CN101516338A - A pharmaceutical composition for oral comprising fenofibrate and preparation method thereof - Google Patents
A pharmaceutical composition for oral comprising fenofibrate and preparation method thereof Download PDFInfo
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- CN101516338A CN101516338A CNA2007800355327A CN200780035532A CN101516338A CN 101516338 A CN101516338 A CN 101516338A CN A2007800355327 A CNA2007800355327 A CN A2007800355327A CN 200780035532 A CN200780035532 A CN 200780035532A CN 101516338 A CN101516338 A CN 101516338A
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- 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
- A61K9/10—Dispersions; Emulsions
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The present invention relates to an oral pharmaceutical composition comprising the fenofibrate and a preparation method thereof. More specifically, the present invention is directed to an orally-administered pharmaceutical composition with improved bioavailability for treating hyperlipidemia and the preparation method thereof, where the solid dispersion is prepared by spray-drying a mixture of 100 parts by weight of fenofibrate dispersed in 20-200 parts by weight of water-soluble polymer, and 5-50 parts by weight of surfactant. The oral pharmaceutical composition has high bioavailability because of the increased solubility of amorphous fenofibrate. In addition, the spraying and drying can be performed at a time and low temperature, and thus a loss of activity of drug can be minimized, unlike the mechanical milling method.
Description
The mutual reference of related application
Application requires to enjoy the rights and interests of on August 1st, 2006 to the korean patent application No.10-2006-0072550 of Korea S Department of Intellectual Property submission, and described application mode integral body is by reference included among the application.
Technical field
The present invention relates to a kind of combination of oral medication that contains fenofibrate (chemistry isopropyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) by name-2 Methylpropionic acid ester) and preparation method thereof.More specifically, the invention provides a kind of fenofibrate combination of oral medication that bioavailability increases that contains, because fenofibrate is amorphous form and is the dosage form of solid dispersion.
Background technology
Fenofibrate is the most widely used in the world a kind of therapeutic agent for the treatment of into human endogenous hypercholesterolemia and HTC.The molecular structure of fenofibrate is C
20H
21ClO
4, molecular weight is 360.84g/mol, is a kind of white powder.Usually the dissolubility of fenofibrate in water is lower.Yet fenofibrate can be partly dissolved in methanol and the ethanol, and is soluble in acetone, ether and the benzene.
WO 01/80828 discloses a kind of method of improving water-fast drug particles, and especially preparation contains the short grained method of the medicine that is insoluble in water.The step of described method comprises: under high shear mix being insoluble in the medicine of water and the mixture of one or more surfactants; With described mixture heated to the fusing point of the medicine that is insoluble in water or higher; And make described heated suspension even.Yet, as described in disclosed in the method, medicine is heated to fusing point or above unsatisfactory, because this can make the crystal structure fracture of described medicine.When the heated mixture of cooling, medicines structure changes amorphous form into or recrystallization is a kind of different isomer, thereby forms a kind of physical property compositions different with structure.
EP 0904781 discloses the method that a kind of fenofibrate with solid dispersion is made pellet, and more specifically, the step of described method comprises: the fusing fenofibrate; In the fenofibrate of fusing, sneak into disintegrating agent and curing mixture.Solid disintegrant is a polymer, as starch, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and crosslinked polyvinylpyrrolidone (PVP).PVP is insoluble in the fenofibrate of fusing, and has the phase consistency problem, referring to M.T.Sheu et al., Int.J.Pharm.1994,103 (2), 137-146.In addition,, make decentralized photo and compositions unsatisfactory, thereby influence the bioavailability of active substance for the granule of fenofibrate by the fusing and the method for solidification process pharmaceutical compositions because fenofibrate and PVP are incompatible.In addition, " congruent melting " process also needs special equipment (referring to WO 2004/000279).
WO1998/031361 discloses the method that a kind of preparation comprises the pharmaceutical composition of fenofibrate, and its step comprises: fenofibrate is suspended in particulate form in the solution that contains hydrophilic polymer, solvent and surfactant (optional) to form suspension; Then with described suspension spray to inert carrier.Wherein said hydrophilic polymer is a polyvinylpyrrolidone, and described inert carrier is a lactose, and described surfactant is a sodium lauryl sulphate.This preparation method is widely used, and compares with conventional method and can improve dissolubility and bioavailability.Yet, according to the complex process fenofibrate as activating agent micronize for a long time, thereby in atomization process, reduced thermo-labile medicine productive rate and heat stability.And sodium lauryl sulphate can cause pessimal stimulation to gastrointestinal mucosa.
Summary of the invention
In order to solve the problems of the prior art, the objective of the invention is to provide the solid dispersion dosage form of the amorphous fenofibrate of the remedy for hyperlipemia that a kind of conduct is insoluble in water by spray drying method.Another object of the present invention provides combination of oral medication of bioavailability raising and preparation method thereof.
Description of drawings
In conjunction with the drawings with reference to following detailed, can know and better understand complete value of the present invention with and many attendant advantages, wherein:
Fig. 1 shows to measuring the crystal structure of fenofibrate, the fenofibrate, the solid dispersion of embodiment 2 and the particulate image for preparing by mechanical lapping in comparing embodiment 1 that use X-ray diffractometer to obtain.
Fig. 2 shows the result of relative rate of dissolution test of the solid dispersion of fenofibrate and embodiment 2.
Fig. 3 shows the result of relative rate of dissolution test of the compositions of marketed drugs and embodiment 6,7.
Fig. 4 shows the image of the solid dispersion particle diameter distribution that obtains in embodiment 2.
The specific embodiment
With reference to following specific descriptions, can be clear easily and understand better complete value of the present invention with and many attendant advantages.
Contain the solid dispersion that is dispersed in the amorphous fenofibrate in the pharmaceutical carrier in order to reach purpose of the present invention, to the invention provides, and the combination of oral medication that contains described solid dispersion that is used for the treatment of hyperlipemia.
In addition, the invention provides and contain the solid dispersion that is dispersed in the amorphous fenofibrate in the pharmaceutical carrier by preparation and increase the method for the bioavailability of fenofibrate, dissolubility and/or rate of dissolution.
The invention provides the method that preparation contains the solid dispersion that is dispersed in the amorphous fenofibrate in the pharmaceutical carrier.
Preferably, described solid dispersion is 100 parts fenofibrate by weight to be scattered in the mixture that forms in the surfactant of the water-soluble polymer of 20-200 part and 5-50 part carry out the spray drying preparation.
Described pharmaceutical composition also comprises at least a additive that is selected from excipient, binding agent, disintegrating agent, plasticizer, lubricant and their mixture.
The invention provides a kind of method for preparing solid dispersion, comprise the steps:
In a kind of organic solvent, dissolve fenofibrate, the weight of fenofibrate counted 100 parts, with the water-soluble polymer of 20-200 part by weight and by weight the surfactant of 5-50 part mix mutually, to obtain mixed solution; And
Described mixed solution spraying is dry to obtain to contain the solid dispersion that is dispersed in the amorphous fenofibrate in the pharmaceutical carrier.
In described method, described solid dispersion also comprises at least a excipient, binding agent, plasticizer, disintegrating agent and the lubricant additive of being selected from.
In more detailed mode the present invention is described below.
For improving the bioavailability of medicament of poorly water-soluble, with fenofibrate, water-soluble polymer with show that activating agent dissolves and mixes in a kind of organic solvent, then its spray drying being made fenofibrate is amorphous form, thereby increases the dissolubility of fenofibrate.
The present invention uses solid dispersion can make the littler and homogeneous granules more of method than the mechanical lapping of using prior art, but also is a kind of effective ways that prepare amorphous drug.Usually, term " solid dispersion " is meant at least a active agent that is dispersed in inert carrier or the substrate solid phase.
When using described mechanical grinding method, medicine still keeps crystalline nature after grinding.Yet, in spray drying process, by suitably controlling the composition of medicine and hydrophilic polymer, and the spray drying condition, can form amorphous state fully.In mechanical grinding method, process of lapping can produce a large amount of heats, thereby has destroyed the crystalline nature of medicine unfriendly.Spray drying process prepares granule by evaporation under optimum temperature and operating condition, does not influence medicine, does not also change the crystalline nature of medicine.
Especially, the low melting point (79-82 ℃) and the fenofibrate of poorly water-soluble are dissolved in the organic solvent, and dry for preparing under granule condition the best, that do not change fusing point, to produce solid dispersion.Therefore, compare, the invention provides higher productivity ratio, stability, dissolubility and bioavailability with traditional method.
Grind to obtain the decline of water-insoluble medicine particle size increased the theoretical dissolution surface area, thereby but these microgranules are accumulated in make the dissolving difficulty together.Therefore, this paper has proposed the method for a kind of preparation dispersion that dissolubility partly increases in solid dispersion, and makes solute contact area and the maximized method of carrier dissolubility.The medicine of poorly water-soluble is dispersed in the polymer with molecular level, so that it is suitable for most is oral.
The present invention relates to contain the solid dispersion (hereinafter to be referred as solid dispersion) of amorphous fenofibrate, its preparation method is that fenofibrate is mixed with water-soluble polymer, surfactant and organic solvent, then spray drying.
The mean particle dia of fenofibrate is 1 to 220 μ m in the solid dispersion of the present invention.Solid dispersion is at pH 6.5-7.5, and dissolubility is 5-15 μ g/ml under 25 ℃ the condition, and this is 25 times of the fenofibrate do not handled according to the present invention.When by at pH 6.5-7.5, when measuring the rate of dissolution of the pharmaceutical composition that contains solid dispersion according to the stirring and dissolving method under 25 ℃ the condition, the rate of dissolution that began 30 minutes is about 72w/w% (the dissolved drug amount accounts for the percentage ratio of original medication amount).
Water-soluble polymer comprises cellulosic polymer, polyalkenyl ketopyrrolidine, ployalkylene glycol and methacrylic acid copolymer.Can with the example of the blended water-soluble polymer of fenofibrate be selected from hyprolose, hydroxypropyl emthylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxybutyl cellulose, hydroxyl amyl cellulose, hydroxypropyl butyl cellulose, hydroxypropylalkylce,lulose, polyvinylpyrrolidone, polyvinyl alcohol and their mixture at least a.Amount based on fenofibrate is 100 parts by weight, and the amount of water-soluble polymer is 20-200 part by weight.In the present invention, the consumption of water-soluble polymer is less relatively, has therefore reduced the weight of compositions and the inconvenience of taking medicine.
If the consumption of water-soluble polymer is less than 20 weight portions, the structure of fenofibrate just can not be converted into amorphous form, so dissolubility is lower.If the consumption of water-soluble polymer surpasses 200 weight portions, the increase of preparation size and volume can cause the inconvenience of taking medicine.
Surfactant can be amphoteric, non-ionic, cationic and anionic, but is not limited to this.Surfactant comprises the hydrophilic polymer that pH is relevant.The example of surfactant is for being selected from least a of monoleate, single Lauryl Ester, monopalmitate, monostearate, polyoxyethylene, sorbitan ester, dioctyl sodium succinate, lecithin, stearyl alcohol, cetostearyl alcohol (cetostearylalcohol), cholesterol, polyoxyethylene castor oil, polyoxyethylene fatty acid, polyoxyethylene polyoxypropylene block copolymer (as poloxamer) and macrogol derivant (as cremophor).Consider the raising of drug solubility and the weight of solid dispersion, be 100 parts by weight based on the amount of fenofibrate, then the amount of surfactant is 5-50 part (by weight), is preferably 10 to 50 parts (by weight).If the content of described surfactant is less than 5 parts (by weight), just can not provide required dissolubility.If the content of surfactant surpasses 50 parts, then reduction of the amorphous property of the solid dispersion of Chan Shenging and weight must increase.
The organic solvent that is used to prepare solid dispersion can be the multiple solvent that can dissolve fenofibrate, and its consumption is unrestricted, because it is used for the lytic activity agent, shows activating agent and water-soluble polymer.And described solvent preferred examples is be selected from ethanol, dichloromethane, acetone and methanol at least a.More preferably, affiliated solvent is with the ethanol of 1: 1 mixed of volume ratio and the mixture of dichloromethane.
Described solid dispersion passes through spray drying method for preparation, more specifically, can followingly implement.
In a preferred embodiment, with fenofibrate, hydroxypropyl emthylcellulose and such as the surfactant dissolves of poloxamer or cremophor in organic solvent to obtain mixed solution (8% (w/v)), then by the spray drying method drying to produce solid dispersion.Promptly in spray-drying process, to divide into after customization is equipped with particulate optimum temperature in the situation that does not influence the fenofibrate fusing point, blended solution is sprayed and is dry under optimal condition of the present invention immediately.In spraying of the present invention and exsiccant combined process, spraying and drying are carried out simultaneously, and therefore drying makes crystal not have adequate time to reset fast.Therefore, the amorphous fenofibrate in the acquisition solid dispersion.
More preferably, carry out spray drying under the following conditions with spray dryer: feeding temperature is 75-77 ℃, and chamber temperature is 55-58 ℃, and rotary speed is 7,000-10, and 000rpm/min, flow velocity are 16-20kg/h.
The solid dispersion that produces can be turned to exsiccant pellet by granule before being made into pharmaceutical composition.
In addition, the invention provides the combination of oral medication that contains described solid dispersion.
Used term " pharmaceutical composition " is meant the solid dispersion that the comprises fenofibrate pharmaceutical composition as activating agent.Described combination of oral medication also comprises pharmacy acceptable additive such as liquid state or solid carrier usually, and excipient.Preferably, described compositions comprises the solid dispersion of 30.0-70.0 weight %; And at least a excipient, disintegrating agent, plasticizer, binding agent and the lubricant additive of being selected from of 30.0-70.0 weight %.If the amount of solid dispersion is lower than 30%, the weight of compositions too increases, thereby causes administration inconvenience.If consumption surpasses 70%, then can not obtain enough rate of dissolutions.
Described excipient is to be selected from least a in lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheaten starch, pregelatinized starch, microcrystalline Cellulose or cellulose derivative, dextrin, dalcium biphosphate, calcium hydrogen phosphate, calcium carbonate, polacrilin potassium, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid and the ascorbyl palmitate.Amount of excipient accounts for the 20.0-60.0 weight % of contained additive level in the pharmaceutical composition.
Described disintegrating agent is at least a in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, primojel, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospolyvinylpyrrolidone and their mixture.The disintegrating agent consumption accounts for the 0.1-20.0 weight % of the contained additive level of pharmaceutical composition.
Described plasticizer is at least a in anhydride silica colloid, precipitation of silica, magnesium stearate, stearic acid, Polyethylene Glycol (PEG) and their mixture.Plasticizer consumption accounts for the 0.1-3.0 weight % of the contained additive level of pharmaceutical composition.
The dosage form of combination of oral medication can be solid dosage, liquid dosage form etc.Described combination of oral medication can be made into peroral dosage form such as tablet, granule, powder, pill and dry syrup, more preferably for being used for oral tablet or capsule.
Preferred preparation exists with the unit form of medication.Described compositions is divided into the unit administration form of the active agents that contains appropriate amount.Described unit administration form is the packaged preparation that contains the active agents of equivalent, as tablet, capsule or be packaged in powder in cast bottle or the ampoule bottle.More preferably, described preparation is a capsule form.Effective dose is 160mg every day.
Further explain the present invention in more detail with reference to following embodiment.Yet, should not think that these embodiment limit the present invention by any way.
Embodiment 1-5
According to the spray drying method for preparation solid dispersion
Composition by table 1 prepares the solid dispersion that contains fenofibrate of the present invention.
Table 1
Fenofibrate is dissolved in 1: 1 by volume blended mixture of ethanol and dichloromethane, adds hydroxypropyl emthylcellulose again as water-soluble polymer, to obtain the mixed solution of 8% (w/v).In mixed solution, add poloxamer 188, poloxamer 407, cremophor RH-40 and soybean lecithin more respectively as surfactant, to prepare every kind of solution.With the dish-type spray dryer every kind of solution is carried out spray drying to obtain solid suspension, wherein fenofibrate is scattered in the hydroxypropyl emthylcellulose.Spray drying is implemented under the following conditions: feeding temperature is 75-77 ℃, and chamber temperature is 55-58 ℃, and rotary speed is 7,000-10, and 000rpm/min, flow velocity are 16-20kg/h.
Comparing embodiment 1-4
Carry out mechanical lapping with freezing mill and prepare compound particles
Compositions by mechanical lapping table 2 is made compound particles.
Table 2
With fenofibrate, as hydroxypropyl emthylcellulose and every kind of additive mixing of water-soluble polymer, freezing 5 minutes, milled 5 minutes with the freeze grinding machine then.Consider the hygroscopic nature of water-soluble polymer, the sample for preparing was dewatered 1 day with vacuum pump.These comparing embodiments are to use simple mixing and grinding to carry out, not with an organic solvent.
Embodiment 6-7
Contain the preparation of the tablet of fenofibrate solid dispersion
According to the dry granulation method fenofibrate solid dispersion of embodiment 2 is made granule, mix fully with microcrystalline Cellulose, lactose and the crospolyvinylpyrrolidone of equivalent, remix colloid anhydrous silicic acid is as plasticizer, and magnesium stearate produces tablet then as lubricant.
Among the embodiment 6, fenofibrate solid dispersion crospolyvinylpyrrolidone as the situation of disintegrating agent under granulating, and in embodiment 7, then do not add crospolyvinylpyrrolidone.
Table 3
Test implementation example 1
Dissolubility relatively
The solid dispersion that contains fenofibrate that obtains among the test implementation example 1-5 and the dissolubility of untreated fenofibrate.In order to measure dissolubility, as the pH value regulator, with the sodium hydroxide solution of 118mL 0.2mol/L, moisturizing is made required solution (pH 6.8) to 1000mL again with the basic potassium saline solution of 250mL 0.2mol/L.The solution that obtains is water white.Add excessive solid dispersion in described solution (pH6.8), stirred 2 hours down at 25 ℃, supersound process 2 hours is filtered with 0.45 μ m PVDF injection filter, analyzes filter liquor with HPLC then, thereby records dissolubility.Analysis result is as shown in table 4.
Chromatographic column: XterraTM RP18 5 μ m, 4.6 * 150mm post
Mobile phase: acetonitrile: distilled water=7: 3 (v/v transfers to pH 2.5)
Sample size: 10 μ l
Flow velocity: 1.0ml/ minute
Detect: 286nm
Table 4
| Classification | Rate of dissolution (μ g/ml) |
| Raw material | 0.2 |
| |
5.2 |
| |
9.9 |
| |
8.3 |
| |
10.6 |
| |
5.9 |
As described in Table 4, the dissolubility of solid dispersion of the present invention is raw-material 25 times or 50 times or higher.Therefore, thus the invention provides dissolubility increases the active agents that bioavailability increases.
Test implementation example 2
The XRD figure sample of raw material and solid dispersion is analyzed
With X-ray diffractometer (Rigaku) determine fenofibrate, the crystal structure of the solid dispersion that in embodiment 2 and comparing embodiment 1, obtains, the result is as shown in Figure 1.Quantity of sample fully is pressed into the wide thin layer of 0.3mm to prevent to produce direction on diascope, in 5-40 ℃ scope, carries out x x ray diffraction type detection one time then every 0.5 ℃.X x ray diffraction type detection is at voltage 40kv, electric current 70mA and wavelength 1.542
Condition under carry out.An analysis result is that the peak crystallization of the fenofibrate that is untreated is very high and sharp, the performance of this expression highly crystalline.For carrying out the compound particles that mechanical lapping makes with the freeze grinding machine in the comparing embodiment 1, peak crystallization is lower than the peak crystallization of the fenofibrate that is untreated, but has also shown good crystal property.On the other hand, for the solid dispersion among the embodiment 2, because peak crystallization is obviously low and crystal property is very low, therefore demonstrating dissolubility and bioavailability increases.
Test implementation example 3
Rate of dissolution test relatively
According to the described second kind of dissolving method of Pharmacopoeia Coreana (stirring and dissolving method) solid dispersion of untreated fenofibrate and embodiment 2 is carried out relative rate of dissolution test.In described solubility test, use a kind of solvent soln (pH 6.8, add 1% Tween 80) that the content of fenofibrate is carried out the HPLC quantitative analysis, stir speed (S.S.) is 50rpm.The results are shown among Fig. 2.As shown in Figure 2, the rate of dissolution of the solid dispersion that obtains among the embodiment 2 has remarkable increase.
Test implementation example 4
Rate of dissolution test relatively
According to tablet and a kind of commodity medicine (the Lipidil supra of the described second kind of dissolving method of Pharmacopoeia Coreana (stirring and dissolving method) to obtaining among the embodiment 6-7
TM, Green cross.Co.Ltd, Republic of Korean) relative rate of dissolution detect.In described solubility test, use a kind of solvent soln (pH 6.8, add 15% Tween 80) that the content of fenofibrate is carried out the HPLC quantitative analysis, stir speed (S.S.) is 50rpm.The result is shown in Fig. 3 and table 5.
Table 5 (unit: wt%)
| 5 |
10 |
15 |
30 |
1 |
2 |
4 hours | |
| Embodiment 6 | 34.4 | 50.6 | 59.1 | 71.9 | 79.7 | 84.0 | 85.5 |
| Embodiment 7 | 27.1 | 41.2 | 49.2 | 61.5 | 71.3 | 78.6 | 83.2 |
| The commodity medicine | 12.8 | 34.1 | 45.9 | 62.3 | 70.1 | 80.5 | 84.0 |
Shown in Fig. 3 and table 5, embodiment 6 equates with the commodity medicine with 7 relatively demonstration rate of dissolution of the present invention.
The invention provides a kind of combination of oral medication, it is that the described medicine of spray drying, water-soluble polymer and surfactant are made at short notice then by fenofibrate, hydroxypropyl emthylcellulose and the surfactant (as poloxamer or cremophor) of dissolving poorly water-soluble in organic solvent.Therefore, described compositions can be made at short notice, and has the amorphous form that bioavailability greatly improves.In addition, amorphous solid suspension of the present invention will mix with appropriate carriers and granulating, and conventional pelletising process can be used for the present invention.Therefore, the present invention is a method simply and easily, can be easily and commercialization economically.
Claims (17)
1. a solid dispersion contains the amorphous fenofibrate that is scattered in the water-soluble polymer.
2. the solid dispersion of claim 1, wherein 100 parts fenofibrate is scattered in the surfactant of the water-soluble polymer of 20-200 weight portion and 5-50 weight portion by weight.
3. the solid dispersion of claim 1, wherein said solid dispersion be by will be by weight the surfactant mixtures of the water-soluble polymer of 100 parts of fenofibrate, 2-200 weight portion and 5-50 weight portion carry out spray drying and make.
4. the solid dispersion of claim 1, wherein the dissolubility of the fenofibrate in the solid dispersion is at pH 6.5-7.5, is 5-15 μ g/ml during 25 ℃ of temperature.
5. the solid dispersion of claim 1, wherein the particle diameter of solid dispersion is 1-220 μ m.
6. the solid dispersion of claim 1, wherein said water-soluble polymer is cellulosic polymer, polyalkenyl ketopyrrolidine, ployalkylene glycol or methacrylic acid copolymer.
7. the solid dispersion of claim 6, wherein water-soluble polymer is at least a in hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxybutyl cellulose, hydroxyl amyl cellulose, hydroxypropyl butyl cellulose, hydroxypropylalkylce,lulose, polyvinylpyrrolidone, polyvinyl alcohol and their mixture.
8. the solid dispersion of claim 2, wherein said surfactant are at least a in monoleate, single Lauryl Ester, monopalmitin, glyceryl monostearate, polyoxyethylene, sorbitan ester, dioctyl sodium succinate, lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene castor oil, polyoxyethylene fatty acid, polyox-yethylene-polyoxypropylene block copolymer, macrogol derivant (as cremophor) and composition thereof.
9. combination of oral medication, it contains each described solid dispersion that is scattered in the amorphous fenofibrate in the water-soluble polymer that contains just like claim 1-8.
10. the combination of oral medication of claim 9, wherein said compositions also contains and at least aly is selected from excipient, disintegrating agent, plasticizer, binding agent and lubricant additive, and described solid dispersion and described content of additive are respectively 30-70 weight % and 70-30 weight %.
11. the combination of oral medication of claim 10, wherein said excipient are to be selected from least a in lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheaten starch, pregelatinized starch, microcrystalline Cellulose or cellulose derivative, dextrin, dalcium biphosphate, Calcium monohydrogen phosphate, calcium carbonate, polacrilin potassium, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, ascorbyl palmitate and their mixture.
12. the combination of oral medication of claim 10, wherein said disintegrating agent are at least a in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, primojel, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospolyvinylpyrrolidone and their mixture.
13. the combination of oral medication of claim 10, wherein said plasticizer is for being selected from least a in anhydride silica colloid, precipitation of silica, magnesium stearate, stearic acid, Polyethylene Glycol (PEG) and their mixture.
14. the combination of oral medication of claim 10, wherein said lubricant are to be selected from least a in magnesium stearate, stearic acid, zinc stearate, calcium stearate, Pulvis Talci, sodium stearyl fumarate, silicon dioxide, silica sol and their mixture.
15. the combination of oral medication of claim 9, wherein the dosage form of pharmaceutical composition is tablet, capsule, granule, powder, pill or dry syrup.
16. a method for preparing solid dispersion, its step comprises:
Dissolving fenofibrate in a kind of organic solvent, is 100 parts based on the weight of fenofibrate, with fenofibrate and the water-soluble polymer of 20-200 part by weight and by weight the surfactant of 5-50 part mix mutually, to obtain mixed solution;
Again that described mixed solution spraying is dry to obtain to contain the solid dispersion that is dispersed in the amorphous fenofibrate in the pharmaceutical carrier.
17. the method for preparing solid dispersion of claim 16, wherein said spray drying are to be 75-77 ℃ with the dish-type spray dryer at feeding temperature, chamber temperature is to carry out under 55-58 ℃ the condition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020060072550A KR100767349B1 (en) | 2006-08-01 | 2006-08-01 | A pharmaceutical composition for oral comprising fenofibrate and preparation method thereof |
| KR1020060072550 | 2006-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101516338A true CN101516338A (en) | 2009-08-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800355327A Pending CN101516338A (en) | 2006-08-01 | 2007-08-01 | A pharmaceutical composition for oral comprising fenofibrate and preparation method thereof |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR100767349B1 (en) |
| CN (1) | CN101516338A (en) |
| BR (1) | BRPI0715538A2 (en) |
| WO (1) | WO2008016260A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988339A (en) * | 2012-11-05 | 2013-03-27 | 沈阳药科大学 | Preparation method and application of fenofibrate nano-crystal powder |
| CN103284952A (en) * | 2012-02-29 | 2013-09-11 | 北京万生药业有限责任公司 | Medical composition containing fenofibrate |
| CN106420633A (en) * | 2016-12-20 | 2017-02-22 | 广州中大南沙科技创新产业园有限公司 | Solid dispersion as well as preparation method and application thereof |
| CN114025744A (en) * | 2019-04-08 | 2022-02-08 | 北京科信必成医药科技发展有限公司 | Method for improving dissolution of drug substance and product thereof |
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| US8846154B2 (en) | 2005-06-07 | 2014-09-30 | S.C. Johnson & Son, Inc. | Carpet décor and setting solution compositions |
| US20090182053A1 (en) * | 2007-12-19 | 2009-07-16 | Tong Sun | Fenofibric acid amorphous dispersion; method of making; and method of use thereof |
| FR2940118B1 (en) * | 2008-12-24 | 2013-08-09 | Ethypharm Sa | PHARMACEUTICAL FORMULATION OF NANONIZED FENOFIBRATE |
| JP2012527491A (en) * | 2009-05-27 | 2012-11-08 | サムヤン バイオファーマシューティカルズ コーポレイション | Slightly soluble drug-containing microspheres with improved bioavailability and method for producing the same |
| WO2011029181A1 (en) * | 2009-09-09 | 2011-03-17 | Bernard Charles Sherman | Choline fenofibrate delayed release compositions |
| WO2011034396A2 (en) * | 2009-09-21 | 2011-03-24 | 주식회사 삼양사 | Solid dispersion comprising a fibrate drug, and method for preparing the solid dispersion |
| EP2510924B1 (en) * | 2009-12-08 | 2014-10-08 | IL Hwa Co., Ltd | SOLID DISPERSIONS CONTAINING 20-O-ß-D-GLUCOPYRANOSYL-20(S)-PROTOPANAXADIOL |
| EP2632436B1 (en) * | 2010-10-29 | 2018-08-29 | Abbvie Inc. | Solid dispersions containing an apoptosis-inducing agent |
| KR102237799B1 (en) | 2012-11-14 | 2021-04-08 | 더블유.알. 그레이스 앤드 캄파니-콘. | Compositions containing a biologically active material and a non-ordered inorganic oxide |
| UY36046A (en) * | 2014-03-26 | 2015-10-30 | Millennium Pharm Inc | PHARMACEUTICAL FORMULATIONS, PREPARATION PROCESSES AND METHODS OF USE |
| KR101719907B1 (en) * | 2015-06-17 | 2017-03-24 | 동국대학교 산학협력단 | Omega-3 phospholipid-based formulation of fenofibrate and preparation method thereof |
| CA3080197C (en) * | 2017-10-27 | 2023-12-19 | Plexxikon Inc. | Formulations of a compound modulating kinases |
| WO2022071768A1 (en) * | 2020-09-29 | 2022-04-07 | Addpharma Inc. | A pharmaceutical composition comprising fenofibrate particles with improved bioavailability |
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| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| FR2795961B1 (en) * | 1999-07-09 | 2004-05-28 | Ethypharm Lab Prod Ethiques | PHARMACEUTICAL COMPOSITION CONTAINING MICRONIZED FENOFIBRATE, A SURFACTANT AND A BINDING CELLULOSIC DERIVATIVE AND PREPARATION METHOD |
| US20030224058A1 (en) | 2002-05-24 | 2003-12-04 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| EP1350792A1 (en) * | 2000-12-11 | 2003-10-08 | Takeda Chemical Industries, Ltd. | Medicinal compositions improved in solublity in water |
| US20040121003A1 (en) | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
| CN1200067C (en) * | 2003-07-02 | 2005-05-04 | 顾雏军 | Energy-saving environment-protecting mixed refrigerant |
| CA2540984C (en) | 2003-10-10 | 2011-02-08 | Lifecycle Pharma A/S | A solid dosage form comprising a fibrate |
| EP1827416A1 (en) * | 2004-12-03 | 2007-09-05 | Abbott Laboratories | Pharmaceutical compositions |
-
2006
- 2006-08-01 KR KR1020060072550A patent/KR100767349B1/en active IP Right Grant
-
2007
- 2007-08-01 CN CNA2007800355327A patent/CN101516338A/en active Pending
- 2007-08-01 BR BRPI0715538-7A patent/BRPI0715538A2/en not_active IP Right Cessation
- 2007-08-01 WO PCT/KR2007/003705 patent/WO2008016260A1/en active Application Filing
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103284952A (en) * | 2012-02-29 | 2013-09-11 | 北京万生药业有限责任公司 | Medical composition containing fenofibrate |
| CN102988339A (en) * | 2012-11-05 | 2013-03-27 | 沈阳药科大学 | Preparation method and application of fenofibrate nano-crystal powder |
| CN106420633A (en) * | 2016-12-20 | 2017-02-22 | 广州中大南沙科技创新产业园有限公司 | Solid dispersion as well as preparation method and application thereof |
| CN106420633B (en) * | 2016-12-20 | 2019-10-18 | 广州中大南沙科技创新产业园有限公司 | Solid dispersions and its preparation method and application |
| CN114025744A (en) * | 2019-04-08 | 2022-02-08 | 北京科信必成医药科技发展有限公司 | Method for improving dissolution of drug substance and product thereof |
| CN114025744B (en) * | 2019-04-08 | 2023-10-31 | 北京科信必成医药科技发展有限公司 | Method for improving dissolution of pharmaceutical substances and products thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100767349B1 (en) | 2007-10-17 |
| WO2008016260A1 (en) | 2008-02-07 |
| BRPI0715538A2 (en) | 2013-06-25 |
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