intramuscularly and the gastric pH of the animals was maintained between 2-3, mimicking the human state.
The treatment is as follows:
treatment 1: formulation 2 tablet (200 mg dose calculated as dronedarone), fasted condition, oral route.
Comparative treatment 1: micalon (400 mg dose calculated as dronedarone), fasted condition, oral route.
Treatment 2: formulation 2 tablet (200 mg dose calculated as dronedarone), feeding condition, oral route.
Comparative treatment 2: micalon (400 mg dose calculated as dronedarone), fed condition, oral route.
Sampling and analysis:
blood samples were collected in plastic tubes containing heparin lithium as anticoagulant at the following sample collection times: 0.5,1,1.5,2,2.5,3,4,4.5,5,6,8 and 24 hours before and after each treatment.
The plasma concentration of dronedarone was determined by liquid chromatography mass spectrometry coupling (LC-MS/MS) using a exploratory analysis method. The lower limit of detection for the test compound is 0.5ng/mL.
Representation of the results:
the following pharmacokinetic parameters were measured for each treatment:
cmax (ng/mL): corresponding to the maximum plasma concentration observed,
tmax (h): corresponding to the observation time for obtaining the maximum concentration,
AUClast: the time from t0 to the final quantifiable concentration is calculated by the trapezoidal method corresponding to the area under the curve or integral of the plasma concentration as a function of time t.
AUC: corresponding to the area under the curve or integral of plasma concentration as a function of time extrapolated to infinity.
T1/2z: final elimination half life
The results are shown in Table 7.
Table 7 pharmacokinetic parameters of dronedarone (mean ± SD (CV%)) (n=6 for each formulation)
Under fasted and fed conditions, the Cmax and AUC observed for the low dose dronedarone hydrochloride tablets provided by the present invention are similar to those calculated for the commercially available high dose formulation, madarone.

Claims (7)

1. A preparation method of a low-dose dronedarone hydrochloride tablet, which comprises the following steps:
(1) Blending dronedarone hydrochloride bulk drug with polymer and silicon dioxide;
(2) Extruding the mixture obtained in the step (1) through a double-screw hot-melt extruder, wherein the extrusion temperature of the double-screw hot-melt extruder is set to be 1 zone 20-30 ℃,2 zone 80-100 ℃,3-6 zone 150-160 ℃,7-9 zone 145-155 ℃, the screw rotating speed is 300+/-50 rpm, and the feeding speed is 20+/-5 rpm;
(3) Cooling the extrudate obtained in the step (2), crushing the cooled extrudate by using a cone-type granulator, and crushing the crushed extrudate by using a hammer crusher to obtain a crushed material with the D90 of 250-300 mu m and the D50 of 150-180 mu m;
(4) Uniformly mixing the crushed material obtained in the step (3) with a filler, a disintegrating agent and a lubricant, and tabletting; wherein the ratio of the raw materials is 32-43%, the ratio of the polymer is 32-43%, the ratio of the silicon dioxide is 0.6-1.3%, the ratio of the disintegrating agent is 8-10%, the ratio of the lubricant is 0.5-1.0%, and the ratio of the filling agent is the rest ratio.
2. The method of claim 1, wherein the polymer of step (1) is selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
3. The method of claim 2, wherein the polymer of step (1) is copovidone.
4. The process of claim 1 wherein the twin screw hot melt extruder of step (2) is a Leistritz ZSE 12mm twin screw extruder.
5. The preparation method according to claim 1, wherein the filler in the step (4) is one or more selected from lactose, mannitol and microcrystalline cellulose; the disintegrating agent is selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide and sodium stearyl fumarate.
6. The method of claim 5, wherein the filler in step (4) is lactose; the disintegrating agent is crospovidone; the lubricant is magnesium stearate or a mixture of magnesium stearate and silicon dioxide.
7. The preparation method according to any one of claims 1 to 6, wherein the dronedarone hydrochloride tablet comprises the following components: the composition comprises 33% of bulk drugs, 33% of polymers, 0.6-1.0% of silicon dioxide, 10% of disintegrating agents, 0.5-1.0% of lubricants and the balance of fillers.
CN202210882365.6A 2022-07-26 2022-07-26 Preparation method of low-dose dronedarone hydrochloride tablet Pending CN117482055A (en)

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