CN104379174B - Dispersion containing active ingredient solids based on diethyl aminoethyl methacrylate copolymer - Google Patents

Dispersion containing active ingredient solids based on diethyl aminoethyl methacrylate copolymer Download PDF

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CN104379174B
CN104379174B CN201380032615.6A CN201380032615A CN104379174B CN 104379174 B CN104379174 B CN 104379174B CN 201380032615 A CN201380032615 A CN 201380032615A CN 104379174 B CN104379174 B CN 104379174B
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acid
solid dispersions
solid
active ingredient
liquid mixture
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CN104379174A (en
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K·科尔特
M·安格尔
M·卡尔
S·格伯特
M·K·米勒
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BASF SE
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BASF SE
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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
    • 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 
    • 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
    • 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
    • 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

It is 35 the invention discloses hydrophobic active ingredient and monomer weight ratio:65‑55:The solid dispersions of 45 methacrylic acid N, N diethylamino ethyl ester and the cation copolymer of methyl methacrylate.

Description

Based on diethyl aminoethyl methacrylate copolymer containing active ingredient solids point Granular media
The present invention relates to the solid dispersions of the hydrophobic active ingredient for pharmaceutical dosage form, and it is based on monomer weight ratio 35:65-55:45 methacrylic acid N, N- diethylamino ethyl ester and the cation copolymer of methyl methacrylate.This hair The preparation and use of the bright this kind of solid dispersions further to for pharmaceutical dosage form.
WO 00/05307, WO 02/067906 and WO 2004/019918 describe cation acrylic aminoalkyl ester Copolymer and its purposes as coating and adhesive.
WO 2009/016258 discloses the sun for being based on methacrylic acid N, N- diethylamino ethyl ester as used in the present invention The preparation of the aqueous polymer dispersion of ionomer and its purposes in coated medicament.
Term " solid dispersions " description wherein active component is embedded in the body in polymeric matrix in the form of differential dissipates farmland System.This kind of system is true solid dispersions in the sense that dispersed phase and continuous phase are solid phase.
In addition, term " solid dispersions " also includes so-called " solid solution ", wherein active component is to be embedded in solid polymerization Molecule discrete form in thing phase (matrix) is present.This kind of solid solution is for example in the solid drugs performance with microsolubility active component Form using when cause improved active component to discharge.The important requirement of this kind of solid solution be they be it is stable, i.e., it is active into Dividing to crystallize out, and be also such when long-term storage.In addition, the capacity of solid solution, in other words, forms to have and to the greatest extent may be used The ability of the stable solid solution of energy most highly active component content is also important.
So-called " solid dispersions " improve medicine solubility and bioavailability in purposes and its pass through dissolving side Method or melt extrusion prepare it is commonly known, therefore for example by " Ch.Leuner, J.Dressman, European Journal It is known in of Pharmaceutics and Biopharmaceutics50 (2000) 47-60 ".Cation amino acrylate Such asE use is also described in the bibliography in general manner.
However it has been found that also serve asE PO listingsStability of the E in solid dispersions Still have much room for improvement with the load capacity aspect of active component.Generally, under higher active component load, it is brilliant to produce active component Body or relatively large active component farmland.
However, highest load capacity is critically important as far as possible.
It is therefore an object of the present invention to the hydrophobic active ingredient without these shortcomings is prepared in cationic polymer Solid dispersions.
Thus, it is found that hydrophobic active ingredient and monomer weight ratio are 35:65-55:45 methacrylic acid N, N- diethyl The solid dispersions of the cation copolymer of base amino ethyl ester and methyl methacrylate.
It moreover has been found that preparing the dispersion containing active ingredient solids of hydrophobic active ingredient, it, which is included, passes through monomer weight Than for 35:65-55:45 methacrylic acid N, N- diethylamino ethyl ester and methyl methacrylate radical polymerization and obtain Cation copolymer as matrix polymer, wherein the liquid of matrix polymer and at least one hydrophobic active ingredient is mixed Compound changes into solid.
Liquid mixture can be used as solution or melt to exist.Liquid mixture is homogeneous mixture.
Preferable matrix polymer is that monomer weight ratio is 45:55 methacrylic acid N, N- diethylamino ethyl ester and first The copolymer of base methyl acrylate.
Cationic base polymer can be obtained by free-radical emulsion polymerization.Methyl is based on being prepared by emulsion polymerization The matrix polymer of acrylic acid N, N- diethylamino ethyl ester, the clearly disclosure with reference to WO 2009/016258.
It is preferably used as the copolymer conduct of matrix polymerSmartseal 30D, BASF SE are with moisture The form of granular media is commercially available.Mean molecule quantity (weight is equal) is 200000 dalton.Molecular weight can pass through determination of light scattering.
Cationic base polymer can also be used in the form of partly neutralizing.Therefore, 0.1-30, preferably 2-20 moles of %'s Basic group can use suitable acid moieties to neutralize.Therefore, all inorganic or organic acids being physiologically resistant to very well are suitable.
Suitable inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid.Suitably there are monocarboxylic acid, such as acetic acid, formic acid, propionic acid, first It is alkyl sulfonic acid, ethane sulfonic acid, benzoic acid, salicylic acid, gentianic acid, hydroxyacetic acid, lactic acid, caproic acid, octanoic acid, capric acid, ascorbic acid, different Ascorbic acid, nicotinic acid, 2- hydroxyethanesulfonic acids, dichloroacetic acid, pyroglutamic acid, cinnamic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, camphor Sulfonic acid, gluconic acid, glucuronic acid, hippuric acid, lactobionic acid, mandelic acid, naphthalene sulfonic acids, oleic acid, orotic acid, or tricarboxylic acids such as lemon Acid.
It is particularly suitable to the dicarboxylic acids with the chain length of 3-10 carbon atom.Suitable dicarboxylic acids mainly has end The non-branching dicarboxylic acids of acidic group.Suitable dicarboxylic acids also has those substituted by one or two hydroxyl.
According to the present invention it is preferred to use with the first pK more than 2aValue and the 2nd pK more than 4aThe dicarboxylic acids of value is with portion Divide and neutralize.Particularly preferably using with the first pK more than 2.5aValue and the 2nd pK more than 5aThe dicarboxylic acids of value.pKaIt is worth for acid The negative log of constant10。
In addition to acidic group, without other substituents suitable dicarboxylic acids for saturation alkane dicarboxylic acid, malonic acid, butanedioic acid, Glutaric acid, adipic acid or decanedioic acid.The suitable alkane dicarboxylic acid substituted by one or two hydroxyl is malic acid (2- hydroxysuccinimidyls Acid) or tartaric acid (2,3- dihydroxysuccinic acids).Suitable unsaturated dicarboxylic particularly fumaric acid.
The mixture of this kind of dicarboxylic acids can also be used.
For example, the dicarboxylic acids of particularly preferred coating resistance can will be advisably produced with producing particularly preferred powder redispersibility Those acid mixing.Suitable mixture is such as adipic acid and sulfuric acid or butanedioic acid and oxalic acid.
In the context of the invention, part, which neutralizes, means 2-25, and preferably 4-16 moles % diethylamino ethyl is with salt Form exist.
Particularly preferably use dicarboxylic acids, such as adipic acid or butanedioic acid.
According to the present invention, term " hydrophobic active ingredient " means that active component has and is less than 0.25% in 20 DEG C of water (m/m), preferably smaller than 0.1%, particularly preferably less than 0.01% solubility.
The solid dispersions obtained by the inventive method exist with amorphous form." amorphous " means lyophobic dust Gross weight of the crystalline portion based on solid dispersions be less than 5 weight %.
Can be by XRD (X-ray diffraction) and DSC (differential scanning calorimetry) according to the solid dispersions that the present invention obtains Research amorphism or crystallinity are not present.The amorphous state is also referred to as X ray amorphous state.Carried out it is preferred that assessing with XRD.
Using DSC, can also study with the presence or absence of crystalline portion.Crystalline portion can be identified by sharp fusing point.DSC researchs are excellent Choosing is carried out with the 20K/min rate of heat addition.
For screening, crystalline portion can also be carried out by optical microscopy.Suitable optical for the purpose is micro- Mirror has 167 linear right/mm resolution ratio, this minimum distinguishable object structures equivalent to 3 μm.
According to the present invention, gained solid may depend on embodiment and be deposited in solid form as film or particle or powder .
It is in principle film method, spray drying and melt extrusion method, wherein solid point suitable for prepare solid dispersions Granular media is changed into by conversion comprising hydrophobicity acid composition and the solution of matrix polymer or the liquid mixture of melt form Solid form.
According to an embodiment, all the components of preparation are dissolved in suitable solvent each other first, then removed molten Agent.This can be carried out by the drying means of all suitable types, such as spray drying, film method (evaporation of solvent), fluid bed Dry, using supercritical gas drying, freeze-drying.Also can process solutions to obtain film.
According to another embodiment, solid pharmaceutical preparation is prepared by extruding.Polymer can be in powder form or with solution Or the form of dispersion is fed in extruder.The dispersion or solution of polymer can by by dispersant or solvent with melt-liquid State removes and melt cooling is changed into solid form in an extruder.
Methods described is described in greater detail in hereinafter.
Film method is this method：Wherein the clear solution of polymer and active component is moulded to obtain because solvent steams The film sent out and solidified.Clear solution means the muddiness unobvious in normal inspection.This method particularly useful as method for sieving with Just the load limit of solid dispersions is determined in a straightforward manner.For method for sieving, film can be by by with respective concentration It on a glass and is scratched and prepared with obtaining film by the solution of polymer and active component by blade.Generally, by film Scratch to 50-200 μm of thickness degree.Then gained film is dried and therefore solidified by isolating solvent.It is preferred that solvent exists In vacuum, such as removed under 1-100hPa.Drying can be carried out for example in vacuum drying chamber or suitable vacuum plant.Separately Outside, the removing of solvent can be carried out by the effect of temperature.
For method for sieving, then caused film is stored in time for being specified under controllable weather conditions-usual 14 days. Weather conditions are 23 DEG C/53% relative humidity.
Then film can be assessed under 40 times of multiplication factors by microscope.Limpid film is the signal of amorphous system.It is muddy Turbid film refers to relatively large crystalline portion.
In principle, film can also be prepared in commercial pharmaceutical form.On this point, also using suitable tilting device The solution of polymer and active component is poured on suitable surface and is scratched to required thickness degree or is applied on roller and does It is dry.
Suitable solvent is essentially all solvents for equally dissolving polymer and hydrophobic active ingredient.
According to another embodiment of the present invention, spray drying is suitable to prepare solid dispersions.To prepare polymer/activity Constituents mixt, material is weighed and is put into suitable container.Add the solvent of respective amount and stir mixture until polymer It is completely dissolved with active component.
Suitable solvent is such as acetone, dichloromethane, ethanol, propyl alcohol, methanol, isopropanol, dimethylformamide, acetic acid Ethyl ester, MEK, tetrahydrofuran, twoAlkane, diethyl ether.
Then can be by liquid to be dried by atomization, while remove solvent and change into solid.In principle, atomization can borrow Help nozzle or carried out by rotating disk.Suitable nozzle is mono-material or more material nozzles, such as double material nozzles.What cocurrent flowed through Hot inert gas are by scattered droplet drying to obtain particle diameter as 5-100 μm of solid particle.Dry gas used is preferably nitrogen Gas.In the entrance area of spray dryer, dry gas is preferably tangentially fed.Dry product grain can be in cyclone or filter Middle separation.The temperature of dry gas can be 30-150 DEG C.Atomizing pressure can be 0.1-20MPa.Spray drying can also be with The form configuration of accumulation spray drying (such as FSD technologies), it causes 100-1000 μm of larger aggregation.
According to another embodiment of the present invention, solid dispersions are prepared by screw extruder.It is suitable to extrusion in principle Method is conventional extruders type.It is preferred that use double screw extruder.However, the multiple screw extruder with more than two screw rod It is and suitable.Extruder suitable for the purpose generally comprises shell, variable speed drive units, and by extrusion arbor or is equipped with spiral shell The machining cell of the axle composition of rod element, the screw element are considered modular construction in this case.Conventional screw element For transmission element, kneading disk, spare part or the element with special geometric for influenceing design parameter.This class component is this area Known to technical staff, it can establish suitable screw rod geometry by several preliminary experiments.On this point, it is necessary to ensure that cut Cutting load will not become too high.
Generally, free volume relatively large in inlet region is also advisably established, then reduces the raising of proper time.
Each area of extruder is usually that can heat or coolable.Temperature adjustment can pass through cationic polymerization to be extruded The glass transition temperature of the mixture of thing, hydrophobic active ingredient and other possible mixtures dominates.Temperature can pass through adjustment The internal temperature regulation of cylinder.The temperature specifically established is dominated by the decomposition temperature of component and the fusing point of active component.
To prepare liquid mixture, by component hydrophobic active ingredient and matrix polymer and optional other adjuvants Mixture is heated to the temperature more than glass transition temperature of mixture.The glass transition temperature of mixture can pass through DSC Determined with the 20K/min rate of heat addition.
The temperature in each extruder area can be 30-200 DEG C, preferably 40-180 DEG C, be hereby intended that as inner cylinder temperature. In the firstth area, select temperature for it is low and in subsequent area improve until it fully far above mixture glass transition Temperature is to form uniform melt.Improving uniformity of melt has limpid outward appearance.
Selection temperature profile forms domination by preparaton in particular situations.
Preparaton for extrusion can be fed in extrusion method in a different manner.Following methods A- can be used in principle E：
If additionally adding solvent, the solvent about description for preparing with film can be used.
The melt form of the matrix polymer, hydrophobic active ingredient and the optional other adjuvants that prepare in an extruder Liquid mixture can be extruded by one or more nozzles.
Round nozzle used can have 0.5-5mm diameter.Other nozzle forms, such as narrow slit type nozzle can also be used, It is if it is intended to especially true if relatively large material handling capacity.
Gained cured extrudate bar can be pelletized to machining to obtain particle, the particle can further be crushed again (grinding) is to obtain powder.Particle or powder can be inserted in capsule or be suppressed using conventional tableting aid to obtain piece Agent.On this point, it is possible to use other release control adjuvants.
In addition, water, organic solvent, buffer material or plasticizer can be used during extrusion.Especially, water or volatility Alcohol is selection here.This method can make to react under relatively low temperature.The amount of solvent or plasticizer is usually extrudable material 0-30 weight %.Water or solvent can under standard pressure by the ventilation point in extruder or by applying vacuum and Remove.Alternatively, these components are evaporated when extrudate leaves extruder and pressure is down to normal pressure.In smaller volatility In the case of component, then correspondingly extrudate can be dried.
When melt is extruded by nozzle, melt is preferably free of solvent.This means that solvent is less than 1 weight %.
In a particular variant of preparation method, after extrusion rolled thermoplastic to obtain piece Shape compact, it forms final form of medication., can be advisably before extrusion or period has added it in the change programme Its component, such as polymer is to adjust glass transition temperature and melt viscosity, disintegrant, solubilizer, plasticizer, dyestuff, tune Taste substance, sweetener etc..In principle, these materials first can also crush extrudate, be used when then suppressing to obtain tablet.
The amorphous solid dispersion obtained according to the present invention can have the gross weight 2-60 weights based on solid dispersions Measure % hydrophobic active ingredient load.It is preferred that the content of hydrophobic active ingredient is 10-50 weight %, particularly preferred 20-50 Weight %.The cationic base polymer content of diethyl aminoethyl methacrylate and methyl methacrylate can be 5- 95 weight %.In addition, dispersion can include other medicines additive.It can be 0.1-60 that the amount of other additives, which is based on total preparation, Weight %.Due to adding (the at most 50 weight % of polymeric matrix) hydrophilic polymer, can influence to extrude obtained by deenergized period The decomposition rate of thing.By improving hydrophily, wetting faster in release can be achieved and decompose faster.Therefore, with low point Son amount (<100000 dalton) hydrophilic polymer be specially suitable.With higher molecular weight (>100000 dalton) Hydrophilic polymer can be considered as gained solid solution stabilizer because they improve matrixes rigidity, and prevent activity into Divide and crystallized from supersaturated solution.Therefore, the stable supersaturated solid solution with especially high medicament contg can be prepared.
Hydrophilic polymer is water miscible at least in the range of specific pH.On this point, it is water-soluble to mean at 20 DEG C At least 0.1g is dissolved in 1ml.
Suitable hydrophilic polymer is for example：The polyvinylpyrrolidone of K values with 12-90, N- vinyl pyrrolidines Ketone copolymers, such as the copolymer with vinyl esters such as vinyl acetate or propionate, particularly weight ratio are 60:40 The copolymer of N- vinylpyrrolidones and vinyl acetate, polyvinyl alcohol, hydroxyalkylated celluloses derivative, such as hydroxypropyl are fine Dimension plain (HPC) or hydroxypropyl methyl cellulose (HPMC), hydroxyalkylation and carboxylation alkylation cellulose derivative, acrylic acid-methyl Acrylic copolymer.
The polyethylene glycol of mean molecule quantity with 1000-6000 is also suitable.Suitably there is polyethylene glycol and gather The graft polymers of vinyl alcohol units, such as conductIR, BASF are commercially available, or this kind of graft polymers is with gathering The mixture of vinyl alcohol.It is suitable to also have the N- caprolactams and vinyl acetate list of polyethylene glycol and grafting thereon The graft copolymer of member, for example, it is commercially available, BASF SE.
To adjust the glass transition temperature of preparaton, the water-soluble polymeric with high glass-transition temperature can be used Thing, such as polyvinylpyrrolidone, hydroxy alkyl cellulose or the hydroxyalkyl starch of the K values with 17-120.Preparaton it is too high Glass transition temperature can be reduced by adding plasticizer.Be suitable to the purpose in principle is to be additionally operable to owning for medication coat Plasticizer, such as triethyl citrate, ATBC, acetyltributyl citrate, acetin, propane diols, polyethylene glycol 400th, dibutyl sebacate, glycerin monostearate, laurate, cetostearyl alcohol.This kind of plasticizer can be with based on dispersion Weight 0.1-20 weight % amount use.
In addition, the surfactant of extrusion temperature that also can by reduction melt viscosity and therefore is incorporated in preparation.These Material also can have actively impact to possible crystallization, and produce more preferable preparaton wetting and dissolving faster.Suitably Material is ion and nonionic surfactant, such as KolliphorTMHS 15 (hydroxy stearic acid esters of Macrogol 15),80, polyoxyethylated derivative of fatty acid, such as KolliphorTM(the hydrogenated castors of Polyoxyl 40 of RH 40 Oil, USP), KolliphorTMEL (castor oil of Polyoxyl 35, USP), poloxamer, docusate sodium or NaLS.
In addition, advisably antioxidant can be added with the amount of the gross weight 0.1-10 weight % based on solid dispersions solid In body dispersion.According to the present invention, suitable antioxidant is slightly water-soluble antioxidant, i.e. its solubility in 20 DEG C of water Antioxidant no more than 1g/l.
Mainly lipophilic substance tocopherol, tocopherol acetate, the ascorbic acid palm of antioxidant are suitable for herein Acid esters, ascorbyl stearate, tertiary butylated hydroquinone, butylhydroxy anisole, tert-butyl hydroxy toluene, octyl gallate Or lauryl gallate or its combination.
The preparation obtained by these methods is ready to use in and contained available for wherein water-insoluble or slightly water-soluble material in principle Develop in water formulation or in water-bearing media in all spectra of its effect.
In the context of the invention, hydrophobic active ingredient preferably should be understood that means bioactive substance, such as Active constituents of medicine, cosmetics or the agrochemical active ingredient of humans and animals, or health products 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 essentially decomposition point of the fusing point in copolymer under extrusion condition Following all solids active component.Copolymer can generally be extruded at a temperature of at most 200 DEG C.Under lowest temperature each case Domination is formed by mixture to be extruded and microsolubility material to be processed.
Active component may be from any designated area.
The example that can be mentioned herein is benzene phenodiazine, antihypertensive, vitamin, cytostatics-particularly Japanese yew Phenol, anesthetic, neuroleptic drug, antidepressants, antiviral agent for example Anti-HIV agents, antibiotic, antifungal, anti-senile dementia medicine, Fungicide, chemotherapeutic drug, urological department medicine, platelet aggregation inhibitor, sulfamido, antispasmodic, hormone, immune globulin In vain, serum, thyroid gland curative, psychopharmaceutical, Parkinson's medication and other anti-hyperkinesia medicines, ophthalmic medicine, god Through sick preparation, Calcium Metabolism Regulation agent, muscle relaxant, arcotic, lipid lowering agent, Remed for hepatopathy, coronal (coronary) medicament, Cardiotonic drug, immunotherapy medicine, regulation peptide and its inhibitor, hypnotic, sedative, gynecological drug, gout therapertics, plasmin Antidote, enzyme preparation and transport protein, enzyme inhibitor, emetic, blood flow ameliorant, diuretics, diagnosticum, adrenal cortex lipoid Alcohol, cholinergic agent, bile duct curative, antiasthmatics, bronchus medicine (broncholytics), receptor blocking agent, calcium antagonist, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, artery sclerosis medicine, antiphlogistic, anticoagulation, antihypertensive, antihypoglycemic, anti-hypertonic medicine, antifibrin Dissolve medicine, antiepileptic, antiemetic, antidote, antidiabetic, antiarrhythmics, Antianemic Agents, antiallergic, drive intestines Worm agent, anodyne, stimulant, aldosterone antagonists, fat-reducing auxiliary agent.
In said medicine preparation, particularly preferably those of oral administration preparation.To prepare pharmaceutical administration form such as Tablet, extrudate can be mixed with conventional medicine adjuvant.
These are the material from following classification：Filler, plasticizer, chaotropic agent, adhesive, silicate and disintegrant and Absorbent, lubricant, glidant, dyestuff, stabilizer such as antioxidant, wetting agent, preservative, releasing agent, spices or sweetener, Preferred filler, plasticizer and chaotropic agent.
The filler that can be added be such as inorganic filler such as magnesium, aluminium, the oxide of silicon, titanium carbonate or calcium carbonate, calcium phosphate or Magnesium phosphate, or organic filler such as lactose, sucrose, D-sorbite, mannitol.
Suitable plasticizer is such as acetin, triethyl citrate, glyceryl monostearate, low molecular poly or Poloxamer.
Suitable other chaotropic agents are the interface active agent with HLB (hydrophile-lipophile balance) value more than 11, such as With the rilanit special (Kolliphor of 40 ethylene oxide unit ethoxylationsTMRH40), with 35 ethylene oxide unit second Castor oil (the Kolliphor of epoxideTMEL), polysorbate 80, poloxamer or NaLS.
Workable lubricant is the stearate of aluminium, calcium, magnesium and tin, and magnesium silicate, polysiloxanes etc..
Workable glidant is such as talcum or colloidal silica.
Suitable adhesive is such as microcrystalline cellulose.
Disintegrant can be PVPP or crosslinked carboxymethyl fecula sodium.Stabilizer can be ascorbic acid Or tocopherol.
Dyestuff is such as ferriferous oxide, titanium dioxide, triphenhlmethane dye, azo dyes, quinoline dye, indigo-blue dye Material, carotenoid, form of medication are dyed, opacifier such as titanium dioxide or talcum, to improve transparency and the saving to light Dyestuff.
In addition to the application in cosmetics and medicine, preparation prepared in accordance with the present invention applies also for field of food, such as Slightly water-soluble or water-insoluble nutrient, adjuvant or additive such as liposoluble vitamin or carotenoid are incorporated to.It can mention Example be with carotenoid colour beverage.
Use of the preparation obtained according to the present invention in agrochemicals can especially include comprising agricultural chemicals, herbicide, kill very The preparaton of microbial inoculum or insecticide, main those systems for also having the crop production compositions used as preparaton of spraying or water Agent.
By the inventive method, the so-called solid solution with microsolubility material can be obtained.According to the present invention, solid solution is to use In the term for referring to the system without the crystalline portion for observing microsolubility material.
Embodiment
According to the present invention, matrix used polymer is prepared for the embodiment 1 similar to WO 2009/016258, by weight ratio For 55:The polymer that 45 methyl methacrylate and diethyl aminoethyl methacrylate obtains, its conductSmartseal 30D are commercially available in the form of aqueous dispersion.Diethyl aminoethyl methacrylate:Methyl-prop E pioic acid methyl ester mol ratio 3:7；Tg：63 DEG C (being measured by DSC with the 20 ° of K/min rate of heat addition)；Weight (passes through SEC light scattering It is determined as 200000 dalton).
Polymer uses as freeze-dried powder or as spray-dried powders.
In certain embodiments, polymer uses also in the form of partly neutralizing：6 moles of part degree of neutralization：6 moles of % alkali Property group with adipic acid part neutralize
8 moles of part degree of neutralization：8 moles of % basic groups are neutralized with succinic acid moiety.
For contrastEPO is that mol ratio is 2:1:1 acrylate, acrylic acid The base copolymer of butyl ester and methyl methacrylate.
Method 1：Film method
General procedure
To prepare polymer/mixture of active principles, material is weighed with respective amount and is put into 50ml XiLin (penicillin) in bottle.
Concentration [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 mixtures are stirred 24 hours until composition dissolves on magnetic stirring apparatus.It is (limpid in visually rank solution Solution) after, solvent is separated using 120 μm of blades on a glass.By gained film in fume hood in the room of 22+/- 2 DEG C Temperature is lower to be dried 0.5 hour, then in vacuum drying chamber 0.5 hour under 50 DEG C and 1MPa.Under 23 DEG C/54% relative humidity Storage passes through the load limit of active component in microscopic analysis visually rank polymer in 7 days later.Limpid film is (without work Property composition crystal) represent molecular disperse solution, muddy film (active composition crystal) represents crystallizing system.
Method 2：Spray drying
General procedure
To prepare polymer/mixture of active principles, material is weighed and is put into suitable storage container.Add respective amount Solvent and stir mixture until polymer and active component are completely dissolved.Prepared for fenofibrate (fenofibrate) Agent, solvent are acetone, and for Itraconazole (itraconazole) preparaton, solvent is dichloromethane, for naproxen (naproxen) preparaton, acetone are used as solvent.For all experiments, the solids content of spray solution is 20 weight %.Spray Mist drying is carried out with laboratory scale.
Purposes to be dried is used into double material nozzle atomizations.The hot gas (being herein nitrogen) of concurrent flow is by distribution Droplet drying is to obtain particle diameter as 5-20 μm of solid particle.In the inlet area of spray dryer, dry gas is tangentially Feed.Dry product grain is isolated in the cyclone.
Method 3：Extrusion
General procedure
Double screw extruder for preparing preparaton described in following examples has 16mm screw diameter and 40D length Degree.Extruder by 10 including nozzle can heating zone form.Selection screw-rod structure causes in area 5 and 7, uses kneading Element, it is other to use transmission element.Also nozzle (area 10) is heated.
For listed extrusion embodiment later, technological parameter used is described.Area's temperature is the inside of cylinder Temperature.
The sign of products therefrom
The sign of solid dispersions is carried out with visually rank, XRD (X-ray diffraction) and DSC (differential scanning calorimetry).
When the stable solid solution of visually rank, amorphous component is not shown.Visually rank it is available with or without The light microscope of polarizing filter is carried out with 40 times of enlargement ratios.
The solid solution prepared using following equipment and condition by XRD or DSC researchs by extrusion method and spray drying Crystallinity and/or amorphism (amorphicity)：
XRD
Instrument：D 8Advance diffractometers (Bruker/AXS) with 9 times of sample changers
Measuring method：θ-θ reflect geometry
2 θ angular regions：2-40°
Step width：0.02°
Time of measuring per stepping angle：2.4 the second
Divergent slit：With 1.0mm patchholesMirror
Antiscatter slits：Soller slits
Detector：Sol-X detectors
Temperature：Room temperature
Generator is set：40kV/50mA
DSC
Instrument：Q2000 (TA Instruments, the U.S.)
Dry：Sample is dried overnight at 40 DEG C under vacuo, then weighs and is put into 20 bar pressure close crucibles.
The rate of heat addition：20K/min
Discharged by active component and characterize solid solution
The solid solution that manually or semi-automatically active component releasing research is prepared from extrusion method and spray drying：
Manual active component release (method 1) from Itraconazole (itraconazole) extrudate
Active component release is according to USP equipment (paddle method) 2,700ml 0.08N HCl, 37 DEG C, 50rpm (BTWS 600, Pharmatest) carry out.Extrudate bar is reduced in size to 3mm length using granulator, and feeds release in this manner Put.In each case, often release container uses 100mg active components (non-sink conditions).After at the appointed time putting and pass through After 10 μm of filter filterings, manually detected by UV-VIS spectrum (Agilent 8453UV-VIS spectrometers, Agilent) The active component discharged.
Active component release (method 2) from Itraconazole (itraconazole) extrudate
Active component is released according to USP equipment (paddle method) 2,700ml 0.08N HCl, 37 DEG C, 75rpm (BTWS 600, Pharmatest) carry out.Extrudate bar is reduced in size to 3mm length using granulator, and feeds release in this manner.Often In the case of kind, often discharge container and use 100mg active components (non-sink conditions).At the appointed time put later and pass through 45 μm of mistakes After filter filtering, semi-automatically detected and released by UV-VIS spectrum (Agilent 8453UV-VIS spectrometers, Agilent) The active component put.
Active component release (method 3) from DANAZOL (danazol) extrudate
Active component discharges has 0.1% according to USP equipment (paddle method) 2,700ml80 0.08N HCl, 37 DEG C, 100rpm (BTWS 600, Pharmatest) is carried out.Extrudate bar is reduced in size to 3mm's using granulator Length.The extrudate bar of reduction is used into MF 10basic mill (sieves：0.5mm, IKA Werke) crush and feed in this manner and release Put.In each case, often release container uses 100mg active components (non-sink conditions).After at the appointed time putting and pass through After 45 μm of filter filterings, semi-automatically examined by UV-VIS spectrum (Agilent 8453UV-VIS spectrometers, Agilent) Survey discharged active component.
Active component release (method 4) from Spray dried products
Active component release is according to USP equipment (paddle method) 2,700ml 0.08N HCl, 37 DEG C, 75rpm (BTWS 600, Pharmatest) carry out.Product by spray drying is poured into gelatine capsule (size：0) feed in and in this manner Release.To prevent capsule from floating, them are made to bear a heavy burden using platinum filament.In each case, often release container uses 100mg active components (non-sink conditions).After at the appointed time being filtered after point and by 45 μm of filters, pass through UV-VIS spectrum (Agilent 8453UV-VIS spectrometers, Agilent) semi-automatically detect discharged active component.
Embodiment 1
Contrast has different activities compositionSmartseal and part neutralize Smartseal withEPO load capacity.The concentration provided herein in film refer to molecule dispersing and dissolving activity into Point load capacity, i.e., still without observing active component crystal in film.Higher load causes crystalline portion.
DMF dimethylformamides
Cl2CH2Dichloromethane
Smartseal andSmartseal (part neutralizes) ratio Active component is obviously better dissolved into solid solution by EPO.
Embodiment 2
By 2925g'sSmartseal (lyophilized) and 75g butylated hydroxytoluenes, which are weighed, to be put into Turbula and mixes Close in container and mixed 10 minutes in Turbula blenders T10B.Use gravity dosage device DDW-MD2-DDSR20-10 (Brabender Technologie) adds the mixture dosage in extruder and using gravity feeding unit Mini Twin MT1 (Brabender Technolgie) adds active component fenofibrate (fenofibrate).
Mixture is squeezed in following condition using the screw diameter with 16mm and the double screw extruder of 40D length Go out：
The cylinder of area's temperature control one：45℃；Second cylinder：85℃
Area's temperature of 3rd cylinder：150℃
Screw speed 50rpm
Handling capacity：500g/h
Nozzle diameter 3mm
By the preparation of mass content of the XRD researchs with 34% (w/w) fenofibrate (fenofibrate), it is the discovery that It is unbodied.
Embodiment 3
By 2925g'sSmartseal (lyophilized) and 75g butylated hydroxytoluenes, which are weighed, to be put into Turbula and mixes Close in container and mixed 10 minutes in Turbula blenders T10B.Use gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) adds the mixture dosage in extruder.By 250g's Smartseal mixtures (have butylated hydroxytoluene) and 250g Itraconazoles Smartseal (itraconazole) weigh and be put into Turbula stainless steels and mixed 10 minutes in Turbula blenders T2C.Should Mixture of active principles is by second gravity feeding system Mini Twin MT1 (Brabender Technologie) dosimeter Enter in extruder.
Mixture is squeezed in following condition using the screw diameter with 16mm and the double screw extruder of 40D length Go out：
The cylinder of area's temperature control one：50℃；Second cylinder：100℃
3rd cylinder to cylinder 10 area's temperature：160℃
Screw speed 50rpm
Handling capacity：400g/h
Nozzle diameter 3mm
Find that at most 38% Itraconazole (itraconazole) is unbodied with XRD research solid solution.2 hours with The active component release (method 1) from extrudate is 89% (Fig. 1) in 0.08N HCl afterwards.
Fig. 1：In 0.08N HCl Itraconazole (itraconazole) fromIn Smartseal extrudates Discharged with 50rpm active components.
Embodiment 4
By each polymer of respective amount (Smartseal, 8 moles of parts neutralize Smartseal,EPO) weigh and be put into corresponding active component carbamazepine (carbamazepine) In Turbula stainless steels (being 400g under the total amount each case of polymer+active component) and in Turbula blenders T2C Middle mixing 10 minutes.This is mixed using gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) Agent amount is added in extruder.
Mixture is squeezed in following condition using the screw diameter with 16mm and the double screw extruder of 40D length Go out：
The cylinder of area's temperature control one：40℃；Second cylinder：80℃
3rd cylinder to cylinder 10 area's temperature：160℃
Screw speed 200rpm
Handling capacity：1000g/h
Nozzle diameter 3mm
Using the preparation prepared by dsc analysis, on the amorphous and crystalline active ingredient in preparaton.
The amorphous preparatons of A (do not have active component crystal)
K crystallization preparatons (active composition crystal)
From extrusion and solid solution (the amorphous preparation with carbamazepine (carbamazepine) from film method Agent) Comparative result.
WithEPO load capacity is compared,Smartseal and 8 mole of part neutralizesSmartseal, which is shown, to be extruded and carbamazepine (carbamazepine) load higher in film method.
Embodiment 5
By the particular polymers of respective amount (Smartseal, 6 moles of parts neutralize Smartseal、EPO) weigh and be put into corresponding active component Itraconazole (itraconazole) In Turbula stainless steels (being 400g under the total amount each case of polymer+active component) and in Turbula blenders T2C Middle mixing 10 minutes.This is mixed using gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) Agent amount is added in extruder.
Mixture is squeezed in following condition using the screw diameter with 16mm and the double screw extruder of 40D length Go out：
The cylinder of area's temperature control one：50℃；Second cylinder：90℃
3rd cylinder to cylinder 9 area's temperature：160℃
The cylinder of area's temperature control 10：150℃
Screw speed 200rpm
Handling capacity：1000g/h
Nozzle diameter 3mm
Preparaton prepared by visually rank and amorphous (limpid extrudate) in preparaton (muddiness starts) and Crystalline active ingredient is assessed.
The amorphous preparatons of A (do not have active component crystal)
K crystallization preparatons (active composition crystal)
From extrusion and solid solution (the amorphous preparation with Itraconazole (itraconazole) from film method Agent) Comparative result.
WithEPO load capacity is compared,Smartseal and 6 mole of part neutralizesSmartseal, which is shown, to be extruded and Itraconazole (itraconazole) load higher in film method.
In 0.08N HCl Itraconazole (itraconazole) (30+45%w/w) from Smartseal, 30% (w/w) 6 moles of parts neutralizeSmartseal and with 25,30,35% (w/w) she Triaconazole (itraconazole)Release (method 2) in EPO extrudate show 1.5 hours with Quickly and completely active component discharges afterwards.
Embodiment 6
By each polymer of respective amount (Smartseal、EPO it is) and corresponding active Composition DANAZOL (danazol), which is weighed, to be put into Turbula stainless steels (under the total amount each case of polymer+active component For 400g) and mixed 10 minutes in Turbula blenders T2C.Use gravity feeding cells D DW-MD2-DDSR20-10 (Brabender Technologie) adds the mixture dosage in extruder.
Mixture is squeezed in following condition using the screw diameter with 16mm and the double screw extruder of 40D length Go out：
The cylinder of area's temperature control one：40℃；Second cylinder：80℃
3rd cylinder to cylinder 10 area's temperature：180℃
Screw speed 200rpm
Handling capacity：1000g/h
Nozzle diameter 3mm
Using XRD analysis preparation, on the amorphous and crystalline active ingredient in preparaton.
The amorphous preparatons of A (do not have active component crystal)
K crystallization preparatons (active composition crystal)
With 0.1%In 80 0.08N HCl, 25% (w/w) DANAZOL (danazol) fromSmartseal andThe EPO release (method 3) ground in extrudate is shown in Fig. 2. The recrystallization of DANAZOL (danazol) existsIn the case of EPO extrudates since 5 minutes,In the case of Smartseal extrudates since 14 minutes and therefore can extend 9 minutes.DANAZOL (danazol) maximum activity composition release can be also improved to 40% in the preparaton.Show Kollicoat Larger area causes larger bioavailability under Smartseal release profiles.
Release profiles are shown in Fig. 2：With 0.1%In 80 0.08N HCl, DANAZOL (danazol) fromSmartseal andDischarged in EPO extrudates (crushing) with 100rpm.
Embodiment 7
With different activities composition in spray dryingSmartseal load capacity.Spraying is dry Dry experiment is carried out with laboratory scale.
1. Itraconazole：With 40+50% (w/w) Itraconazole (itraconazole) Smartseal
2. fenofibrate：With 40+50% (w/w) fenofibrate (fenofibrate) Smartseal
3. naproxen：With 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 spray drying,Smartseal is by the work of high concentration Property composition Itraconazole (itraconazole), fenofibrate (fenofibrate) and naproxen (naproxen) be dissolved into it is solid Solution.
In 0.08 N HCl, Itraconazole (itraconazole) (40+50%w/w) from Release (method 4) in Smartseal (spray drying) shows the quickly and completely release of active component after 2 hours (Fig. 3).
The active component release of Itraconazole (itraconazole) is shown in Fig. 3：In 0.08N HCl, Yi Qukang Azoles (itraconazole) with spray drying process from being preparedDischarged in Smartseal with 75rpm.

Claims (15)

1. hydrophobic active ingredient and monomer weight ratio are 35:65-55:45 methacrylic acid N, N- diethylamino ethyl ester with The solid dispersions of the cation copolymer of methyl methacrylate, it includes 20-50 weight % hydrophobic active ingredients.
2. solid dispersions according to claim 1, it is 45 that it, which includes monomer weight ratio,:55 methacrylic acid N, N- diethyl The cation copolymer of amino ethyl ester and methyl methacrylate.
3. solid dispersions according to claim 1, it includes other medicines additive.
4. solid dispersions according to claim 2, it includes other medicines additive.
5. solid dispersions as claimed in one of claims 1-4, it includes plasticizer.
6. solid dispersions as claimed in one of claims 1-4, it includes antioxidant.
7. hydrophobic active ingredient and monomer weight ratio as claimed in one of claims 1-6 are prepared as 35:65-55:45 The method of the solid dispersions of the cation copolymer of DEAEMA and methyl methacrylate, Wherein prepare the liquid mixture comprising hydrophobic active ingredient and cation copolymer and liquid mixture is changed into solid Form.
8. method according to claim 7, wherein liquid mixture exist in the form of solution or melt.
9. the conversion of method according to claim 7, wherein liquid mixture to solid form is carried out by being spray-dried.
10. method according to claim 7, wherein liquid mixture are prepared under heating in screw extruder, and are being extruded Pass through cooling and solidifying later.
11. method according to claim 7, obtain film by the way that liquid mixture is moulded wherein changing into solid form and incite somebody to action It solidifies and carried out.
12. according to any one of claim 7-11 method, wherein cation copolymer is used in the form of partly neutralizing.
13. according to any one of claim 7-11 method, wherein cation copolymer part used be neutralized to based on sun from 2-15 moles of % of subbase group.
14. according to any one of claim 7-11 method, wherein by cation copolymer C used3-C10Dicarboxylic acid moiety Neutralize.
15. preparing medicine, cosmetics, agrochemical formulations, drink according to any one of claim 1-14 solid dispersions Eat the purposes in preparation or health-care preparation.
CN201380032615.6A 2012-06-22 2013-06-11 Dispersion containing active ingredient solids based on diethyl aminoethyl methacrylate copolymer Active CN104379174B (en)

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