CN104379174A - Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers - Google Patents
Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers Download PDFInfo
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- CN104379174A CN104379174A CN201380032615.6A CN201380032615A CN104379174A CN 104379174 A CN104379174 A CN 104379174A CN 201380032615 A CN201380032615 A CN 201380032615A CN 104379174 A CN104379174 A CN 104379174A
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- active ingredient
- acid
- active component
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Abstract
Disclosed are solid dispersions consisting of hydrophobic active ingredients and cationic copolymers of N,N-diethylaminoethyl methacrylate and methyl methacrylate, the monomers being provided at a weight ratio of 35:65 to 55:45.
Description
The present invention relates to the solid dispersion of the hydrophobic active ingredient for pharmaceutical dosage form, it is the DEAEMA of 35:65-55:45 and the cation copolymer of methyl methacrylate based on monomer weight ratio.The invention further relates to the preparation for this kind of solid dispersion of pharmaceutical dosage form and purposes.
WO 00/05307, WO 02/067906 and WO 2004/019918 describe cation acrylic aminoalkyl ester copolymer and the purposes as coating and binding agent thereof.
WO 2009/016258 discloses as used in the present invention based on the preparation of the aqueous polymer dispersion of the cationic polymer of DEAEMA and the purposes in coated medicament thereof.
Term " solid dispersion " describes the system that wherein active component falls apart in the form embedded polymer thing matrix on farmland with differential.This kind of system is that the meaning of solid phase is true solid dispersion at decentralized photo and continuous phase.
In addition, term " solid dispersion " also comprises so-called " solid solution ", and wherein active component exists with the molecular dispersion form embedded in solid polymer phase (matrix).This kind of solid solution such as causes the active component release improved when using with the solid drugs form of expression of microsolubility active component.The important requirement of this kind of solid solution is them is stable, and namely active component can not crystallize out, even if be also like this when long term storage.In addition, the capacity of solid solution, in other words, the ability forming the stable solid solution with as far as possible most high active ingredient content is also important.
So-called " solid dispersion " purposes in the dissolubility improving medicine and bioavailability and by dissolving method or melt extrusion preparation normally known, therefore such as by known in " Ch.Leuner; J.Dressman, European Journal of Pharmaceutics and Biopharmaceutics50 (2000) 47-60 ".Cation amino acrylate as
the use of E is also described in this list of references in general manner.
But, find also conduct
e PO goes on the market
e still haves much room for improvement in the stability of solid dispersion and the load capacity of active component.Usually, under higher active component load, produce active component crystal or relatively large active component farmland.
But load capacity the highest is as far as possible very important.
Therefore, the object of the invention is to prepare the solid dispersion of the hydrophobic active ingredient without these shortcomings in cationic polymer.
Therefore, find that hydrophobic active ingredient and monomer weight ratio are the solid dispersion of the DEAEMA of 35:65-55:45 and the cation copolymer of methyl methacrylate.
In addition, find to prepare hydrophobic active ingredient containing active ingredient solids dispersion, it comprises by monomer weight ratio is the methacrylic acid N of 35:65-55:45, the liquid mixture of matrix polymer and at least one hydrophobic active ingredient, as matrix polymer, is wherein changed into solid by N-diethylamino ethyl ester and methyl methacrylate radical polymerization and the cation copolymer obtained.
Liquid mixture can be used as solution or melt exists.Liquid mixture is homogeneous mixture.
Preferred matrix polymer is monomer weight ratio is the DEAEMA of 45:55 and the copolymer of methyl methacrylate.
Cationic base polymer obtains by free-radical emulsion polymerization.About by the matrix polymer of emulsion polymerisation preparation based on DEAEMA, clearly with reference to the disclosure of WO 2009/016258.
Be preferably used as the copolymer conduct of matrix polymer
smartseal 30D, BASFSE are commercially available with the form of aqueous dispersion.Mean molecule quantity (weight average) is 200000 dalton.Molecular weight is by determination of light scattering.
Cationic base polymer also can to use with form in part.For this reason, the basic group of 0.1-30, preferred 2-20 % by mole can neutralize with suitable acid moieties.For this reason, on all physiology, the inorganic or organic acid of tolerance is very well suitable.
Suitable mineral acid is hydrochloric acid, sulphuric acid or phosphoric acid.Suitable also has monocarboxylic acid, such as acetic acid, formic acid, propanoic acid, Loprazolam, ethane sulfonic acid, benzoic acid, salicylic acid, gentisic acid, hydroxyacetic acid, lactic acid, caproic acid, sad, capric acid, ascorbic acid, arabo-ascorbic acid, nicotinic acid, 2-hydroxyethanesulfonic acid, dichloroacetic acid, pyroglutamic acid, cinnamic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, gluconic acid, glucuronic acid, hippuric acid, lactobionic acid, mandelic acid, LOMAR PWA EINECS 246-676-2, oleic acid, orotic acid, or tricarboxylic acids is as citric acid.
Specially suitable is the dicarboxylic acids of the chain length with 3-10 carbon atom.Suitable dicarboxylic acids mainly has the non-branching dicarboxylic acids of terminal carboxylate group.Suitable dicarboxylic acids also has those that replaced by one or two hydroxyl.
According to the present invention, preferably use and there is the pK being greater than 2
avalue and be greater than 4 the 2nd pK
athe dicarboxylic acids of value is with part neutralization.Particularly preferably use and there is the pK being greater than 2.5
avalue and be greater than 5 the 2nd pK
athe dicarboxylic acids of value.PK
avalue is the negative log of acid constant
10.
Except acidic group, be saturated alkane dicarboxylic acid, malonic acid, succinic acid, 1,3-propanedicarboxylic acid, adipic acid or decanedioic acid without other substituent suitable dicarboxylic acids.The suitable alkane dicarboxylic acid replaced by one or two hydroxyl is malic acid (2-hydroxy succinic acid) or tartaric acid (2,3-dihydroxysuccinic acid).Suitable unsaturated dicarboxylic particularly fumaric acid.
Also the mixture of this kind of dicarboxylic acids can be used.
Such as, can advisably the dicarboxylic acids producing particularly preferred coating resistance be mixed with those acid producing particularly preferred powder redispersibility.Suitable mixture is such as adipic acid and sulphuric acid or succinic acid and oxalic acid.
On the invention hereafter in, part neutralization mean 2-25, the diethylamino ethyl of preferred 4-16 % by mole exists in a salt form.
Particularly preferably use dicarboxylic acids, such as adipic acid or succinic acid.
According to the present invention, term " hydrophobic active ingredient " means active component to be had be less than 0.25% (m/m) in 20 DEG C of water, is preferably less than 0.1%, is particularly preferably less than the dissolubility of 0.01%.
The solid dispersion obtained by the inventive method is existed with amorphous form.The crystalline portion that " amorphous " means lyophobic dust based on the gross weight of solid dispersion for being less than 5 % by weight.
The solid dispersion obtained according to the present invention can study not existing of amorphism or degree of crystallinity by XRD (X-ray diffraction) and DSC (differential scanning calorimetry).This amorphous state also can be described as X-ray amorphous state.Preferably, assess and carry out with XRD.
Use DSC, also can examine whether to there is crystalline portion.Crystalline portion can by sharp-pointed fusing point identification.DSC research is preferably carried out with the rate of heat addition of 20K/min.
With regard to screening, crystalline portion is also undertaken by optical microscopy.Suitable optical microscope for this object has the resolution of 167 linear right/mm, and this is equivalent to the minimum distinguishable object structures of 3 μm.
According to the present invention, gained solid can be depending on embodiment to be existed as film or granule or powder in solid form.
What be suitable in principle preparing solid dispersion is film method, spraying dry and melt extrusion method, and wherein solid dispersion comprises hydrophobicity acid composition and the solution of matrix polymer or the liquid mixture of melt form by transforming and changes into solid form.
According to an embodiment, first all the components of preparation is dissolved in suitable solvent each other, then except desolventizing.This drying means by all suitable type carries out, such as spraying dry, film method (evaporation of solvent), fluid bed drying, the drying of application supercritical gas, lyophilization.Also can process solutions to obtain thin film.
According to another embodiment, solid preparation is by extruding preparation.Polymer can feed in extruder in powder form or with the form of solution or dispersion.The dispersion of polymer or solution are by removing dispersant or solvent in an extruder with melt-liquid state and melt cooling being changed into solid form.
Described method is described in greater detail in hereinafter.
Film method is this method: wherein the clear solution of polymer and active component be molded to obtain due to solvent evaporation and the thin film of solidification.It is not obvious that clear solution means the muddiness when normal inspection.The method is particularly useful as method for sieving to measure the load limit of solid dispersion in a straightforward manner.For method for sieving, film is by by the solution of the polymer and active component with respective concentration on a glass and prepared to obtain film by its blade coating by blade.Usually, by the layer thickness of film blade coating to 50-200 μm.Then by gained film, by isolating solvent, therefore drying also solidifies.Preferably, solvent in a vacuum, such as, removes under 1-100hPa.Drying can such as be carried out in vacuum drying oven or suitable vacuum equipment.In addition, the effect removed by temperature of solvent is carried out.
For method for sieving ,-usual 14 days time of specifying under then the film of generation being stored in controlled weather conditions.Weather conditions are 23 DEG C/53% relative humidity.
Then under 40 times of amplifications, film is assessed by microscope.Limpid film is the signal of amorphous system.Muddy film refers to relatively large crystalline portion.
In principle, film can also be prepared in commercial pharmaceutical form.On this point, also use suitable tilting device to be poured into by the solution of polymer and active component on suitable surface and blade coating to required layer thickness or to be applied on roller and dry.
Suitable solvent is all solvents of equally dissolve polymer and hydrophobic active ingredient in principle.
According to another embodiment of the present invention, spraying dry is suitable for preparing solid dispersion.For preparing polymer/mixture of active principles, material being weighed and puts into suitable container.Add the solvent of respective amount and stir the mixture until polymer and active component dissolve completely.
Suitable solvent is such as acetone, dichloromethane, ethanol, propanol, methanol, isopropyl alcohol, dimethyl formamide, ethyl acetate, butanone, oxolane, two
alkane, diethyl ether.
Then by liquid to be dried by atomization, solid can be changed into except desolventizing simultaneously.In principle, atomization can be carried out by nozzle or by rotating disk.Suitable nozzle is mono-material or many materials nozzle, such as two material nozzle.And the hot inert gas that flows through of stream by the droplet drying of dispersion to obtain the solid particle that particle diameter is 5-100 μm.Dry gas used is preferably nitrogen.At the entrance area of spray dryer, dry gas preferably tangentially feeds.Dry product granule can be separated in cyclone or filter.The temperature of dry gas can be 30-150 DEG C.Atomizing pressure can be 0.1-20MPa.Spraying dry also can configure with the form of accumulation spraying dry (such as FSD technology), and it causes the larger aggregation of 100-1000 μm.
According to another embodiment of the present invention, solid dispersion is prepared by screw extruder.What be suitable for extrusion method in principle is conventional extruders type.Preferred use double screw extruder.But the multiple screw extruder had more than two screw rods is also suitable.The extruder being suitable for this object comprises shell, variable speed drive units usually, and the machining cell be made up of the axle extruding arbor or be equipped with screw element, and described screw element thinks modular construction in this case.Conventional screw element is conveying element, kneading disk, spare part or the element with special geometric affecting design parameter.This class component is well known by persons skilled in the art, and it can set up suitable screw rod geometry by several preliminary experiment.On this point, must guarantee that shear load can not become too high.
Usually, also set up free volume relatively large in inlet region advisably, then reduce the raising of proper time.
Each district of extruder is generally can heat or coolable.Temperature adjustment is by the glass transition temperature domination of the mixture of cationic polymer to be extruded, hydrophobic active ingredient and other possibility mixture.Temperature regulates by the internal temperature adjusting cylinder.The decomposition temperature of temperature by component of concrete foundation and the fusing point domination of active component.
For preparing liquid mixture, the mixture of component hydrophobic active ingredient and matrix polymer and optional other adjuvant is heated to the temperature of more than the glass transition temperature of mixture.The glass transition temperature of mixture is determined with the rate of heat addition of 20K/min by DSC.
The temperature in each extruder district can be 30-200 DEG C, preferred 40-180 DEG C, is intended for inner cylinder temperature herein.In the firstth district, selective temperature be low and improve in district subsequently until it fully far above the glass transition temperature of mixture to form uniform melt.Improving uniformity of melt has limpid outward appearance.
Selective temperature feature forms domination by preparaton in particular situations.
Preparaton for extruding can feed in extrusion method in a different manner.Following methods A-E can be used in principle:
If additionally add solvent, then can use and the solvent of the preparation of film about describing.
The liquid mixture of the matrix polymer prepared in an extruder, hydrophobic active ingredient and the optional melt form of other adjuvant can be extruded by one or more nozzle.
Round nozzle used can have the diameter of 0.5-5mm.Also other nozzle form can be used, such as narrow slit type nozzle, if want relatively large material handling capacity especially true.
By the processing of gained cured extrudate bar granulator to obtain granule, described granule can be pulverized (grinding) further to obtain powder again.Can granule or powder be inserted in capsule or use conventional tableting aid to suppress to obtain tablet.On this point, other release control adjuvant can also be used.
In addition, water, organic solvent, buffer material or plasticizer can be used during extruding.Especially, water or volatile alcohol are select herein.The method can make to react under relative low temperature degree.The amount of solvent or plasticizer is generally the 0-30 % by weight that can extrude material.Water or solvent can remove by the ventilation point in extruder or by applying vacuum under standard pressure.As selection, these components leave extruder and Pressure Drop evaporates to during normal pressure at extrudate.When less volatile component, subsequently can be correspondingly dry by extrudate.
When being extruded by nozzle by melt, melt is not preferably containing solvent.This means solvent for being less than 1 % by weight.
In a particular variant of preparation method, be directly that it forms final form of medication by thermoplastic calendering to obtain lamellar compact after extruding.In this change programme, can advisably before extruding or period added other component, such as polymer to adjust glass transition temperature and melt viscosity, disintegrant, solubilizing agent, plasticizer, dyestuff, flavouring agent, sweetener etc.In principle, these materials also can, first being pulverized by extrudate, then be suppressed to use when obtaining tablet.
The amorphous solid dispersion obtained according to the present invention can have the hydrophobic active ingredient load of the gross weight 2-60 % by weight based on solid dispersion.Preferably, the content of hydrophobic active ingredient is 10-50 % by weight, particularly preferably 20-50 % by weight.The cationic base polymer content of diethyl aminoethyl methacrylate and methyl methacrylate can be 5-95 % by weight.In addition, dispersion can comprise other medicines additive.The amount of other additive can be 0.1-60 % by weight based on total preparation.(polymeric matrix at the most 50 % by weight) hydrophilic polymer, can affect the decomposition rate of deenergized period gained extrudate owing to adding.By improving hydrophilic, moistening faster and decomposing faster in release can be realized.For this reason, the hydrophilic polymer with low-molecular-weight (<100000 dalton) is specially suitable.The hydrophilic polymer with higher molecular weight (>100000 dalton) can be considered to the stabilizing agent of gained solid solution, because they improve the rigidity of matrix, and prevents active component crystallization from supersaturated solution.Therefore, the stable supersaturated solid solution with high especially medicament contg can be prepared.
Hydrophilic polymer is at least water miscible within the scope of specific pH.On this point, the water-soluble at least 0.1g that to mean at 20 DEG C is dissolved in 1ml.
Suitable hydrophilic polymer is such as: the polyvinylpyrrolidone with the K value of 12-90, N-nvp copolymer, such as with the copolymer of vinyl esters as vinyl acetate or propionate, particularly weight ratio is the N-vinylpyrrolidone of 60:40 and the copolymer of vinyl acetate, polyvinyl alcohol, hydroxyalkylated celluloses derivant, such as hydroxypropyl cellulose (HPC) or hydroxypropyl emthylcellulose (HPMC), hydroxyalkylation and carboxylation alkylation cellulose derivative, acrylic acid-methacrylic acid copolymer.
The Polyethylene Glycol with the mean molecule quantity of 1000-6000 is also suitable.The suitable graft polymers also having Polyethylene Glycol and polyvinyl alcohol units, as conduct
iR, BASF are commercially available, or the mixture of this kind of graft polymers and polyvinyl alcohol.Suitable also have Polyethylene Glycol and grafting N-caprolactam thereon and the graft copolymer of vinyl acetate unit, such as commercially available
, BASF SE.
For adjusting the glass transition temperature of preparaton, the water-soluble polymer with high glass-transition temperature can be used, such as, there is the polyvinylpyrrolidone of the K value of 17-120, hydroxy alkyl cellulose or hydroxyalkyl starch.The high glass-transition temperature of crossing of preparaton reduces by adding plasticizer.What be suitable for this object in principle is also for all plasticizers of medication coat, such as triethyl citrate, tributyl citrate, acetyltributyl citrate, vinegar essence, propylene glycol, PEG400, dibutyl sebacate, glyceryl monostearate, lauric acid, cetearyl alcohol.This kind of plasticizer can use with the amount of the weight 0.1-20 % by weight based on dispersion.
In addition, also the surfactant reducing melt viscosity and extrusion temperature therefore can be incorporated in preparation.These materials also can have positive impact on possible crystallization, and produce better preparaton moistening and dissolve faster.Suitable material is ion and non-ionic surface active agent, such as Kolliphor
tMhS 15 (Macrogol 15 hydroxy stearic acid ester),
80, polyoxyethylated derivative of fatty acid, such as Kolliphor
tMrH 40 (Polyoxyl 40 castor oil hydrogenated, USP), Kolliphor
tMeL (Polyoxyl 35 Oleum Ricini, USP), poloxamer, docusate sodium or sodium lauryl sulfate.
In addition, can advisably antioxidant be added in solid dispersion with the amount of the gross weight 0.1-10 % by weight based on solid dispersion.According to the present invention, suitable antioxidant is slightly water-soluble antioxidant, and namely its dissolubility in 20 DEG C of water is not more than the antioxidant of 1g/l.
Be suitable for mainly lipophilic substance tocopherol, tocopherol acetas, ascorbyl palmitate, ascorbyl stearate, tertiary butylated hydroquinone, butylhydroxy anisole, tert-butyl hydroxy toluene, gallateoctylester or the lauryl gallate or its combination of making antioxidant herein.
The preparation obtained by these methods be can be used for wherein water-insoluble or slightly water-soluble material in principle and is ready to use in all spectra developing its effect in aqueous compositions or in water-bearing media.
On the invention hereafter in, hydrophobic active ingredient is preferably to be understood that and means bioactive substance, such as, for the active constituents of medicine of humans and animals, cosmetics or agrochemical active ingredient, or health product or dietary active composition.
In addition, suitable solubilisation of hydrophobic active component also has dyestuff, such as inorganic or organic pigment.
According to the present invention, suitable bioactive substance is that fusing point is at all solids active component of copolymer below the decomposition point under extrusion condition in principle.Copolymer can be extruded usually at the temperature of 200 DEG C at the most.Lowest temperature is often planted and is formed domination by mixture to be extruded and microsolubility material to be processed in situation.
Active component can from any appointed area.
The example herein can mentioned is benzene phenodiazine
, antihypertensive, vitamin, cytostatics-particularly taxol, anesthetis, neuroleptic drug, antidepressants, antiviral agents is as Anti-HIV agents, antibiotic, antifungal agent, anti-senile dementia medicine, antifungal, chemotherapeutic drug, urology department medicine, platelet aggregation inhibitor, sulfonamides, spasmolytic, hormone, immunoglobulin, serum, thyroid curative, psychopharmaceutical, parkinson disease medication and other anti-hyperkinesis medicine, ophthalmic medicine, neuropathy preparation, Calcium Metabolism Regulation agent, muscle relaxant, anesthetics, lipid lowering agent, Remed for hepatopathy, crown (coronary) medicament, cardiac tonic, immunotherapy medicine, regulate peptide and inhibitor thereof, sleeping pill, tranquilizer, gynecological drug, gout therapertics, fibrinolysis, enzyme preparation and transport protein, enzyme inhibitor, emetic, blood flow ameliorant, diuretic, diagnostic agent, adrenocorticosteroid, cholinergic agent, bile duct curative, antiasthmatics, bronchus medicine (broncholytics), receptor blocking agent, calcium antagonists, ACE inhibitor, arteriosclerosis medicine, antibiotic medicine, anticoagulation, antihypertensive, antihypoglycemic, anti-height oozes medicine, antifibrinolytics, antuepileptic, Bendectin, antidote, antidiabetic drug, antiarrhythmics, anti-anemic drug, antiallergic agent, anthelmintic, analgesic, beta stimulant, aldosterone antagonists, fat-reducing auxiliary agent.
In said medicine preparation, be particularly preferably those of oral administration preparaton.For preparing pharmaceutical administration form as tablet, extrudate can be mixed with conventional medicine adjuvant.
These are the material from following classification: filler, plasticizer, chaotropic agent, binding agent, silicate and disintegrant and absorbent, lubricant, fluidizer, dyestuff, stabilizing agent as antioxidant, wetting agent, antiseptic, releasing agent, spice or sweeting agent, preferred filler, plasticizer and chaotropic agent.
The filler that can add is such as inorganic filler as the oxide of magnesium, aluminum, silicon, titanium carbonate or calcium carbonate, calcium phosphate or magnesium phosphate, or organic filler is as lactose, sucrose, Sorbitol, mannitol.
Suitable plasticizer is such as vinegar essence, triethyl citrate, glyceryl monostearate, low molecular poly or poloxamer.
Other suitable chaotropic agent is the interface active agent with HLB (hydrophile-lipophile balance) value being greater than 11, such as, use the castor oil hydrogenated (Kolliphor of 40 ethylene oxide unit ethoxylations
tMrH40), with the Oleum Ricini (Kolliphor of 35 ethylene oxide unit ethoxylations
tMeL), polysorbate 80, poloxamer or sodium lauryl sulfate.
Spendable lubricant is the stearate of aluminum, calcium, magnesium and stannum, and magnesium silicate, polysiloxanes etc.
Spendable fluidizer is such as Talcum or colloidal silica.
Suitable binding agent is such as microcrystalline Cellulose.
Disintegrant can be crospolyvinylpyrrolidone or crosslinked carboxymethyl fecula sodium.Stabilizing agent can be ascorbic acid or tocopherol.
Dyestuff is such as iron oxides, titanium dioxide, triphenhlmethane dye, azo dye, quinoline dye, indigo dye, carotenoid, so that form of medication is dyeed, opacifier as titanium dioxide or Talcum, to improve the transparency of light and to save dyestuff.
Except the application in cosmetics and medicine, preparation prepared in accordance with the present invention is also applicable to field of food, and such as slightly water-soluble or water-insoluble nutrient, adjuvant or additive are incorporated to as fatsoluble vitamin or carotenoid.The example that can mention is with the painted beverage of carotenoid.
The preparaton comprising pesticide, herbicide, antifungal or insecticide can be especially comprised, main those preparations also having the crop production compositions used as spraying or the preparaton that waters according to the use of preparation in agrochemicals that the present invention obtains.
By the inventive method, the so-called solid solution with microsolubility material can be obtained.According to the present invention, solid solution is the term of the system being used in reference to the crystalline portion wherein not observing microsolubility material.
Embodiment
According to the present invention, matrix used polymer is prepared by the embodiment 1 being similar to WO 2009/016258, is the polymer that the methyl methacrylate of 55:45 and diethyl aminoethyl methacrylate obtain by weight ratio, its conduct
smartseal 30D is commercially available with the form of aqueous dispersion.Diethyl aminoethyl methacrylate: methyl methacrylate mol ratio 3:7; Tg:63 DEG C (being measured with the rate of heat addition of 20 ° of K/min by DSC); Weight average (be 200000 dalton by SEC determination of light scattering).
Polymer uses as freeze-dried powder or as spray-dried powders.
In certain embodiments, polymer also uses with the form of part neutralization: part degree of neutralization 6 moles: 6 % by mole of basic group adipic acid parts neutralize
Part degree of neutralization 8 moles: 8 % by mole of basic group succinic acid moiety neutralize.
For what contrast
the base copolymer of the acrylate of EPO to be mol ratio be 2:1:1, butyl acrylate and methyl methacrylate.
method 1: film method
general procedure
For preparing polymer/mixture of active principles, material being weighed with respective amount and puts into 50ml XiLin (penicillin) bottle.
| Concentration [% by weight] | Polymer [g] | Active component [g] | Solvent [g] |
| Blank | 2.00 | - | 18.00 |
| 5 | 2.00 | 0.11 | 17.89 |
| 10 | 2.00 | 0.22 | 17.78 |
| 15 | 2.00 | 0.35 | 17.65 |
| 20 | 2.00 | 0.50 | 17.50 |
| 25 | 2.00 | 0.67 | 17.33 |
| 30 | 2.00 | 0.86 | 17.14 |
| 35 | 2.00 | 1.08 | 16.92 |
| 40 | 2.00 | 1.34 | 16.66 |
| 45 | 2.00 | 1.63 | 16.37 |
| 50 | 2.00 | 2.00 | 16.00 |
All mixture are stirred on magnetic stirring apparatus 24 hours until component dissolves.After visually rank solution (clear solution), use 120 μm of blades by separated from solvent on a glass.By gained film in fume hood under the room temperature of 22+/-2 DEG C dry 0.5 hour, then in vacuum drying oven under 50 DEG C and 1MPa 0.5 hour.The load limit by active component in microscopic analysis visually rank polymer after 7 days is stored under 23 DEG C/54% relative humidity.Limpid film (not having active component crystal) represents molecular disperse solution, and muddy film (having active component crystal) represents crystallizing system.
method 2: spraying dry
general procedure
For preparing polymer/mixture of active principles, material being weighed and puts into suitable storage capsule.Add the solvent of respective amount and stir the mixture until polymer and active component dissolve completely.For fenofibrate (fenofibrate) preparaton, solvent is acetone, and for itraconazole (itraconazole) preparaton, solvent is dichloromethane, for the preparaton with naproxen (naproxen), acetone is used as solvent.For all experiments, the solids content of spray solution is 20 % by weight.Spraying dry carries out with laboratory scale.
Purposes to be dried is used two material nozzle atomization.The hot gas of concurrent flow (being herein nitrogen) by the droplet drying of distribution to obtain the solid particle that particle diameter is 5-20 μm.In the inlet area of spray dryer, dry gas tangentially feeds.Isolate dry product granule in the cyclone.
method 3: extrude
general procedure
For the preparation of the double screw extruder of preparaton described in following examples, there is the screw diameter of 16mm and the length of 40D.Extruder can be made up of the thermal treatment zone 10 of comprising nozzle.Select screw-rod structure to make in district 5 and 7, use kneading member, other uses conveying element.Also nozzle (district 10) is heated.
Listed by after a while, extrude embodiment, technological parameter used is described.Described district temperature is the internal temperature of cylinder.
The sign of products therefrom
the sign visually rank of solid dispersion, XRD (X-ray diffraction) and DSC (differential scanning amount
full-boiled process) carry out.
When the solid solution that visually rank is stable, do not demonstrate amorphous component.Visually rank can carry out with 40 times of enlargement ratios with the optical microscope or do not have with polarizing filter.
Following equipment and condition is used to study degree of crystallinity and/or the amorphism (amorphicity) of the solid solution prepared by extrusion method and spraying dry by XRD or DSC:
XRD
Instrument: the D 8Advance diffractometer (Bruker/AXS) with 9 times of sample changers
Measuring method: θ-θ reflects geometry
2 θ angle range: 2-40 °
Walk wide: 0.02 °
The Measuring Time of every stepping angle: 2.4 seconds
Divergent slit: there is 1.0mm patchhole
mirror
Antiscatter slits: Suo Le slit
Detector: Sol-X detector
Temperature: room temperature
Generator is arranged: 40kV/50mA
DSC
Instrument: Q2000 (TA Instruments, the U.S.)
Dry: by sample dried overnight at 40 DEG C under vacuo, to weigh subsequently and put into 20 bar pressure close crucibles.
The rate of heat addition: 20K/min
solid solution is characterized by active component release
Manually or the solid solution prepared from extrusion method and spraying dry of semi-automatic active component releasing research:
from manual active component release (method 1) of itraconazole (itraconazole) extrudate
Active component release is according to USP equipment (paddle method) 2,700ml 0.08N HCl, and 37 DEG C, 50rpm (BTWS 600, Pharmatest) carries out.Use granulator extrudate bar size to be decreased to the length of 3mm, and feed release in this manner.In often kind of situation, often discharge container and use 100mg active component (non-sink conditions).At the appointed time and by after 10 μm of metre filter, manually detected the active component discharged by UV-VIS spectrum (Agilent 8453UV-VIS spectrometer, Agilent).
active component from itraconazole (itraconazole) extrudate discharges (method 2)
Active component is released according to USP equipment (paddle method) 2,700ml 0.08N HCl, 37 DEG C, and 75rpm (BTWS 600, Pharmatest) carries out.Use granulator extrudate bar size to be decreased to the length of 3mm, and feed release in this manner.In often kind of situation, often discharge container and use 100mg active component (non-sink conditions).At the appointed time and by after 45 μm of metre filter, semi-automatically detected the active component discharged by UV-VIS spectrum (Agilent 8453UV-VIS spectrometer, Agilent).
active component from danazol (danazol) extrudate discharges (method 3)
Active component release has 0.1% according to USP equipment (paddle method) 2,700ml
the 0.08N HCl of 80,37 DEG C, 100rpm (BTWS 600, Pharmatest) carries out.Granulator is used extrudate bar size to be decreased to the length of 3mm.The extrudate bar reduced is used MF 10basic mill (sieve: 0.5mm, IKA Werke) pulverize and feed release in this manner.In often kind of situation, often discharge container and use 100mg active component (non-sink conditions).At the appointed time and by after 45 μm of metre filter, semi-automatically detected the active component discharged by UV-VIS spectrum (Agilent 8453UV-VIS spectrometer, Agilent).
active component from Spray dried products discharges (method 4)
Active component release is according to USP equipment (paddle method) 2,700ml 0.08N HCl, and 37 DEG C, 75rpm (BTWS 600, Pharmatest) carries out.Gelatine capsule (size: also feed release in this manner 0) will be poured into by spray-dired product.For preventing capsule floating, platinum filament is used to make them bear a heavy burden.In often kind of situation, often discharge container and use 100mg active component (non-sink conditions).At the appointed time and by after 45 μm of metre filter, semi-automatically detected the active component discharged by UV-VIS spectrum (Agilent 8453UV-VIS spectrometer, Agilent).
Embodiment 1
Contrast has different activities composition
smartseal and part neutralization
smartseal with
the load capacity of EPO.The concentration herein provided in film refers to the load capacity of the active component that molecular dispersion dissolves, and does not namely still observe active component crystal in film.Higher load causes crystalline portion.
DMF dimethyl formamide
Cl
2cH
2dichloromethane
smartseal and
smartseal (part neutralization) ratio
solubilize active ingredients is obviously become solid solution by EPO better.
Embodiment 2
By 2925g's
smartseal (lyophilizing) and 75g butylated hydroxytoluene are weighed and are put into Turbula mixer and mix 10 minutes at Turbula blender T10B.Gravity dosage device DDW-MD2-DDSR20-10 (Brabender Technologie) is used to be added by this mixture dosage in extruder and to use gravity feeding unit Mini Twin MT1 (Brabender Technolgie) to add active component fenofibrate (fenofibrate).
The double screw extruder with the screw diameter of 16mm and the length of 40D is used to be extruded by mixture in following condition:
District's temperature first cylinder: 45 DEG C; Second cylinder: 85 DEG C
District's temperature of the 3rd cylinder: 150 DEG C
Screw speed 50rpm
Handling capacity: 500g/h
Nozzle diameter 3mm
Had the preparation of the mass content of 34% (w/w) fenofibrate (fenofibrate) by XRD research, discovery is unbodied.
Embodiment 3
By 2925g's
smartseal (lyophilizing) and 75g butylated hydroxytoluene are weighed and are put into Turbula mixer and mix 10 minutes at Turbula blender T10B.Gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) is used to be added in extruder by this mixture dosage.By 250g's
smartseal mixture (has butylated hydroxytoluene
smartseal) and 250g itraconazole (itraconazole) weigh put into Turbula mixer and Turbula blender T2C mix 10 minutes.This mixture of active principles is counted in extruder by the second gravity feeding system Mini Twin MT1 (Brabender Technologie) dosage.
The double screw extruder with the screw diameter of 16mm and the length of 40D is used to be extruded by mixture in following condition:
District's temperature first cylinder: 50 DEG C; Second cylinder: 100 DEG C
3rd cylinder is to district's temperature of cylinder 10: 160 DEG C
Screw speed 50rpm
Handling capacity: 400g/h
Nozzle diameter 3mm
Study solid solution with XRD and find that 38% itraconazole (itraconazole) is for unbodied at the most.In 0.08N HCl, discharging (method 1) from the active component of extrudate is after 2 hours 89% (Fig. 1).
Fig. 1: in 0.08N HCl itraconazole (itraconazole) from
discharge with 50rpm active component in Smartseal extrudate.
Embodiment 4
By each polymer of respective amount (
smartseal, 8 moles of part neutralizations
smartseal,
ePO) and corresponding active component carbamazepine (carbamazepine) weigh and put into Turbula mixer (total amount of polymer+active component is 400g under often planting situation) and mix 10 minutes at Turbula blender T2C.Gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) is used to be added in extruder by this mixture dosage.
The double screw extruder with the screw diameter of 16mm and the length of 40D is used to be extruded by mixture in following condition:
District's temperature first cylinder: 40 DEG C; Second cylinder: 80 DEG C
3rd cylinder is to district's temperature of cylinder 10: 160 DEG C
Screw speed 200rpm
Handling capacity: 1000g/h
Nozzle diameter 3mm
Use the preparation prepared by dsc analysis, about the amorphous and crystalline active ingredient in preparaton.
The amorphous preparaton of A (not there is active component crystal)
K crystallization preparaton (there is active component crystal)
From extruding the Comparative result with the solid solution (amorphous preparaton) with carbamazepine (carbamazepine) from film method.
With
the load capacity of EPO is compared,
smartseal and 8 mole of part neutralization
smartseal demonstrates and is extruding and higher carbamazepine (carbamazepine) load in film method.
Embodiment 5
By the particular polymers of respective amount (
smartseal, 6 moles of part neutralizations
smartseal,
ePO) and corresponding active component itraconazole (itraconazole) weigh and put into Turbula mixer (total amount of polymer+active component is 400g under often planting situation) and mix 10 minutes at Turbula blender T2C.Gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) is used to be added in extruder by this mixture dosage.
The double screw extruder with the screw diameter of 16mm and the length of 40D is used to be extruded by mixture in following condition:
District's temperature first cylinder: 50 DEG C; Second cylinder: 90 DEG C
3rd cylinder is to district's temperature of cylinder 9: 160 DEG C
District's temperature control 10 cylinder: 150 DEG C
Screw speed 200rpm
Handling capacity: 1000g/h
Nozzle diameter 3mm
Preparaton prepared by visually rank is also assessed according to amorphous (the limpid extrudate) in preparaton (muddy beginning) and crystalline active ingredient.
The amorphous preparaton of A (not there is active component crystal)
K crystallization preparaton (there is active component crystal)
From extruding the Comparative result with the solid solution (amorphous preparaton) with itraconazole (itraconazole) from film method.
With
the load capacity of EPO is compared,
smartseal and 6 mole of part neutralization
smartseal demonstrates and is extruding and higher itraconazole (itraconazole) load in film method.
In 0.08N HCl, itraconazole (itraconazole) (30+45%w/w) is from having
the neutralization of Smartseal, 30% (w/w) 6 moles part
smartseal and there is 25,30,35% (w/w) itraconazole (itraconazole)
release (method 2) in the extrudate of EPO to demonstrate at 1.5 hours later fast and active component release completely.
Embodiment 6
By each polymer of respective amount (
smartseal,
ePO) and corresponding active component danazol (danazol) weigh and put into Turbula mixer (total amount of polymer+active component is 400g under often planting situation) and mix 10 minutes at Turbula blender T2C.Gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) is used to be added in extruder by this mixture dosage.
The double screw extruder with the screw diameter of 16mm and the length of 40D is used to be extruded by mixture in following condition:
District's temperature first cylinder: 40 DEG C; Second cylinder: 80 DEG C
3rd cylinder is to district's temperature of cylinder 10: 180 DEG C
Screw speed 200rpm
Handling capacity: 1000g/h
Nozzle diameter 3mm
Use XRD analysis preparation, about the amorphous and crystalline active ingredient in preparaton.
The amorphous preparaton of A (not there is active component crystal)
K crystallization preparaton (there is active component crystal)
Have 0.1%
in the 0.08N HCl of 80,25% (w/w) danazol (danazol) is from having
smartseal and
the release (method 3) ground in extrudate of EPO is shown in Fig. 2.The recrystallize of danazol (danazol) exists
beginning from 5 minutes when EPO extrudate,
started from 14 minutes when Smartseal extrudate and therefore can extend 9 minutes.The maximum activity composition of danazol (danazol) is released in this preparaton and also can be increased to 40%.Area larger under presenting the release profiles of Kollicoat Smartseal causes larger bioavailability.
Release profiles is shown in Fig. 2: have 0.1%
in the 0.08N HCl of 80, danazol (danazol) from
smartseal and
discharge with 100rpm in EPO extrudate (pulverizing).
Embodiment 7
There is different activities composition in spraying dry
the load capacity of Smartseal.Spray drying experiment carries out with laboratory scale.
1. itraconazole: there is 40+50% (w/w) itraconazole (itraconazole)
smartseal
2. fenofibrate: there is 40+50% (w/w) fenofibrate (fenofibrate)
smartseal
3. naproxen: there is 40+50% (w/w) naproxen (naproxen)
smartseal
Experiment condition:
| Technological parameter | Itraconazole | Fenofibrate | Naproxen |
| Nozzle | 1.2mm | 1.2mm | 1.2mm |
| Nozzle exit pressure | 0.3 absolute MPa | 0.3 absolute MPa | 0.3 absolute MPa |
| Orifice gas temperature | Room temperature | Room temperature | Room temperature |
| Entering air temperature | 50℃ | 50℃ | 50℃ |
| Outlet air temperature | 38℃ | 36℃ | 36℃ |
Compared with the result from film method, in spraying dry,
the active component itraconazole (itraconazole) of high concentration, fenofibrate (fenofibrate) and naproxen (naproxen) are dissolved into solid solution by Smartseal.
In 0.08 N HCl, itraconazole (itraconazole) (40+50%w/w) from
release (method 4) in Smartseal (spraying dry) demonstrate active component after 2 hours fast and discharge (Fig. 3) completely.
The active component release of itraconazole (itraconazole) is shown in Fig. 3: in 0.08N HCl, itraconazole (itraconazole) is from preparing with spray drying process
discharge with 75rpm in Smartseal.
Claims (16)
1. hydrophobic active ingredient and monomer weight ratio are the solid dispersion of the DEAEMA of 35:65-55:45 and the cation copolymer of methyl methacrylate.
2. solid dispersion according to claim 1, it comprises monomer weight ratio is the DEAEMA of 45:55 and the cation copolymer of methyl methacrylate.
3., according to the solid dispersion of claim 1 or 2, it comprises 10-50 % by weight hydrophobic active ingredient.
4. solid dispersion as claimed in one of claims 1-3, it comprises 20-50 % by weight hydrophobic active ingredient.
5. solid dispersion as claimed in one of claims 1-4, it comprises other medicines additive.
6. solid dispersion as claimed in one of claims 1-5, it comprises plasticizer.
7. solid dispersion as claimed in one of claims 1-6, it comprises antioxidant.
8. preparation hydrophobic active ingredient as claimed in one of claims 1-7 and monomer weight ratio are the methacrylic acid N of 35:65-55:45, the method of the solid dispersion of the cation copolymer of N-diethylamino ethyl ester and methyl methacrylate, wherein preparation comprises the liquid mixture of hydrophobic active ingredient and cation copolymer and liquid mixture is changed into solid form.
9. method according to claim 8, wherein liquid mixture exists with the form of solution or melt.
10. method according to claim 8, wherein liquid mixture is undertaken to the conversion of solid form by spraying dry.
11. methods according to claim 8, wherein liquid mixture is prepared under heating in screw extruder, and passes through cooling curing after extruding.
12. methods according to claim 8, wherein change into solid form by being molded liquid mixture to obtain film and to be solidified and carry out.
13. methods according to Claim 8 any one of-12, wherein cation copolymer uses with the form of part neutralization.
14. methods according to Claim 8 any one of-13, wherein cation copolymer part used is neutralized to based on cation group 2-15 % by mole.
15. methods according to Claim 8 any one of-13, wherein by cation copolymer C used
3-C
10dicarboxylic acid moiety neutralizes.
16. solid dispersion any one of claim 1-15 are as the purposes of medicine, cosmetics, agrochemical formulations, diet formulation or health-care preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12173172 | 2012-06-22 | ||
| EP12173172.3 | 2012-06-22 | ||
| PCT/EP2013/061972 WO2013189776A1 (en) | 2012-06-22 | 2013-06-11 | Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104379174A true CN104379174A (en) | 2015-02-25 |
| CN104379174B CN104379174B (en) | 2018-01-26 |
Family
ID=48669889
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380032615.6A Active CN104379174B (en) | 2012-06-22 | 2013-06-11 | Dispersion containing active ingredient solids based on diethyl aminoethyl methacrylate copolymer |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2863953A1 (en) |
| JP (1) | JP6189429B2 (en) |
| CN (1) | CN104379174B (en) |
| WO (1) | WO2013189776A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115052586A (en) * | 2020-02-07 | 2022-09-13 | 拜耳公司 | Pharmaceutical composition comprising regorafenib and a stabilizer |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015145459A1 (en) * | 2014-03-26 | 2015-10-01 | Sun Pharma Advanced Research Company Ltd. | Abuse deterrent immediate release coated reservoir solid dosage form |
| BR122022001868B1 (en) | 2015-12-10 | 2022-09-13 | Adama Makhteshim Ltd. | AGRICULTURAL MATERIAL COMPOSITION, PEST PREVENTION AND CONTROL AND PLANT GROWTH IMPROVEMENT METHOD, AGRICULTURAL MATERIAL COMPOSITION PREPARATION PROCESS AND USE OF A BLOCK COPOLYMER |
| EP3668484B1 (en) * | 2017-08-17 | 2022-07-13 | F. Hoffmann-La Roche AG | Novel pharmaceutical compositions for basic or neutral, low molecular weight compounds |
| WO2019063478A1 (en) * | 2017-09-26 | 2019-04-04 | Capsugel Belgium Nv | Submicron particle formulations |
| AR114185A1 (en) | 2018-01-23 | 2020-07-29 | Adama Makhteshim Ltd | SYNTHESIS OF 5-CHLORINE-2 - [(3,4,4-TRIFLUORO-3-BUTEN-1-IL) THIO] -THAZOLE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460148A (en) * | 2006-04-10 | 2009-06-17 | 鲁汶天主教大学研究开发部 | Solid dispersion of poorly soluble drugs in graft copolymers |
| CN102119021A (en) * | 2008-08-08 | 2011-07-06 | 拜耳先灵医药股份有限公司 | Progestin-containing drug delivery system |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19918435A1 (en) | 1998-07-23 | 2000-01-27 | Roehm Gmbh | Coating or binding agent for medicaments, prepared using finely divided acrylic copolymer powder, used e.g. for taste-masking coatings or in transdermal delivery systems |
| KR100510356B1 (en) | 2001-02-27 | 2005-08-24 | 룀 게엠베하 운트 콤파니 카게 | Pharmaceutical formulations comprising a coating and binding agent with improved storage stability and process for the preparation thereof |
| DE10239999A1 (en) | 2002-08-27 | 2004-03-04 | Röhm GmbH & Co. KG | Granules or powders for the preparation of coating and binding agents for dosage forms |
| CN101778870B (en) | 2007-08-02 | 2012-11-07 | 巴斯夫欧洲公司 | Aqueous polymer dispersion based on n,n-diethylaminoethyl methacrylate, its preparation and use |
| JP2013536821A (en) * | 2010-09-07 | 2013-09-26 | ビーエーエスエフ ソシエタス・ヨーロピア | Use of copolymers based on amino-containing polymers as matrix binders in the preparation of active compound-containing granules and dosage forms |
-
2013
- 2013-06-11 JP JP2015517670A patent/JP6189429B2/en active Active
- 2013-06-11 CN CN201380032615.6A patent/CN104379174B/en active Active
- 2013-06-11 WO PCT/EP2013/061972 patent/WO2013189776A1/en active Application Filing
- 2013-06-11 EP EP13730156.0A patent/EP2863953A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460148A (en) * | 2006-04-10 | 2009-06-17 | 鲁汶天主教大学研究开发部 | Solid dispersion of poorly soluble drugs in graft copolymers |
| CN102119021A (en) * | 2008-08-08 | 2011-07-06 | 拜耳先灵医药股份有限公司 | Progestin-containing drug delivery system |
Non-Patent Citations (1)
| Title |
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| KAREL SIX，ET AL.: "Increased physical stability and improved dissolution properties of itraconazole,a class II drug,by solid dispersions that combine fast- and slow-dissolving polymers", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115052586A (en) * | 2020-02-07 | 2022-09-13 | 拜耳公司 | Pharmaceutical composition comprising regorafenib and a stabilizer |
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| Publication number | Publication date |
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| JP2015523356A (en) | 2015-08-13 |
| EP2863953A1 (en) | 2015-04-29 |
| JP6189429B2 (en) | 2017-08-30 |
| CN104379174B (en) | 2018-01-26 |
| WO2013189776A1 (en) | 2013-12-27 |
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