CN102905695A - Preparations of biologically active substances with enlarged surface area based on amphiphilic copolymers - Google Patents
Preparations of biologically active substances with enlarged surface area based on amphiphilic copolymers Download PDFInfo
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Abstract
The invention relates to preparations of biologically active substances based on amphiphilic copolymers with increased surface area.
Description
The present invention relates to can process based on thermoplasticity the solid preparation with the bioactive substance that increases the surface of amphipathic copolymer, wherein used amphipathic copolymer comprises at least a graft polymers that contains polyethers.In addition, the present invention relates to produce the method for said preparation.
The increase on surface realizes via the partially or completely foaming of preparation.
Known foamed plastic can be produced via the extruding of melt of containing volatile foaming agent.The known condition that can affect the foam form also.
For example, the people such as M.Lee are at Polymer Engineering and Science, and the 38th volume, has been described extruding with the polyethylene foamed/polystyrene blend of supercritical carbon dioxide in 1998 at the 7th phase.
In addition, Han etc. have described in " Polymer Engineering and Science, the 42nd volume, o. 11th, 2094-2106 " with the foaming of the polystyrene of supercritical carbon dioxide and have extruded.
W.Michaeli etc., ANTEC 2007/ 3043-3045 page or leaf; Lee etc., Polym Int 49:712-718 (2000) is for relating to other publications of this theme.
WO 2007/051743 discloses the water solublity of N-vinyl lactam, vinyl acetate and polyethers or the water-dispersible copolymer purposes as solubilizing agent in medicine, cosmetics, food technology, farm technology or other technologies are used.The document has illustrated that very in general manner corresponding graft polymers also can process with melt with active component.
WO 2009/013202 discloses and these graft polymers of N-vinyl lactam, vinyl acetate and polyethers can have been melted in extruder and mixed with powder or liquid actives, and wherein said extrusion method carries out under the temperature of the fusing point that significantly is lower than this active component.
EP-A 0 932 393 discloses the solid foamed pharmaceutical dosage form of extruding and foaming and obtain via the polymer melt that contains active component of the homopolymer that comprises active component and thermoplastic polymer such as NVP and copolymer.These foaming pharmaceutical dosage forms are allegedly compared the release of the active component that demonstrates remarkable improvement with the extrudate of not foaming.
WO 2005/023215 has described the sheet polymer granule that contains active component, and wherein these are via melt extrusion with by using gas that flux foaming is obtained.Described polymer comprises polyvinyl pyrrolidone-vinyl acetate or Eudragit E100PO.The lamellar expanded beads allegedly can be in aqueous environment release of active ingredients more quickly.
Yet the known foam preparaton that is used for bioactive substance is still unsatisfactory aspect the mechanical stability of foam up to now.
In addition, in the situation of the preparation of the active component that is slightly soluble in water, solubility property is still unsatisfactory.
The present invention seeks to find the active agent preparation that contains that the improvement that can obtain and allow active component by the attracting method of melt extrusion discharges.Another purpose provides the stable amorphous embedding of active component.Purpose of the present invention also comprises the improvement of the mechanical performance of preparaton.
Thereby found defined preparation in the foreword.Also found the method for the active component dosage form of production the type.
The increase of dosage surface is carried out via the partially or completely foaming of preparation." partially or completely foaming " refers to that in the present invention foaming method realized the density of 1-99% of the density of compacting preparation.Gained density is preferably 2-50%.Foaming method can be estimated by optics or electron micrograph naked eyes, or can measure via direct density measurement.Hereinafter used term " foaming " also is the synonym of " partially or completely foaming ".
Solid foamed active agent preparation of the present invention can comprise the arbitrary substance as active component, and it can not mix in the polymer melt with not decomposing under process conditions.
Suitable amphipathic copolymer is the graft polymers that contains polyethers.These polymer obtain via vinyl monomer radical polymerization in the presence of polyether component, and polyethers is as the grafting matrix.
The material that is particularly suitable for producing the foaming preparation is the polyether grafting polymer, it obtains via the free radical polymerization of the mixture of following component: i) 30-80 % by weight N-vinyl lactam, ii) 10-50 % by weight vinyl acetate, and iii) 10-50 % by weight polyethers, condition is i), ii) and iii) sum be 100 % by weight.
In a process program, copolyether is closely mixed with the polymer that is slightly soluble in water and the active component that is slightly soluble in water, and this mixture is heated more than the glass transition temperature of copolymer.
Copolyether is soluble in water, and this refers to be dissolved in 1-10 part water at 20 ℃ of lower 1 part of copolymers.
In one embodiment of the invention, the preferred, polyethers copolymer is obtained by following component:
I) 30-70 % by weight N-vinyl lactam,
Ii) 15-35 % by weight vinyl acetate, and
Iii) 10-35 % by weight polyethers.
The copolyether that particularly preferably uses can be obtained by following component:
I) 40-60 % by weight N-vinyl lactam,
Ii) 15-35 % by weight vinyl acetate,
Iii) 10-30 % by weight polyethers.
The copolymer that very particularly preferably uses can be obtained by following component:
I) 50-60 % by weight N-vinyl lactam,
Ii) 25-35 % by weight vinyl acetate, and
Iii) 10-20 % by weight polyethers.
With regard to preferred and particularly preferred composition, also applicable component i), ii) and iii) sum is the condition of 100 % by weight.
Used N-vinyl lactam can comprise N-caprolactam or NVP or its mixture.The preferred N-caprolactam that uses.
Polyethers is used as the grafting matrix.Operable polyethers preferably includes poly alkylene glycol.The molecular weight of poly alkylene glycol can be 1000-100000D[dalton], preferred 1500-35000D, particularly preferably 1500-10000D.Molecular weight is based on the OH pH-value determination pH of measuring according to DIN 53240.
Operable particularly preferred poly alkylene glycol comprises Polyethylene Glycol.Other suitable materials are polypropylene glycol, PolyTHF or the polytetramethylene glycol that obtained by 2-ethyl oxirane or 2,3-dimethyl ethylene oxide.
Other suitable polyethers are the copolymer of the random or block type of the poly alkylene glycol that obtained by ethylene oxide, propylene oxide or butylene oxide, and wherein example is PLURONIC F-127.Block copolymer can be AB type or ABA type.
Preferred poly alkylene glycol especially also have on one or two OH end group alkylating those.Operable alkyl comprises branching or non-branching C
1-C
22Alkyl, preferred C
1-C
18Alkyl, for example methyl, ethyl, normal-butyl, isobutyl group, amyl group, hexyl, octyl group, nonyl, decyl, dodecyl, tridecyl or octadecyl.
The conventional method of production copolyether of the present invention is that itself is known.Production method is used free radical polymerization, preferably in solution, in non-aqueous organic solvent or in mixing non-water/aqueous solvent.Suitable production method for example is described among WO 2007/051743 and the WO 2009/013202, and clearly the general wherein is incorporated herein by reference about the disclosure of production method.
The implication of statement " being slightly soluble in water " is as follows in the present invention: in the present invention, term " is slightly soluble in water " and comprises the microsolubility material to basic insoluble substance and refers to that every g material demand is 100g to 1000g water at least for material is water-soluble under 20 ℃.In the situation of basic insoluble substance, every g material demand is 10000g water at least.
Hereinafter used breviary term " microsolubility " refers to " being slightly soluble in water " in description.
Said preparation is for the compounding pharmaceutical active component, and especially the microsolubility active component is suitable especially.
The example of suitable active component is: acebutolol, acetylcysteine, aspirin, acyclovir, alprazolam, albumin, alfacalcidol, allantoin, allopurinol, Ambroxol, amikacin, amiloride, glycine, amiodarone, amitriptyline, amlodipine, the amoxicillin, the ampicillin, ascorbic acid, aspartame, astemizole, atenolol, acemetacin, beclometasone, benserazide, benzalkoniumhydroxide, benzocaine, benzoic acid, betamethasone (betametasone), bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide; bufexamac; buflomedil; buspirone; caffeine; Camphora; captopril; carbamazepine; carbidopa; carboplatin; cefaclor (cefachlor); cefalexin; cefadroxil; cefazolin; cefixime; cefotaxime; ceftazidime; ceftriaxone; cefuroxime; chloromycetin; chlorhexidine; chlorphenamine; chlortalidone; choline; cyclosporin A; cilastatin; cimetidine; ciprofloxacin; cisapride; cisplatin; clarithromycin; clavulanic acid; clomipramine; clonazepam; clonidine; clotrimazole; clozapine; codeine; colestyramine; cromoglicic acid; cobalamin; cyproterone; desogestrel; dexamethasone; Dexpanthenol; dextromethorphan; dextropropoxyphene (dextropropoxiphene); diazepam; diclofenac; digoxin; dihydrocodeine; dihydroergotamine; diltiazem
Diphenhydramine (diphenhydramine), dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, enrofloxacin, ephedrine, epinephrine, vitamin D2, Ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus Labill (Eucalyptus globules), famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide (FMN), fluconazol, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flutamide, furosemide, gemfibrozil, gentamycin, Semen Ginkgo, glibenclamide, glipizide, Glycyrrhiza glabra L. (Glycyrrhiza glabra), guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, hydroxyl tetracycline (hydroxytetracycline), ipratropium hydroxide, ibuprofen, imipenum, indomethacin, iohexol, iopamidol, sorbide nitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalon, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lignocaine, lipase, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, compound vitamin and mineral, nystatin, methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotiamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, nizatidine, norethindrone, norfloxacin, norgestrel, nortriptyline, ofloxacin, omeprazole, ondansetron, pancreatinum, pantothenylol, pantoprazole, pantothenic acid, acetaminophen, benzylpenicillin, penicillin V, phenobarbital, pentoxifylline, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, proglumetacin, Propafenone, Propranolol, Pseudoephedrine, pyridoxol, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutin, glucide, albuterol, salcatonin, salicylic acid, sldenafil, simvastatin, growth hormone, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulpiride, tamoxifen, ftorafur, tenoxicam, teprenone, terazosin, terbutaline, terfenadine, theophylline, thiamine, tiaprofenic acid, ticlopidine, timolol, tranexamic acid, retinoic acid, triamcinolone, the naphthalene moral, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine, zotepine.Can also prepare vitamin according to the present invention.These comprise the vitamin of A family, B family, therefore and not only B1, B2, B6 and B12 and nicotinic acid and nicotiamide, the chemical compound such as adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, para-amino benzoic acid, inositol and the alpha-lipoic acid that have in addition the vitamin B performance, and the vitamin of C family, D family, E family, F family, H family, l and J family, K family and P family.
Operable other active component are used material in plant protection reagent, other biological kill agent or the veterinary drug.
Said preparation can also receive the reinforced of other thermoplasticity processable polymers and amphipathic copolymer.
Other thermoplasticity processable polymers that can be used for polymeric matrix are unbodied thermoplastic polymer of the present invention.
Specially suitable polymer is the mixture of the machinable homopolymer of the water insoluble thermoplastic of NVP or copolymer or described polymer.The glass transition temperature of this polymer is generally 80-190 ℃, preferred 90-175 ℃.The example of suitable homo is that Fikentscher K value is the polymer of 10-30.Suitable copolymer can comprise as the unsaturated carboxylic acid of comonomer such as methacrylic acid, .beta.-methylacrylic acid, maleic acid or itaconic acid and with have 1-12, ester or hydroxyethyl acrylate or acrylic acid hydroxypropyl ester and the corresponding methacrylate of the alcohol of preferred 1-8 carbon atom, (methyl) acrylamide, the acid anhydride in maleic acid and itaconic acid and half ester (wherein half ester preferably only forms after polyreaction), or vinyl monomer such as N-caprolactam, vinyl acetate, vinyl butyrate and propionate, or the mixture of these comonomers.Therefore, suitable material for example is the terpolymer of NVP, vinyl acetate and propionate.
Acrylic acid is that preferred comonomer and vinyl acetate are particularly preferred comonomer.The amount of the comonomer that comprises can be the 20-70 % by weight.Very particularly preferably following copolymer in the present invention, it is obtained by 60 % by weight NVPs and 40 % by weight vinyl acetates.
Other examples of suitable polymer are the homopolymer of vinyl chloride, polyvinyl alcohol, polystyrene, poly butyric ester or the copolymer of copolymer and ethylene and vinyl acetate.
In addition, active agent preparation can also comprise starch, degradable starch, casein, pectin, chitin, chitosan, gelatin or lac as matrix component, and wherein these can be processed with melt under the conventional plasticizer of adding.
In addition, preparation of the present invention can comprise conventional medicine auxiliary agent such as filler, lubricant, releasing agent, flowing regulator, plasticizer, dyestuff and stabilizing agent with the amount of 50 % by weight at the most.This tittle and following amount are always based on the gross weight (=100%) of preparation.
The example of the filler that can mention is magnesium, aluminum, silicon and titanyl compound and lactose, mannitol, sorbitol, xylitol, tetramethylolmethane and derivant thereof, and wherein the amount of filler is the 0.02-50 % by weight, preferred 0.2-20 % by weight.
The example of the flowing regulator that can mention is monoglyceride, diglyceride, the triglyceride of long-chain fatty acid such as C12, C14, C16 and C18 fatty acid, wax such as Brazil wax and lecithin, and wherein this measures the % by weight into 0.1-30, preferred 0.1-5 % by weight.
The example of the plasticizer that can mention not only has low-molecular-weight polyoxyalkylene such as Polyethylene Glycol, polypropylene glycol and poly-ethylene propylene glycol, also has polyhydric alcohol such as propylene glycol, glycerol, tetramethylolmethane and Sorbitol and diethyl sodium sulfosuccinate, glyceryl monoacetate, Glycerine 1,3-diacetate and glycerol triacetate and stearic macrogol ester.Amount at this plasticizer is about 0.5-15 % by weight, preferred 0.5-5 % by weight.
The example of the lubricant that can mention is stearate and Talcum and the polysiloxanes of aluminum or calcium, and wherein these amount is the 0.1-5 % by weight, preferred 0.1-3 % by weight.
The example of the stabilizing agent that can mention is the stabilizing agent that light stabilizer, antioxidant, free radical scavenger and combating microorganisms infect, and wherein these amount is preferably the 0.01-0.05 % by weight.
For production preparation of the present invention, active ingredient components can and be extruded subsequently with the polymer premix, perhaps can add the polymer melt that comprises foaming agent in extrusion.
The quantitative ratio of each component can change in wide region in the preparation.As the dosage of active component and the function of active component rate of release, its amount can be the 0.1-90 % by weight of active agent preparation.The amount of polymer can be the 10-99.9 % by weight.This material can also comprise one or more auxiliary agents of 0-50 % by weight.
Production foaming activity component preparation of the present invention preferably carries out via extruding of melt, this melt comprises at least a amphipathic copolymer and optional other thermoplasticity processable polymers and optional conventional auxiliary agent and one or more active component, and wherein this melt is with the upper acceptable volatile foaming agent dipping of physiology.
The harmless foaming agent of suitable volatility physiology is gaseous foaming agent such as carbon dioxide, nitrogen, air, noble gas such as helium and argon, propane, butane, dimethyl ether, vinyl chloride, Chlorofluorocarbons (CFCs), Difluoroethane, or nitrous oxide (laughing gas), wherein preferably carbon dioxide and/or nitrogen.Carbon dioxide very particularly preferably.Gaseous foaming agent can use with supercriticality, but preferably uses with supercriticality.
Melt is preferably in extruder, particularly preferably in producing in the double screw extruder.Active component can carry out before or after polymer melted by conventional in the art method with mixing of polymer and optional additives gas.Particularly during to responsive to temperature, can only after the thermoplastic fusing, add these active component at active component.Melt can at 20-200 ℃, obtain under preferred 70-200 ℃ the temperature, and suitable temperature especially depend on the glass transition temperature of institute's addition polymerization compound.As the function of the component of mixture that exists in the melt, extrusion method can also carry out under the temperature below the amphipathic copolymer glass transition temperature.Also possible is that foaming agent reduces the required temperature of acquisition melt, because it has the reduced viscosity effect.
Polymer melts under its temperature more than glass transition temperature usually.
Preferably under pressure, realize with foaming agent dipping melt.Under these conditions, 1-15 % by weight foaming agent is dissolved in the melt.Can be with the pressure of 30MPa at the most at this gas, the pressure of preferred 1-20MPa is introduced.To at the most 20 % by weight at this, preferred 1-20 % by weight gas inject melt.
With plasticising foaming agent such as CO
2Therefore the melt that dipping has reduced the viscosity of melt and comprised foaming agent is lower than the corresponding temperature that does not contain the melt of foaming agent in its lower temperature that can extrude.The performance that comprises the polymer melt of foaming agent is conducive to mix heat-labile active component.
Before extruding by mould, the melt cooling that will comprise foaming agent is to this temperature of 70 ℃ at the most more than mixture glass transition temperature.The temperature at mould place is preferably the above 10-40 of preparaton glass transition temperature ℃.Particularly preferred temperature range is 15-30 ℃.
In the situation to temperature especially responsive active component, can after foaming agent mixing and temperature reduction, add in the melt.
The inventive method can be carried out in having single extruder in different temperatures district.Yet, system is extruded in the series connection that preferably is made of two extruders that intercouple, wherein first extruder that wherein carries out that is added in of polymer melted and foaming agent is preferably the double screw extruder with good immixture, and wherein the second extruder is the single screw extrusion machine with less shear action and high cooling capacity.
The extrudate that is occurred by extruding machine mold still for plasticity and under the leading atmospheric pressure in the extruder outside foaming obtain foam.
Add the form that the amount of foaming agent and extrusion temperature can be used for control foaming degree and active agent preparation therefore.
The high-foaming degree obtains relatively low density and the therefore two-forty of active component dosage form dissolving.If wish relatively high density, then can via reducing the high-foaming agent content favourable to preparation at the immediate vicinity devolatilization of mould slit, obtain thus the only product of slight foaming.Then make the foaming activity component preparation suffer forming method, for example by using granulation, pelletize or tabletting to obtain corresponding required active component dosage form by known method.
The density of solid active agent preparation is generally 20-1000g/I, preferred 25-600g/I, particularly preferably 30-500g/l.Foam can be perforate or closed-cell foam.
Compare with conventional extrudate, preparation of the present invention can have the surface of increase.
Can also use coextrusion to produce the multi-lamellar partially or completely foaming dosage form that comprises active component.At this, at least two kinds of compositionss of coextrusion, and suffer subsequently forming method to obtain required dosage form, and each compositions comprises at least a above-mentioned thermoplastic adhesives, at least aly in these compositionss comprise at least a active component, and at least a in the above described manner with the harmless foaming agent dipping of gaseous state physiology in these compositionss.
Before the coextrusion method, separate the compositions for the preparation of each layer of active component dosage form.For this reason, make corresponding starting ingredient in the extruder that separates, obtain comprising the melt of active component above process program is processed under the described condition.The operation of each layer can be carried out under the corresponding desirable condition to concrete material at this.For example can select different processing temperatures to each layer.Correspondent composition can also for example with not commensurability foaming agent dipping, produce the layer with different foaming degrees thus.
Make melting or plastic composition from each extruder add shared co-extrusion die, extrude and discharging.Required active component dosage form is depended in the molding of co-extrusion die.For example suitable mould is for having those and those of discharging cross section with rounded form of slits of the material slit (being known as slit die) of clearing.
The design of mould is depended on used polymer adhesive and required form at this.
After by the co-extrusion die discharging, carry out forming method to obtain required active component dosage form or pharmaceutical dosage form.Function as the character of co-extrusion die and forming method can produce the dosage form of wide region at this.The extrudate that is for example occurred by slit die and especially have two or three layers can be used for by punching or cutting method, for example uses incandescent wire and produces open multilayer tablet.
Perhaps, open multilayer tablet can have by use the mould use die face sickle in the discharging cross section of rounded form of slits, namely via being close to by cutting extrudate behind the mould discharging or preferably using the cold cut segmentation method, namely produce cooling off at least rear cutting extrudate.
Airtight active component dosage form, the layer that namely wherein comprises active component are not contained dosage form that the layer of active component surrounds fully and are especially obtained via the processing of extrudate in suitable material pressing device by the mould that use has a discharging cross section of rounded slit.
When skin cooled off, the internal layer of multilayer tablet can plastic deformation be favourable when entering material pressing device still at this.The method especially can be for the production of tablet, preferred rectangle tablet, sweet tablet, lozenge and pellet.
In another process program, the foaming dosage form that comprises active component can be by will not only comprising one or more active component but also is comprised the melt extrusion of thermoplasticity amphipathic copolymer, make melt when keeping its plasticity, suffer moulding process also to use subsequently one of above-mentioned gaseous foaming agent dipping to comprise the solid dosage forms of active component, for example in conventional autoclave, cling at 10-300, under the pressure of preferred 50-200 bar, and make subsequently this material foaming and produce.
When being decompressed to atmospheric pressure, the dosage form through flooding foams and the dosage form that partially or completely foamed.
Foaming degree depends on the persistent period of impregnating process and can regulate as required.This process program preferably is suitable for production department and divides the foaming agent type, and it has outside foaming covering and the nuclear that do not foam, and therefore has dispose procedure stage by stage.
The foaming dosage form can also provide the conventional coating of permeable active component, obtains easily thus the buoyancy dosage form.This buoyancy dosage form can be used for medicinal purpose or be used for veterinary medicine or product for agriculture, and wherein example is the fish food for the production of slow decreasing.
The solid foamed active agent preparation that obtains among the present invention and comprise the active component that is dispersed in polymeric matrix dissolve very fast and so allows the quick release of active component.The inventive method can obtain the foaming activity component preparation with simple and the effective mode of cost.Another advantage is that the reduced viscosity effect of foaming agent allows to extrude under those the temperature that significantly is lower than when not having foaming agent, and wherein the result is the less thermal stress of active component.
Preparation of the present invention has the active component with the amorphous form embedding.Amorphous finger is crystal form by the active component that is not more than 3 % by weight of dsc measurement.Dsc measurement carries out with the rate of heat addition of 20K/min usually.
The use of solubilizing polymers provides remarkable advantage with the polymer phase ratio that becomes known for before melt extrusion method at this.By solubilization, can realize even have the solid solution of the active component of special low-solubility.The relative high-specific surface area of the solid solution that obtains by foaming method provides and the not further increase of the active component rate of release of the solid solution phase ratio of foaming at this.Astoundingly, use the foam of solubilizing polymers production when mixing relatively a large amount of oleophylic active component, not break.This is unexpected event, because sharply the breaking of the reinforced foaming structure that causes resistance aqueous foam such as polysiloxanes of oleophylic.
The gas that is used as temporary transient plasticizer in extrusion no longer can detect at end product, can suppose that therefore stability is greater than the solid solution with permanent plasticizer, because a rear preparation demonstrates relatively low hardness.
Yet highest hardness is highly to wish with regard to the easiness of the grinding of foamed product.Product with relative high rigidity is more crisp, easier breaking and less impact of being out of shape in process of lapping.Thereby be to keep the porous minor structure better.The present invention's preparation that foams has good hardness.
Embodiment
Screw diameter for the production of the double screw extruder of preparaton described in following examples is that 16mm and extruder length are 40D.Whole extruder by 8 independently the machine barrel of controllable temperature consist of.Introduce for improving material, the temperature of initial two machine barrels is controlled at respectively under 20 ℃ and 70 ℃.Set constant temperature at the 3rd machine barrel, and the gas input is also carried out directly entering extruder via mould at this.The gases used CO that comprises by the dosing pump input
2
The temperature of ensuing machine barrel is regulated in this process so that obtain being 70 ℃ mould place temperature at the most more than the glass transition temperature of this mixture.After cooling, use analysis mill (IKA A10) that the foaming extrudate was ground 30 seconds.For following examples, used screen grading is divided after grinding less than 250 μ m.
Use following instrument and condition by crystallization or the amorphous property of XRD (X-ray diffraction method) and the resulting foam of polymers of DSC (differential scanning calorimetry) research.
XRD
Gauge: the D 8Advance diffractometer (Bruker/AXS) with 9 pipe sample changers
Measuring type: θ-θ reflects how much
2 θ angle range: 2-80 °
Go on foot wide: 0.02 °
The Measuring Time in every angle step: 4.8 seconds
Divergent slit: the mirror with 0.4mm patchhole
Anti-scatter slit: Soller slit
Detector: Sol-X detector
Temperature: room temperature
Generator arranges: 40kV/50mA
DSC
DSC Q 2000 from TA Instruments
Parameter:
Used weight: about 8.5mg
The rate of heat addition: 20K/ minute
The foam that grinds is added in the hard gelatine capsule.USP equipment (oar formula method) 2,37 ℃ used in the release of active component, and (BTWS 600, Pharmatest) carry out in 0.1M hydrochloric acid two hours for 50rpm.UV spectrographic method (Perkin Elmer Lamda 2) is for detection of the active component that discharges.The sample that takes out is directly diluted to prevent the microsolubility active component by solution crystallization out with methanol afterwards in filtration.The production of polymer 1
In mixing plant, will not contain the initial charge of charging 2 of part amount at N
2Under be heated to 77 ℃.In case internal temperature reaches 77 ℃, just add the charging 2 of partly measuring and carried out premature polymerization 15 minutes.Then, in 5 hours, be metered into charging 1, and in two hours, be metered into charging 2.In case be metered into all chargings, the polymerization of reactant mixture continued 3 hours again.Behind the polymerization technique that continues, solution is adjusted to the solids content of 50 % by weight.
Initial charge: 25g ethyl acetate
104.0g?PEG?6000
1.0g charging 2
Charging 1:240g vinyl acetate
Charging 2:456g caprolactam
The 240g ethyl acetate
Charging 3 10.44g cross the neopentanoic acid tert-butyl ester (concentration 75 % by weight are in the aliphatic compounds mixture)
67.90g ethyl acetate.
Then, via the nebulization desolventizing and obtain powdered product.Recording the K value in concentration is the ethanol of 1 % by weight is 16.The glass transition temperature of the polymer of measuring by DSC is 70 ℃.
Embodiment 1: polymer 1+5.5 % by weight CO
2
The flux of polymer: 18.95kg/h
CO
2Injection: 1.05kg/h
Melt temperature before the mould: 135 ℃
Melt pressure before the mould: 160 bar
Embodiment 2: polymer 1+8.4 % by weight CO
2
The flux of polymer: 18.45kg/h
CO
2Injection: 1.55kg/h
Melt temperature before the mould: 120 ℃
Melt pressure before the mould: 130 bar
Embodiment 3: polymer 1+11.1 % by weight CO
2
The flux of polymer: 18kg/h
CO
2Injection: 2kg/h
Melt temperature before the mould: 107 ℃
Melt pressure before the mould: 135 bar
Embodiment 4: polymer 1+ fenofibrate+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 20 % by weight fenofibrate (fusing point is 81 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+fenofibrate): 18.75kg/h
CO
2Injection: 1.25kg/h
Melt temperature before the mould: 80 ℃
Melt pressure before the mould: 135 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 100% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 5: polymer 1+ cinnarizine+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 20 % by weight cinnarizines (fusing point is 122 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+cinnarizine): 18.75kg/h
CO
2Injection: 1.25kg/h
Melt temperature before the mould: 105 ℃
Melt pressure before the mould: 130 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 95% at active component after 70 minutes.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 6: polymer 1+ itraconazole+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 40 % by weight itraconazoles (fusing point is 166 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+itraconazole): 18.9kg/h
CO
2Injection: 1.1kg/h
Melt temperature before the mould: 120 ℃
Melt pressure before the mould: 130 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 90% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 7: polymer 1+ danazol+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 20 % by weight danazol (fusing point is 225 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+danazol): 18.75kg/h
CO
2Injection: 1.25kg/h
Melt temperature before the mould: 130 ℃
Melt pressure before the mould: 135 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 90% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 8: polymer 1+ piroxicam+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 30 % by weight piroxicams (fusing point is 199 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+piroxicam): 18.85kg/h
CO
2Injection: 1.15kg/h
Melt temperature before the mould: 135 ℃
Melt pressure before the mould: 140 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.Active component is released to 69% in 0.1MHCl after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 9: polymer 1+ felodipine+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 40 % by weight felodipines (fusing point is 145 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+felodipine): 18.9kg/h
CO
2Injection: 1.1kg/h
Melt temperature before the mould: 110 ℃
Melt pressure before the mould: 130 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 91% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 10: polymer 1+ carbamazepine+CO2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 40 % by weight carbamazepines (fusing point is 192 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+carbamazepine): 18.8kg/h
CO
2Injection: 1.1kg/h
Melt temperature before the mould: 130 ℃
Melt pressure before the mould: 132 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 78% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Embodiment 11: polymer 1+ clotrimazole+CO
2
Add the V blender and mixed 60 minutes based on weigh polymer 1 and 15 % by weight clotrimazoles (fusing point is 148 ℃) of the total amount of polymer+active component.
The flux of mixture (polymer+clotrimazole): 18.7kg/h
CO
2Injection: 1.3kg/h
Melt temperature before the mould: 105 ℃
Melt pressure before the mould: 135 bar
Study the foaming extrudate and be found to be unbodied by XRD and DSC.In 0.1M HCl, be released to 63% at active component after two hours.Said preparation is still unbodied 30 ℃ of lower storages after 6 months.
Claims (10)
1. one kind has the preparation based on the bioactive substance of amphipathic copolymer that increases the surface.
2. according to claim 1 preparation, it partially or completely foams.
3. according to claim 1 and 2 preparation, it comprises the copolyether that is obtained by the radical polymerization of 30-70 % by weight N-vinyl lactam, 15-35 % by weight nytril 0-35 % by weight polyethers as amphipathic copolymer.
4. each preparation according to claim 1-3, it comprises the copolyether that is obtained by 40-60 % by weight N-vinyl lactam, 15-35 % by weight nytril 0-30 % by weight polyethers.
5. each preparation according to claim 1-4, it comprises other thermoplasticity processable polymers.
6. the method for each preparation in the production according to claim 1-5 comprises making comprising bioactive substance, at least a amphipathic copolymer and optional other auxiliary agents and as melt extrusion and the foaming of volatility physiology's innocuous gas of foaming agent.
7. according to claim 6 method wherein makes melt load volatility physiology innocuous gas under the gas pressure of 1-30MPa.
8. according to claim 6 or 7 method, wherein the concentration of gas in melt is the 1-15 % by weight.
9. each method according to claim 6-8, wherein melt can obtain under 20-200 ℃ temperature.
10. each method according to claim 6-9, wherein melt can obtain under 70-200 ℃ temperature.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10163653 | 2010-05-21 | ||
| EP10163653.8 | 2010-05-21 | ||
| PCT/EP2011/058236 WO2011144727A1 (en) | 2010-05-21 | 2011-05-20 | Preparations of biologically active substances with enlarged surface area based on amphiphilic copolymers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102905695A true CN102905695A (en) | 2013-01-30 |
Family
ID=44123460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800251818A Pending CN102905695A (en) | 2010-05-21 | 2011-05-20 | Preparations of biologically active substances with enlarged surface area based on amphiphilic copolymers |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2571493A1 (en) |
| JP (1) | JP2013526561A (en) |
| CN (1) | CN102905695A (en) |
| WO (1) | WO2011144727A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110022937A (en) * | 2016-07-12 | 2019-07-16 | 赫尔普百治疗有限公司 | Combination comprising Zidovudine and carbapenem |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8636929B2 (en) | 2010-05-21 | 2014-01-28 | Basf Se | Nanoporous foamed active compound-containing preparations based on pharmaceutically acceptable thermoplastically workable polymers |
| DE102017112527B4 (en) * | 2017-06-07 | 2019-01-03 | Lts Lohmann Therapie-Systeme Ag | Fast disintegrating foam wafers with a high basis weight |
| DE102020110089A1 (en) * | 2020-04-09 | 2021-10-14 | Karl-Franzens-Universität Graz | Process for the production of a porous active substance carrier by means of hot melt extrusion |
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| DE19635676A1 (en) * | 1996-09-03 | 1998-03-05 | Basf Ag | Solid foamed active ingredient preparations |
| CN1205626A (en) * | 1995-10-23 | 1999-01-20 | 莱雅公司 | Keratinous fiber treating comosition containing at least binding polymer and at least ceramide-type compound and methods |
| WO2005023215A2 (en) * | 2003-09-10 | 2005-03-17 | Janssen Pharmaceutica N.V. | Particles shaped as platelets |
| CN1771898A (en) * | 2004-07-29 | 2006-05-17 | 欧莱雅 | Cosmetic composition and method for using the composition and use of the composition |
| US20060228317A1 (en) * | 2003-03-14 | 2006-10-12 | Basfaktienglesellschaft | Graft polymers and use thereof in cosmetic formulations |
| WO2007051743A2 (en) * | 2005-11-04 | 2007-05-10 | Basf Se | Use of a copolymer in the form of a solubiliser for a poorly water-soluble compound |
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| WO2009013202A1 (en) * | 2007-07-26 | 2009-01-29 | Basf Se | Process for preparing copolymers obtained by graft polymerization in solution and based on polyethers in solid form |
| US20090124528A1 (en) * | 2007-11-09 | 2009-05-14 | James Lee Danziger | Cleaning compositions comprising a multi-polymer system comprising at least one alkoxylated grease cleaning polymer |
| DE102005058569B4 (en) * | 2005-12-08 | 2010-07-15 | Lts Lohmann Therapie-Systeme Ag | Foam wafer with polyvinyl alcohol-polyethylene glycol graft copolymer |
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2011
- 2011-05-20 CN CN2011800251818A patent/CN102905695A/en active Pending
- 2011-05-20 JP JP2013510633A patent/JP2013526561A/en not_active Withdrawn
- 2011-05-20 EP EP11720524A patent/EP2571493A1/en not_active Withdrawn
- 2011-05-20 WO PCT/EP2011/058236 patent/WO2011144727A1/en active Application Filing
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| CN1205626A (en) * | 1995-10-23 | 1999-01-20 | 莱雅公司 | Keratinous fiber treating comosition containing at least binding polymer and at least ceramide-type compound and methods |
| DE19635676A1 (en) * | 1996-09-03 | 1998-03-05 | Basf Ag | Solid foamed active ingredient preparations |
| US20060228317A1 (en) * | 2003-03-14 | 2006-10-12 | Basfaktienglesellschaft | Graft polymers and use thereof in cosmetic formulations |
| WO2005023215A2 (en) * | 2003-09-10 | 2005-03-17 | Janssen Pharmaceutica N.V. | Particles shaped as platelets |
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| WO2007051743A2 (en) * | 2005-11-04 | 2007-05-10 | Basf Se | Use of a copolymer in the form of a solubiliser for a poorly water-soluble compound |
| DE102005058569B4 (en) * | 2005-12-08 | 2010-07-15 | Lts Lohmann Therapie-Systeme Ag | Foam wafer with polyvinyl alcohol-polyethylene glycol graft copolymer |
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| WO2009013202A1 (en) * | 2007-07-26 | 2009-01-29 | Basf Se | Process for preparing copolymers obtained by graft polymerization in solution and based on polyethers in solid form |
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Cited By (1)
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| CN110022937A (en) * | 2016-07-12 | 2019-07-16 | 赫尔普百治疗有限公司 | Combination comprising Zidovudine and carbapenem |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013526561A (en) | 2013-06-24 |
| WO2011144727A1 (en) | 2011-11-24 |
| EP2571493A1 (en) | 2013-03-27 |
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