CN103169691B - A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom - Google Patents
A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom Download PDFInfo
- Publication number
- CN103169691B CN103169691B CN201210311221.1A CN201210311221A CN103169691B CN 103169691 B CN103169691 B CN 103169691B CN 201210311221 A CN201210311221 A CN 201210311221A CN 103169691 B CN103169691 B CN 103169691B
- Authority
- CN
- China
- Prior art keywords
- dronedarone
- powder
- salt
- phosphatide
- water soluble
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of dronedarone or the powder of its pharmaceutically-acceptable salts and pharmaceutical composition prepared therefrom, it is by by dronedarone or its salt, and more than one in phosphatide or phosphatide with water soluble adjuvant, surfactant are scattered in organic solvent, use spray drying process or hypobaric drying method to remove solvent to prepare, gained dronedarone or the powder of its pharmaceutically-acceptable salts and pharmaceutical composition prepared therefrom have good dissolution rate in the medium of pH value about 7, and the bioavilability of medicine is effectively ensured.
Description
Technical field
The present invention relates to a kind of antiarrhythmic drug dronedarone or the powder of its salt and drug regimen prepared therefrom
Thing.
Background technology
Dronedarone (Dronedarone), chemical entitled N-[2-normal-butyl-3-[4-[3-(dibutylamino) propoxyl group]
Benzoyl]-5-benzofuranyl] Methanesulfomide, molecular formula C31H44N2O5S, molecular weight 556.76, its structural formula such as following formula institute
Show:
Dronedarone hydrochloride is by the treatment of Sai Nuofei-Sheng Delabao company (Sanofi-Synthelabo) recent development
Antiarrhythmic medicament.This product is benzofuran derivative, and structure and features is similar with amiodarone, but dronedarone is without iodine,
Lipophilicity is relatively low, therefore, had both maintained the curative effect that amiodarone is close, and the elimination half-life is 13-19 hour, is more convenient for as medicine
Thing uses.
The water-soluble of dronedarone hydrochloride is low, and its solute effect in a solvent becomes pH dependence, in pH value 3～
Medium in the range of 5 has preferable solubility, is approximately 1～2mg/mL；And solubility becomes in the medium of pH about 6 to 7
The lowest, particularly as medium pH=7, its solubility only has about 10 μ g/mL；After this medicine is by gastrointestinal administration, once
Enter enteron aisle, the medium that pH is about 6 to 7 will be run into, easily separate out into sediment, thus cause bioavailability low.
ZL98808158.X discloses a kind of solid composite medicament containing benzofuran derivatives, and its discovery is a series of
Non-ionic hydrophilic surfactant, all can to a certain degree improve the holding capacity in the solution of dronedarone hydrochloride, but,
Only poloxamer188 is in the case of consumption is little, can be shown that obvious effect, and the surfactant of other kind
It is required to bigger consumption, about about 50%, can be only achieved ideal effect, so, most of non-ionic hydrophilic surfactants
More difficult for formulation products, strongly limit selection and the use of this auxiliary material；Disclosed some non-ionic type water-wetted surface is lived
Property agent such as polysorbate80 etc., because its viscosity is big, being not easy to supplementary material in production process fully mixes, and affects mobility of particle
And tablet shaping.
CN201010131414.X, discloses a kind of pharmaceutical composition, and it contains dronedarone or it is pharmaceutically acceptable
Salt as active component, one or more pharmaceutically acceptable amphipathic lipids surfactants, one or more phosphatide,
And be combined with one or more pharmaceutical excipients.Practice finds, improves medicine dissolving effect and be mainly phosphatide and amphipathic table
Work in coordination with or by caused by amphiphilic surfactant's independent role after the activating agent combination of face；And, disclosed amphipathic lipids
Surfactant, as classified according to whether containing ionic group, should belong to the category of nonionic surfactant, so, its
Prescription is had the advantage that it is more likely that owing to Composed of Non-ionic Surfactant contained in its prescription causes.It addition, institute is public
The amphipathic lipids surfactant opened, as Gelucire 44/14 etc. be many kinds of substance mixture, due to mixing
The factor such as each material proportion of composing and self distinctive physicochemical property in thing so that mixture auxiliary material character in production process
The release of medicine and stability etc. are produced impact by more difficult control；Further, because part amphipathic lipids surfactant is in water
Or oil can only be partly dissolved, certain difficulty is also brought to preparation.
Because the water solubility of dronedarone hydrochloride is low and dissolves the pH dependence in medium, after oral administration, inevitable
Experience process from stomach to enteron aisle is the process that a pH gradually rises, and is easily caused dronedarone hydrochloride at the higher pH ring of enteron aisle
Under border cannot from solid pharmaceutical preparation dissolution or dissolution rate the lowest, this process has had a strong impact on dronedarone absorption in vivo also
Cause low bioavilability.For improving the bioavilability of dronedarone hydrochloride, it is necessary to by the side such as preparation prescription and technique
The approach being suitable for improving dronedarone hydrochloride dissolution rate is found in the research further in face.
Summary of the invention
It is an object of the invention to provide a kind of dronedarone or the powder of its pharmaceutically-acceptable salts and prepared therefrom
Pharmaceutical composition, it is by by dronedarone or its salt, and in phosphatide, water soluble adjuvant, surfactant
Kind or two or more be scattered in organic solvent, use spray drying process or hypobaric drying method to remove solvent and prepare, gained is certainly
How Dalong or the powder of its pharmaceutically-acceptable salts and pharmaceutical composition prepared therefrom having in the medium of pH value about 7 is good
Good dissolution rate, is effectively ensured the bioavilability of medicine.
The dronedarone of the present invention or the powder of its salt, it is by by dronedarone or its salt, and selected from phosphatide or
More than one in phosphatide and water soluble adjuvant, surfactant are scattered in organic solvent, use spray drying process or subtract
Pressure seasoning is removed solvent and is prepared.
Described phosphatide is including but not limited to the one in soybean lecithin, egg yolk lecithin, lecithin, Polyene Phosphatidylcholine
Or the mixture of two or more arbitrary proportion mixing.
(product type is such as including but not limited to HP-β-CD, polyvinylpyrrolidone for described water soluble adjuvant
PVP K30), the mixture of one or more arbitrary proportions mixing in Macrogol 6000 (PEG 6000).
Described surfactant comprises the one in non-ionic hydrophilic surfactant, amphipathic lipids surfactant
Or the mixture of two or more arbitrary proportion mixing, described non-ionic hydrophilic surfactant is including but not limited to poloxamer
The non-ionic hydrophilics such as class, GREMAPHOR GS32 class, ethoxylation polysorbate esters and poly-hydroxystearate class
Surfactant；It is sweet that described amphipathic lipids surfactant comprises Gelucire 44/14, stearic acid polyethylene glycol
Grease, oleic acid LABRAFIL M 1944CS, Labraso, Miglyol 812N, polyglycerol fatty acid
Ester or VE-succinate etc..
In the powder of described dronedarone or its salt, dronedarone or its salt are in terms of dronedarone, with phosphatide, water-soluble auxiliary
Material, the weight ratio of surfactant are 20～80:0～30:0～50:0～30, and wherein phosphatide, water soluble adjuvant, surface
Activating agent is 0 when varying in weight；When in powder containing phosphatide, dronedarone or its salt are in terms of dronedarone, with phosphatide, water
Soluble auxiliary materials, the weight ratio of surfactant are 20～80:5～30:0～50:0～30；When powder contains water soluble adjuvant
Time, dronedarone or its salt are in terms of dronedarone；It is 20～80:0 with phosphatide, water soluble adjuvant, the weight ratio of surfactant
～30:1～50:0～30；When in powder containing surfactant time, dronedarone or its salt in terms of dronedarone, with phosphatide,
Water soluble adjuvant, the weight ratio of surfactant are 20～80:0～30:0～50:5～30.
The gross weight of consumption and powder in order to effectively control phosphatide and/or water soluble adjuvant and/or surfactant,
In the powder of described dronedarone or its salt, preferably dronedarone or its salt are in terms of dronedarone, with phosphatide, water soluble adjuvant,
The weight ratio of surfactant is 50～80:0～20:0～30:0～20, and wherein phosphatide, water soluble adjuvant, surface-active
Agent is 0 when varying in weight；When in powder containing phosphatide, preferably dronedarone or its salt are in terms of dronedarone, with phosphatide, water
Soluble auxiliary materials, the weight ratio of surfactant are 50～80:5～20:0～30:0～20；When powder contains water soluble adjuvant
Time, preferably dronedarone or its salt are in terms of dronedarone；With phosphatide, water soluble adjuvant, the weight ratio of surfactant be 50～
80:0～20:1～30:0～20；When in powder containing surfactant, preferably dronedarone or its salt are in terms of dronedarone,
It is 50～80:0～20:0～30:5～20 with phosphatide, water soluble adjuvant, the weight ratio of surfactant.
Described solvent comprises absolute ethyl alcohol, and the ethanol containing certain moisture is (such as 70% ethanol: moisture and the weight ratio of ethanol
For 3:7), acetone is conventional for the scattered solvent of medicine and/or auxiliary material, the use weight of solvent in the preparation such as dichloromethane
It is the total of dronedarone or its salt and one or more the auxiliary material in phosphatide, water soluble adjuvant, surfactant
More than 5 times of weight, for avoiding the use of solvent to waste, preferably 8～20 times.
The another kind of dronedarone of the present invention or the powder of its salt, it is by by dronedarone or its salt, and phosphatide,
Water soluble adjuvant is scattered in organic solvent, uses spray drying process or hypobaric drying method to remove solvent and prepares, dronedarone
Or its salt in terms of dronedarone and the weight ratio of phosphatide, water soluble adjuvant is 20～80:5～30:1～50, in order to effectively control
Phosphatide, the consumption of water soluble adjuvant and the gross weight of powder, preferably 50～80:5～20:1～30.
Described phosphatide is including but not limited to the one in soybean lecithin, egg yolk lecithin, lecithin, Polyene Phosphatidylcholine
Or the mixture of two or more arbitrary proportion mixing.
(product type is such as including but not limited to HP-β-CD, polyvinylpyrrolidone for described water soluble adjuvant
PVP K30), the mixture of one or more arbitrary proportions mixing in Macrogol 6000 (PEG 6000).
Described solvent comprises absolute ethyl alcohol, and the ethanol containing certain moisture is (such as 70% ethanol: moisture and the weight ratio of ethanol
For 3:7), acetone is conventional for the scattered solvent of medicine and/or auxiliary material, the use weight of solvent in the preparation such as dichloromethane
It is more than 5 times of gross weight of dronedarone or its salt and phosphatide, water soluble adjuvant, for avoiding the use of solvent to waste, preferably 8
～20 times.
Spray drying process of the present invention, refers to make the liquid material of atomisation be dried in hothouse thermal current
Method, the spray drying device of various model and scale can be used to carry out, the correlated condition parameter of spray drying device, such as gas
Stream pressure, EAT, inlet amount, cleansing pin frequency etc., can be selected according to actual conditions, in the preferred embodiment of the present invention, gas
Stream pressure generally 400L/h～1500L/h, preferably 600L/h～1200L/h；EAT is generally 40 DEG C～160 DEG C, preferably
80 DEG C～120 DEG C；Inlet amount is generally 1mL/min～50mL/min, preferably 5mL/min～30mL/min；Cleansing pin frequency is one
As 5 seconds/time～60 seconds/time, preferably 15 seconds/time～30 seconds/time.Cleaner it is provided with (commonly referred to as at the nozzle of spray drying device
For cleansing pin), when nozzle is blocked, cleansing pin moves the tamper that can remove nozzle, makes spray-drying process continued for constant carry out,
Cleansing pin frequency refers to that cleansing pin movement at regular intervals once thus removes tamper, as 5 seconds/time refer to every movement in 5 seconds once.
Described hypobaric drying method, after referring to supplementary material is scattered in organic solvent, takes up in container, makes inside container
Environment is under subatmospheric state, and imposes certain heating-up temperature in the appearance of container, so that solvent evaporative removal
The method of solvent.Such as, after supplementary material is scattered in organic solvent, take up in flask, use Rotary Evaporators decompression to remove
Solvent, imposes certain bath temperature while rotating；Or the decompression drying method that other modes of same principle realize.
The powder of above-mentioned dronedarone or its salt can be any solid drug forms being suitable for and being administered orally, such as particle
Agent, the pharmaceutical composition such as supensoid agent, it is also possible to be by the dronedarone of gained or its salt powder and more than one pharmaceutically can connect
The auxiliary material being subject to, carries out compressing tablet or the technique such as encapsulated makes the medicines such as tablet, or capsule through the preparation method of conventional oral formulations
Compositions.The medicine prepared with more than one pharmaceutically acceptable auxiliary materials by dronedarone or its salt powder of the present invention
Composition, measures dissolution rate with reference to " Chinese Pharmacopoeia " 2010 editions second annex XC, and dronedarone or its salt are in about pH7
Property medium there are good solute effect, solubility to reach more than 95%.
More than one pharmaceutically acceptable auxiliary materials described include but not limited to required filler, disintegration in pharmaceutical preparation
Agent, and lubricant etc.；Filler includes but not limited to pregelatinized starch, lactose, mannitol, one in microcrystalline cellulose etc. or
The mixture of two or more arbitrary proportions mixing；Disintegrant includes but not limited to PVPP, starch, low replacement
The mixture of one or more arbitrary proportions mixing in hydroxypropyl methyl cellulose etc.；Lubricant includes but not limited to hydrogen
Change the one or two in castor oil, hydrogenated vegetable oil, glycerin monostearate, monopalmitin, stearic acid, talcum powder etc.
Plant the mixture of any of the above ratio mixing.
It addition, the dronedarone of the present invention or the powder of its salt or pharmaceutical composition of being prepared by it can according to store and/
The needs of transport etc. are optional carries out conventional formulation coating, it is ensured that the outward appearance of pharmaceutical composition and glossiness etc..
Salt in described dronedarone or its salt includes the form of the various pharmaceutically acceptable salt of dronedarone, such as salt
Acid dronedarone, sulfuric acid dronedarone etc..
The dronedarone of the present invention or the powder of its salt or pharmaceutical composition of being prepared by it can according to dronedarone or its
The pharmacology of salt, clinical profile, for preparing the purposes of the medicine of prevention and treatment mammal relevant disease, include but not limited to
For the purposes etc. in preparation treatment antiarrhythmic medicament.
The dronedarone of the present invention or the powder of its salt or the pharmaceutical composition prepared by it have relative to prior art
Following advantage and beneficial effect:
Dronedarone or its salt low solubility in neutral conditions and be prone to the feature assembled, limit it in vivo
Absorb and utilize.Medicine and one or more in phosphatide, water soluble adjuvant, surfactant are scattered in by the present invention to be had
In machine solvent, employing spray drying process or hypobaric drying method make the powder of medicine be crystallite or amorphous state, add and compare table
Area, when being scattered in solution, reduces the surface tension of medicine, improves the wettability on surface, be greatly improved medicine
Dissolution rate and solubility, it is ensured that dronedarone or its salt have good result of extraction under enteron aisle neutrallty condition, improve medicine
Thing absorption in vivo.And, greatly control the consumption of phosphatide in powder, water soluble adjuvant, surfactant, be more conducive to
Pharmaceutical practice, the gross weight of obtained preparation is easier to control to being suitable to the specification that patient takes.
When powder is made up of with phosphatide, the combination auxiliary material of water soluble adjuvant dronedarone or its salt, because of wherein used
Phosphatide also can form liposome in course of dissolution, promotes the dissolution of medicine；Water soluble adjuvant such as HP-β-CD can be with
Medicine formed inclusion compound, promote drug-eluting, additionally, due to dronedarone or its salt presented in high degree of dispersion in carrier
In, it is also prevented from medicine gathering during storing.Practice proves the addition of water soluble adjuvant, the most effective guarantee
After powder makes the pharmaceutical compositions such as tablet, dronedarone hydrochloride has good solute effect in neutral medium.
The dronedarone of the present invention or the powder of its salt or the pharmaceutical composition prepared by it depend on its prescription, must be through adopting
Dronedarone hydrochloride just can be made to reach preferable result of extraction with spray drying process or hypobaric drying method, gained powder is through X-
The detection of ray difraction spectrum is substantially without absworption peak, and DSC spectrogram is substantially without dronedarone raw material absworption peak；And use identical or etc.
Same prescription, by Typical physical mixed method, such as wet method etc., then can not realize the preferable result of extraction of dronedarone hydrochloride,
Gained powder has obvious absworption peak through X-ray diffraction spectral detection, and DSC spectrogram dronedarone raw material absworption peak is obvious；Also
That is when employing the identical or prescription of equivalent, it is necessary to take this special preparation method to realize, as long as having identical
Or similar result of extraction or X-ray and DSC spectrogram, then should be understood to have employed spray drying process of the present invention or
Hypobaric drying method identical or equivalent method.
Equally, spray-dried method or hypobaric drying method gained powder prepare pharmaceutical composition further, imitate in dissolution
Also the preparation of more conventional physical mixing processes can show obvious difference on fruit, form according to the prescription of pharmaceutical composition and dissolution is imitated
Really, as same or similar with corresponding powder constituent and result of extraction, then it is to be understood that this pharmaceutical composition uses corresponding powder
End prepares.
Accompanying drawing explanation
The DSC spectrogram of Fig. 1 dronedarone raw material
Fig. 2 is the X-ray diffraction spectrogram of embodiment 4 dronedarone powder
Fig. 3 is the DSC spectrogram of embodiment 4 dronedarone powder
Fig. 4 is the X-ray diffraction spectrogram of embodiment 12 dronedarone powder
Fig. 5 is the DSC spectrogram of embodiment 12 dronedarone powder
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but the embodiment of invention is not limited to this.
Embodiment 1
Weight based on dronedarone hydrochloride add the soybean lecithin of weight ratio as shown in table 1, Tween-20, Tween-80,
Gelucire 44/14, is dissolved in the phosphate buffer of pH 4.5 and makes the molten of hydrochloric dronedarone 2mg/mL
Liquid, 37 DEG C are incubated 2 hours, then solution neutral phosphate buffer liquid are diluted 10 times, and final solution pH is 6.8, at 37 DEG C
After being incubated 2 hours, through the filter filtration of 5 μm, solution uses ultraviolet specrophotometer, measures the suction of solution at 217nm wavelength
Shading value A；The phosphate buffer separately taking pH 4.5 makes the solution of hydrochloric dronedarone 2mg/mL, and 37 DEG C are incubated 2 hours,
Then the solution phosphate buffer of pH 4.5 being diluted 10 times, final solution pH is 4.5, after 37 DEG C of insulations 2 hours, and warp
The filter of 5 μm filters, and solution uses ultraviolet specrophotometer, measures the absorbance B in solution, calculate at 217nm wavelength
Percentage=A/B × 100% of the dronedarone hydrochloride in solution, this percentage embodies because pH value rises to 6.8 pairs of hydrochloric acid certainly from 4.5
The impact how Dalong dissolves, percentage is the biggest, then affect the least, result such as table 1 below:
Table 1. surfactant is on dronedarone hydrochloride impact of holding capacity in neutral medium
As can be seen from the above table, when soybean lecithin is at 50% that addition is active component, dronedarone hydrochloride can be made to exist
Solution reaches preferable solute effect, but, too much phosphatide not only can bring difficulty by drug preparation, it addition, along with auxiliary
Dramatically increasing of material weight, the gross weight of pharmaceutical composition also is difficult to control to being suitable to the specification that patient takes.
Non-ionic hydrophilic surface active agent tween-20, the addition of Tween-80 can to a certain degree improve dronedarone hydrochloride
Solute effect in the solution, but, when Tween-20 or Tween-80 addition is active component 50% time, the salt in solution
Acid dronedarone percentage only be respectively 65% and 69%, be extremely difficult to added by enter when medicine substantially completely dissolves due dense
Degree.Amphipathic lipids surfactant has similar effect with non-ionic hydrophilic surfactant.
Embodiment 2 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, soybean lecithin 4g is scattered in 500mL 70% ethanol, uses spray drying instrument to enter
Row is spray-dried to obtain powder.(wherein, the weight of soybean lecithin accounts for about the 8.6% of powder weight)
Spray drying condition: be spray-dried instrument；Nitrogen stream pressure: 600L/h；EAT: 90 DEG C；Leaving air temp: 43 DEG C；
Inlet amount: 5mL/min；Cleansing pin frequency: 15 seconds/time.
Embodiment 3 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, Tween-80 4g is scattered in 500mL absolute ethyl alcohol, uses spray drying instrument to carry out
It is spray-dried to obtain powder.(wherein, the weight of Tween-80 accounts for about the 8.6% of powder weight)
Spray drying condition: be spray-dried instrument；Nitrogen stream pressure: 1200L/h；EAT: 80 DEG C；Leaving air temp: 32 DEG C；
Inlet amount: 15mL/min；Cleansing pin frequency: 30 seconds/time.
Embodiment 4 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, HP-β-CD 10g, soybean lecithin 4g are dissolved in 500mL 70% ethanol,
Use and be spray-dried instrument and carry out being spray-dried to obtain powder, powder through X-ray diffraction spectral detection, detection spectrogram as in figure 2 it is shown,
Substantially without obvious absorption peaks；Powder detects through differential scanning calorimetry, and DSC spectrogram is as shown in Figure 3, hence it is evident that how salt-free acid certainly reaches
Grand raw material absworption peak.(wherein, the weight of soybean lecithin accounts for about the 7.1% of powder weight)
Spray drying condition: be spray-dried instrument；Nitrogen stream pressure: 600L/h；EAT: 90 DEG C；Leaving air temp: 43 DEG C；
Inlet amount: 5mL/min；Cleansing pin frequency: 15 seconds/time.
Wherein, dronedarone hydrochloride raw material DSC spectrogram is as shown in Figure 1.
X-ray diffraction spectral detection condition: Cu target K α 1 ray, voltage 25kV, electric current 35mA, divergent slit 1 °, anti-scatter
Slit 1 °, reception slit 0.3mm, 0.3mm, 2 θ scopes: 3 ° 50 °, 10 °/min；Detecting instrument: D/max-3A, X-ray diffraction
Instrument；Detection foundation: turn target multiple crystal X-ray diffraction method general rule JY/T009-1996.
DSC testing conditions: atmosphere: N2, 20mL/min；Scanning imaging system: be warming up to 210 DEG C with 10 DEG C/min from room temperature, note
Record heating curve；NETZSCH company of Germany DSC 204 differential scanning calorimeter, detection foundation: JY/T 014-1996.
Embodiment 5 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, PVP K3020g, egg yolk lecithin 4g is dissolved in 500mL 70% ethanol, uses spray
Mist drying instrument carries out being spray-dried to obtain powder.(wherein, the weight of egg yolk lecithin accounts for about the 6.0% of powder weight)
Spray drying condition: be spray-dried instrument；Nitrogen stream pressure: 800L/h；EAT: 120 DEG C；Leaving air temp: 69 DEG C；
Inlet amount: 10mL/min；Cleansing pin frequency: 20 seconds/time.
Embodiment 6 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, PEG 6000 20g, lecithin 4g is dissolved in 500mL 70% ethanol, uses and rotates
Evaporation under reduced pressure removes solvent, bath temperature: 50 DEG C, and the solids after removing solvent is vacuum dried 4 hours to obtain powder, prepares
Powder cross 24 mesh sieves.(wherein, the weight of lecithin accounts for about the 6.0% of powder weight)
Embodiment 7 dronedarone hydrochloride powder
Take dronedarone hydrochloride 42.6g, HP-β-CD 20g, Tween-80 4g are dissolved in 500mL 70% ethanol,
Using Rotary Evaporators removal of solvent under reduced pressure, bath temperature: 60 DEG C, the solids after removing solvent is vacuum dried 4 hours
Powder, prepared powder crosses 24 mesh sieves.(wherein, the weight of soybean lecithin accounts for about the 6.0% of powder weight)
Embodiment 8: dronedarone hydrochloride powder (embodiment 2 prescription conventional wet lay prepares powder reference examples)
According to the powder prescription of embodiment 2, use conventional wet lay preparation method, dronedarone hydrochloride is crossed 80 mesh sieves, takes
Dronedarone hydrochloride 42.6g；Weigh soybean lecithin 4g and be scattered in 30mL absolute ethyl alcohol formation homogeneous solution, pour this solution into
Softwood processed in dronedarone hydrochloride, crosses 24 mesh sieves and pelletizes, and particle 50 DEG C is dried, crosses the 20 whole grains of mesh sieve, obtains powder.
Embodiment 9: Dronedarone hydrochloride tablet (embodiment 2 powder film-making reference examples)
According to powder prescription and the preparation method of embodiment 2, take dronedarone hydrochloride 42.6g, soybean lecithin 4g is scattered in
In 500mL 70% ethanol, spray drying instrument is used to carry out being spray-dried to obtain powder；Powder is gathered with pregelatinized starch 5g, crosslinking
Compressing tablet 100 after vinylpyrrolidone 5g, rilanit special 0.6g mixing.
Embodiment 10: Dronedarone hydrochloride tablet (embodiment 8 powder film-making reference examples)
According to the powder prescription of embodiment 2, use conventional wet lay preparation method, dronedarone hydrochloride is crossed 80 mesh sieves, takes
Dronedarone hydrochloride 42.6g；Weigh soybean lecithin 4g and be scattered in 30mL absolute ethyl alcohol formation homogeneous solution, pour this solution into
Softwood processed in dronedarone hydrochloride, crosses 24 mesh sieves and pelletizes, and particle 50 DEG C is dried, crosses the 20 whole grains of mesh sieve, obtains powder；Weigh pre-glue
Change compressing tablet 100 after starch 5g, PVPP 5g, rilanit special 0.6g mixing.
Embodiment 11: Dronedarone hydrochloride tablet
According to powder prescription and the preparation method of embodiment 4, take dronedarone hydrochloride 42.6g, HP-β-CD
10g, soybean lecithin 4g are dissolved in 500mL 70% ethanol, use spray drying instrument to carry out being spray-dried to obtain powder；By powder with pre-
Compressing tablet 100 after gelling starch 5g, PVPP 5g, rilanit special 0.6g mixing.
Embodiment 12: Dronedarone hydrochloride tablet (embodiment 4 prescription conventional wet lay prepares reference examples)
Use conventional wet lay preparation method: dronedarone hydrochloride, water soluble adjuvant HP-β-CD are crossed respectively 80
Mesh sieve, takes dronedarone hydrochloride 42.6g, HP-β-CD 10g mixes；Weigh soybean lecithin 4g and be scattered in 30mL
In absolute ethyl alcohol formed homogeneous solution, pour this solution into the mixed powder of dronedarone hydrochloride and HP-β-CD is made soft
Material, crosses 24 mesh sieves and pelletizes, and the particle 50 DEG C dried mistake 20 whole grain of mesh sieve obtains powder, and powder is through X-ray diffraction spectral detection, inspection
As shown in Figure 4, powder detects light-metering spectrogram through differential scanning calorimetry, and DSC spectrogram is as shown in Figure 5；Weigh pregelatinized starch
Compressing tablet 100 after 5g, PVPP 5g, rilanit special 0.6g mixing.
X-ray diffraction spectral detection condition: Cu target K α 1 ray, voltage 25kV, electric current 35mA, divergent slit 1 °, anti-scatter
Slit 1 °, reception slit 0.3mm, 0.3mm, 2 θ scopes: 3 ° 50 °, 10 °/min；Detecting instrument: D/max-3A, X-ray diffraction
Instrument；Detection foundation: turn target multiple crystal X-ray diffraction method general rule JY/T009-1996.
DSC testing conditions: atmosphere: N2, 20mL/min；Scanning imaging system: be warming up to 210 DEG C with 10 DEG C/min from room temperature, note
Record heating curve；NETZSCH company of Germany DSC 204 differential scanning calorimeter, detection foundation: JY/T 014-1996.
Embodiment 13: dissolution determination
With reference to " Chinese Pharmacopoeia " 2010 editions second annex XC, using paddle method, temperature is 37 DEG C ± 0.5 DEG C, at pH6.8 phosphorus
Phthalate buffer 900mL is medium, in sampling in 45 minutes, and measures absorption value at 217nm by ultraviolet spectrophotometry, calculates
Dissolution rate.Wherein, embodiment 9～12 respectively takes 1 and measures dissolution rate, and embodiment 2～8 weighs powder (the wherein institute of Unit Weight
Drug containing is 400mg based on dronedarone), measure dronedarone hydrochloride dissolution rate, result such as table 2 below:
Table 2. embodiment 2～8 dronedarone hydrochloride powder and embodiment 9～12 dronedarone hydrochloride sheet are at pH6.8 medium
In dissolution rate situation:
As can be seen from the above table, dronedarone hydrochloride and phosphatide or surfactant package, use spray drying process or
Hypobaric drying method prepares powder, and in gained powder, dronedarone hydrochloride has good solute effect in neutral medium, and now
The usage amount of phosphatide or surface active agent tween-80 only needs about 10%, effectively controls the consumption pair of phosphatide or surfactant
The impact of preparation.
And, embodiment 2 prescription such as embodiment 8 method carries out conventional wet lay granulation, and powder embodiment 8 prepared
Compressing tablet (embodiment 10) further, in gained powder and tablet, dronedarone hydrochloride result of extraction in pH6.8 medium is obvious
Relatively use spray drying process to prepare the powder of gained and prepared tablet (embodiment 2 and 9) is poor, those skilled in the art are described
Use identical in specification or the prescription of equivalent, by conventional method, such as wet method etc., it is impossible to realize dronedarone hydrochloride preferable
Result of extraction, say, that when employing the identical or prescription of equivalent, it is necessary to take special preparation method to realize, and work as
When its which type of special preparation method specifically used can not be described, then should be understood to have employed spray drying process of the present invention
Or hypobaric drying method is identical or the method for equivalent.
It addition, after adding a certain amount of water soluble adjuvant in prescription, the powder of dronedarone hydrochloride is in neutral medium
Solute effect slightly increase；Wet method, the powder of spray drying process is used to press further after adding HP-β-CD
Making troche medical composition (embodiment 11 and 12), the addition of water soluble adjuvant HP-β-CD is tieed up to a certain extent
Hold dronedarone hydrochloride solute effect in neutral medium in troche medical composition, but wet method the most relatively spray drying process
Difference.
Above-described embodiment 2～7,9,11 is the present invention preferably embodiment, but embodiments of the present invention are not by upper
State the restriction of embodiment, the change made under other any Spirit Essence without departing from the present invention and principle, modify, substitute,
Combination, simplification, all should be the substitute mode of equivalence, within being included in protection scope of the present invention.
Claims (5)
1. a dronedarone or the powder of its salt, it is characterised in that it is by by dronedarone or its salt, and phosphatide and
Water soluble adjuvant is scattered in organic solvent, and described phosphatide comprises soybean lecithin, egg yolk lecithin, lecithin, polyene phosphatidyl
The mixture of one or more arbitrary proportions mixing in choline；Described water soluble adjuvant comprise HP-β-CD,
The mixture of one or more arbitrary proportions mixing in polyvinylpyrrolidone, Macrogol 6000, uses spraying dry
Dry method or hypobaric drying method are removed solvent and are prepared, and described dronedarone or its salt are in terms of dronedarone, with phosphatide, water solubility
The weight ratio of auxiliary material is 20～80:5～30:1～50.
A kind of dronedarone the most as claimed in claim 1 or the powder of its salt, it is characterised in that described dronedarone or its salt with
Dronedarone meter, is 50～80:5～20:1～30 with the weight ratio of phosphatide, water soluble adjuvant.
A kind of dronedarone the most as claimed in claim 1 or the powder of its salt, it is characterised in that described organic solvent is anhydrous second
Alcohol, the ethanol containing certain moisture or acetone.
4. a dronedarone or the pharmaceutical composition of its salt, it is characterised in that comprise claims 1 to 3 any claim
Described a kind of dronedarone or the powder of its salt and more than one pharmaceutically acceptable auxiliary materials form.
A kind of dronedarone the most as claimed in claim 4 or the pharmaceutical composition of its salt, it is characterised in that more than one pharmacy
Upper acceptable auxiliary material includes but not limited to required filler, disintegrant, and lubricant in pharmaceutical preparation；Filler include but not
It is limited to pregelatinized starch, lactose, mannitol, the mixture of one or more arbitrary proportions mixing in microcrystalline cellulose；
Disintegrant includes but not limited to the one or two in PVPP, starch, low substituted hydroxy-propyl methylcellulose
Plant the mixture of any of the above ratio mixing；Lubricant includes but not limited to rilanit special, and hydrogenated vegetable oil, monostearate are sweet
Grease, monopalmitin, stearic acid, the mixture of one or more arbitrary proportions mixing in talcum powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210311221.1A CN103169691B (en) | 2011-12-22 | 2012-08-29 | A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110438826.2 | 2011-12-22 | ||
| CN2011104388262 | 2011-12-22 | ||
| CN201110438826 | 2011-12-22 | ||
| CN201210311221.1A CN103169691B (en) | 2011-12-22 | 2012-08-29 | A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103169691A CN103169691A (en) | 2013-06-26 |
| CN103169691B true CN103169691B (en) | 2016-08-17 |
Family
ID=48630184
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210311221.1A Expired - Fee Related CN103169691B (en) | 2011-12-22 | 2012-08-29 | A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103169691B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106913539B (en) * | 2015-12-25 | 2021-02-05 | 山东新时代药业有限公司 | Abiraterone acetate sublingual tablet and preparation method thereof |
| TW202227049A (en) * | 2020-10-20 | 2022-07-16 | 大陸商上海博志研新藥物技術有限公司 | Dronedarone hydrochloride pharmaceutical composition, preparation method and use thereof |
| CN115702878B (en) * | 2021-08-16 | 2024-05-10 | 上海云晟研新生物科技有限公司 | Dronedarone hydrochloride injection composition, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102078307A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Medicine composition of dronedarone hydrochloride solid dispersion and preparation method thereof |
| CN102188417A (en) * | 2010-03-19 | 2011-09-21 | 江苏恒瑞医药股份有限公司 | Dronedarone medicinal composition |
| CN102342907A (en) * | 2010-07-30 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | Dronedarone solid dispersoid and preparation method thereof |
-
2012
- 2012-08-29 CN CN201210311221.1A patent/CN103169691B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102078307A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Medicine composition of dronedarone hydrochloride solid dispersion and preparation method thereof |
| CN102188417A (en) * | 2010-03-19 | 2011-09-21 | 江苏恒瑞医药股份有限公司 | Dronedarone medicinal composition |
| CN102342907A (en) * | 2010-07-30 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | Dronedarone solid dispersoid and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103169691A (en) | 2013-06-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10912763B2 (en) | Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine | |
| CN109125261B (en) | Edaravone dosage form | |
| JP6466399B2 (en) | Topiramate rapidly dispersible dosage form | |
| US8623405B2 (en) | Finely divided composition containing poorly water soluble substance | |
| EP2623100B1 (en) | Preparation for improving solubility of poorly soluble drug | |
| CN107308133A (en) | Curcumin pharmaceutical preparation | |
| KR20060115350A (en) | Sustained release dosage forms of ziprasidone | |
| CN102008439A (en) | Curcumin coated liposome preparation and preparation method thereof | |
| US20160256395A1 (en) | Compressed tablet containing delta 9-tetrahydrocannabinol, method for its manufacture and use of such tablet in oral treatment | |
| WO2020150233A1 (en) | Oral disintegrating films for cannabis products | |
| CN103169691B (en) | A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom | |
| CA3160732A1 (en) | Cannabinoid nano-micelle preparation and preparation method thereof | |
| AU2019363244A1 (en) | Pharmaceutical formulation | |
| CN105902525A (en) | Application of chlorogenic acid nano powder inhalation in medicine for treating acute lung injury | |
| CN101780037A (en) | Dipyridamole self-emulsifying medicament administration system and preparation method thereof | |
| CN107921017A (en) | The method treated using cadotril composition | |
| CN102755295B (en) | Stability-enhanced medicament composition containing limaprost and preparation method thereof | |
| CN102470121B (en) | Pharmaceutical compositions comprising dronedarone | |
| CN101224211B (en) | Entecavir solid dispersoid, medicine compounds and preparing method and applications thereof | |
| WO2017204210A1 (en) | Oral pharmaceutical composition and method for producing particulate formulation comprising composition | |
| CN104721827A (en) | Insoluble antifungal medicament solid dispersion and preparation method thereof | |
| IL299941A (en) | Pharmaceutical compositions for improved delivery of therapeutic lipophilic actives | |
| CN103179953A (en) | Pharmaceutical dosage form comprising 6'-fluoro-(n-methyl- or n,n-dimethyl-)-4-phenyl-4,9'-dihydro-3'h-spiro[cylohexane-1,1'-pyrano[3,4,b]indol]-4-amine | |
| CN104739776A (en) | Solid dispersion composition of levocarnitine as well as preparation method and medical application of solid dispersion composition | |
| Zulkifli et al. | The effect of disintegrants on the physical properties of a cocoa butter based fast melt tablet developed by a fusion moulding method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160817 Termination date: 20200829 |