Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
  • C08J9/04—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent
  • C08J9/12—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent by a physical blowing agent
  • C08J9/122—Hydrogen, oxygen, CO2, nitrogen or noble gases
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
  • C08J9/0014—Use of organic additives
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
  • C08J9/0066—Use of inorganic compounding ingredients
  • C08J9/0071—Nanosized fillers, i.e. having at least one dimension below 100 nanometers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J2207/00—Foams characterised by their intended use
  • C08J2207/10—Medical applications, e.g. biocompatible scaffolds

Definitions

• Nanoporosis foamed active substance-containing preparations based on pharmaceutically acceptable thermoplastically processable polymers
• the present invention relates to solid, nanoporous, foamed active substance-containing preparations based on pharmaceutically acceptable thermoplastically processable polymers. Furthermore, the invention relates to processes for the preparation of such preparations. It is well known that foamed plastics can be made by fusion containing volatile blowing agents.
• foams are used as insulating material. Since the mean free path of air is about 60 to 100 nanometers (depending on pressure and temperature), it can be concluded that in a polymer foam with air as the cell gas with an average cell size of less than or equal to 60 to 100 nanometers, the contribution of the cell gas to the total heat conduction of the foam significantly reduced or even eliminated completely. Therefore, foams with the smallest possible small-cell structure would be particularly desirable.
• foams with the smallest possible small-cell structure would be particularly desirable.
• the foam density must be reduced as much as possible so as not to lose the advantage gained over the cell gas by an increased contribution of the polymer matrix to the total heat conduction. This means that a nanoporous foam must also have the lowest possible density in order to have a thermal insulation effect which is improved over standard polymer foams.
• US00595551 1 and EP1424124 describe by way of example processes for the production of microporous and nanoporous polymer foams in which a polymer is charged under pressure at a low temperature below the glass transition temperature of the polymer in a first step under pressure. This loaded polymer is then foamed after pressure release without foaming by increasing the temperature in a separate step.
• WO2008 / 087559 describes continuous extrusion processes for producing nanoporous polymer foams in which a polymer is admitted to the blowing agent at different temperatures under pressure, but the subsequent foaming process is by depressurization but at very low temperatures far below the glass transition temperature of the pure polymer is performed above the glass transition temperature of the gas-laden system.
• foams are also of interest for pharmaceutical applications. From EP-A 0 932 393 it is known to produce solid foamed pharmaceutical forms by extrusion and foaming of active-ingredient-containing polymer melts containing active ingredients and thermoplastic polymers such as homo- and copolymers of N-vinylpyrrolidone. These foamed dosage forms should have a significantly improved release of the active ingredient compared to the non-foamed extrudates.
• WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food-processing, agrotechnical or other technical applications. This generally describes that the corresponding graft polymers can also be processed in the melt with the active ingredients.
• WO 2005/023215 discloses platelet-shaped foamed particles which are produced by loading an active-ingredient-containing polymer melt with a supercritical propellant and expanding the mass.
• polymers copolymers of N-vinylpyrrolidone and vinyl acetate and an acrylate polymer (Eudragit E100 PO).
• the foamed platelet-shaped particles should enable a faster release of the active ingredient in an aqueous environment.
• microporous means that the pore sizes are in the range of 1 to 1000 microns.
• macroporous means dimensions greater than 1000 microns.
• the object is achieved according to the invention such that the process for producing nanoporous foamed preparations with low foam density is divided into at least 3 stages, which, however, all take place in direct connection with each other without removal of the polymeric molding composition until the pressure release step.
• nanoporous foamed active substance-containing preparations have been found in which the active ingredients are embedded in at least one thermoplastically processable pharmaceutically acceptable polymer.
• step a) a loading of a polymer molding composition or a polymer melt containing at least one pharmaceutically acceptable polymer with a blowing agent under a pressure and at a temperature at which the Blowing agent is in the supercritical state, in step b) a tempering of the polymer molding compound or polymer melt loaded in step a) under pressure to a temperature which is in the range of - 40 to + 60 ° C.
• step c) a pressure release of the in step a) loaded polymer molding composition or polymer melt containing at least one active substance, with a pressure release rate in the range of 15,000 to 2,000,000 MPa / s takes place.
• a stage d) may follow, in which comminution of the obtained nanoporous foamed preparations takes place.
• the loaded polymer molding compound or polymer melt is heated so that the temperature at the moment of foaming in the range of - 40 to + 55 ° C is about the glass transition temperature of the non-gas-loaded polymer mass.
• a temperature range which deviates by 0 to + 40 ° C from the glass transition temperature of the mixture of polymer and active ingredient.
• the glass transition temperature is the detectable glass transition temperature.
• the glass transition temperature can be determined by DSC according to DIN-ISO 1 1357-2 at a heating rate of 20 K / min.
• the addition of one or more active ingredients can be done at different times.
• the active ingredient and the polymer component may be mixed before melting.
• the addition of the active ingredient can also be carried out in stage b).
• the addition to the melt is recommended after the blowing agent admixing and subsequent tempering, ie between stage b) and stage c).
• Nanoporose-containing polymer foams having an average cell count in the range from 1 .000 to 100,000 cells / mm, preferably from 2,000 to 50,000 and particularly preferably from 5,000 to 50,000 cells / mm, and a foam density in the range from 10 to 700 are produced with the aid of the method according to the invention kg / m 3 , preferably in the range of 10 to 300 kg / m 3 , particularly preferably in the range of 10 to 500 kg / m 3 prepared.
• nanoporous comprises average cell sizes in the range from 10 to 1000 nanometers, preferably from 20 to 500 nm and particularly preferably from 20 to 200 nm.
• the term "average cell size” describes the average diameter of circular foam cells having cross-sectional areas equivalent to the real cells in typical frequency / size curves, as can be determined from the evaluation of at least 10 real cell areas of representative electron micrographs.
• the term “foam density” or “density” describes the mass to volume ratio of the foamed nanoporous molding composition, which can be determined by the buoyancy method or mathematically results from the quotient mass to volume of a molded part.
• the term “molding compound” or else "melt” includes both pure homopolymers and copolymers as well as mixtures of polymers. Furthermore, the term also includes formulations based on polymers and the most diverse additives. By way of example, reference should be made here only to process additives such as, for example, stabilizers, flow aids, color additives, antioxidants and similar additives known to the person skilled in the art.
• the foams may be closed cell but are preferably open celled. "Closed-cell” means that there is a discontinuous gas phase and a continuous polymer phase.
• Open-celled means that it is a bicontinuous system in which the gas phase and the polymer phase are each continuous phases, the two phases being interpenetrating phases.
• the nanoporous systems have an open-space of more than 40%, preferably more than 50%, particularly preferably more than 75%. Ideally, at least 90% of the cells, up to 100% of the cells, are open, i. that the foam consists only of bars.
• the Offanzmaschine can be determined according to DIN-ISO 4590.
• a polymeric molding compound or melt is charged with a gas or fluid blowing agent under a pressure and a temperature at which the blowing agent is in the supercritical state.
• Suitable volatile, physiologically acceptable blowing agents are gaseous blowing agents such as carbon dioxide, nitrogen, air, noble gases such as helium or argon, furthermore ethane, propane, butane, n-pentane, volatile aliphatic alcohols such as ethanol or isopropanol, chlorofluorohydrocarbons, difluoroethane trifluoromethane, dimethyl ether or nitrous oxide (nitrous oxide), with carbon dioxide, nitrous oxide and / or nitrogen being preferred. Very particular preference is given to carbon dioxide.
• the parameters at which these propellants are in the supercritical state are known to those skilled in the art.
• the critical point is in the range of 31 ° C and 7.375 MPa
• N2O the critical point is in the range of 36.4 ° C and 7.245 MPa.
• the blowing agent loading of the polymeric molding compound or polymer melt can take place in a pressure chamber, for example an autoclave, or in a tool cavity or in an extruder.
• a temperature above the critical temperature of the blowing agent and above the glass transition temperature of the polymeric molding composition for this first loading step is advantageous because the inclusion of the blowing agent via diffusion processes at temperatures above the glass transition temperature of the polymeric molding compound is accelerated and thus shorter loading times are possible.
• a pressure above the critical pressure of the propellant is set for the loading, preferably greater than 10 MPa, particularly preferably greater than 20 MPa. This loading pressure is important for the generation of the highest possible gas concentration in the polymeric molding compound or the polymer melt, and can be adjusted within the technical possibilities of today's pressure vessel up to 200 MPa.
• the loading takes place in an extruder.
• the temperature of the polymeric molding compound in the area of the blowing agent injection is above the glass transition temperature of the molding compound, so that the blowing agent can disperse and dissolve very well and quickly in the polymer melt.
• the loading pressure is generally set higher than the melt pressure in this area.
• the loading pressure is set to a constant high value via a pressure-maintaining valve.
• a blowing agent mass flow is set, which may be 1 to 50% by weight, based on the mass flow of the polymeric molding composition.
• the upper limit here represents the saturation concentration which can be reached in front of the nozzle under the parameters of pressure and temperature of the loaded melt, which can be determined either empirically in the process or by means of gravimetric methods.
• the laden polymeric molding compound or polymeric melt is then cooled to a temperature which is in the range from 40 ° C. to below 55 ° C. above the atmospheric pressure while maintaining the loading pressure greater than 10 MPa, preferably greater than 20 MPa by means of DSC according to DIN-ISO 1 1357-2 at a heating rate of 20 K / min detectable glass transition temperature (Tg) of the mixture of polymer and active ingredient, preferably in the range of 20 ° C under to + 50 ° C above the Tg, more preferably in the range of 0 ° C below to 40 ° C above the Tg,
• Tg detectable glass transition temperature
• this adjustment of the temperature of the polymeric molding compound can be carried out after application of the loading pressure.
• this temperature can also be set before applying the loading pressure.
• care must be taken to allow a sufficient time for the homogenization of the temperature, in particular after injection of the cold blowing agent into the cavity.
• care must be taken in these process variants for a sufficient time to reach the saturation concentration via diffusion, especially for larger volumes of the polymeric molding composition.
• the loading takes place in an extruder, wherein the loaded molding composition or polymer melt is cooled continuously.
• all known to those skilled apparatuses from a cooling extruder to mixers and coolers in any number and combination can be used.
• melt pumps for pressure increase may be appropriate, which can also be introduced in any number and position in the process.
• This is also an advantage of the embodiment of the invention is justified, namely that a segmental structure of the process section provides a great deal of control over the local parameters pressure and temperature and a rapid and homogeneous cooling of the loaded molding compound can be carried out under pressure.
• Condition is, however, that by a sufficient residence time and mixing a homogeneous distribution of the blowing agent molecules takes place and the blowing agent can be completely dissolved in the polymeric molding composition.
• a rapid pressure release of a polymer molding compound or polymer melt in the third stage (stage c) loaded and tempered according to the invention leads to stable nanoporous polymer foams with low density.
• a pressure release rate in the range of 15,000 to 2,000,000 MPa / s, a polymeric molding compound having a very high blowing agent concentration and correspondingly low viscosity, even at homogeneous foaming temperatures above the glass transition temperature of the non-gas-loaded molding composition, can be reduced to a nanoporous foam morphology with significantly less Foam density are produced.
• pressure release rates of 30,000 to 1 .000,000 MPa / s, more preferably 40,000 to 500,000 MPa / s are set. According to another embodiment of the invention, pressure release rates of 15,000 to 200,000 MPa / s may be sufficient.
• a pressure release of the polymer melt laden with propellant and tempered in stage b) takes place at a pressure release rate in the range from 15,000 to 2,000,000 MPa / sec.
• the pressure relief rate refers to the pressure jump occurring within a period of one second before foaming.
• the pressure drop is at least 10 MPa.
• the pressure before the relaxation can be determined via a pressure sensor. Usually it is relaxed to atmospheric pressure. However, a slight overpressure or negative pressure can also be applied. As a rule, the pressure drop occurs abruptly within 0.1 to 10 ms.
• the pressure release rate can be determined, for example, by applying a tangent in the region of the greatest pressure drop in the pressure-displacement diagram. In the continuous embodiment by means of an extruder, the pressure release rate is usually adjusted via the shape of the nozzle.
• a nozzle with at least one nozzle section which preferably has lengths of 1 to 5 mm and a cross section of 0.1 to 25 mm 2, is used for this purpose.
• this third stage can be realized in different ways in the different process variants.
• the pressure release rate according to the invention can optionally be ensured by means of rapidly switching valves or via the controlled response of pressure relief devices, such as, for example, a rupture disk.
• the adjustment of the pressure release rate can take place via rapid enlargement of the cavity.
• the pressure release rate is ensured by the delivery rate of the extruder and the nozzle geometry.
• the present invention relates to other technically feasible apparatuses and methods for producing such nanoporous polymer foams which are familiar to the expert skilled in the art by the above-described inventive rapid depressurization of a polymeric molding composition which has been tempered according to the invention.
• inventive rapid depressurization of a polymeric molding composition which has been tempered according to the invention.
• full profiles or hollow profiles are produced.
• the polymer foam is comminuted in a further process step into shaped bodies in the form of foamed polymer particles, granules or powders, for example by means of a separating disk, a granulator, a blade, a fly knife or a mill.
• the comminution step can preferably be connected directly after the pressure release, but can also be carried out separately at a later time. It may be advantageous to cool the polymer foam, for example by means of ice water, dry ice or liquid nitrogen.
• thermoplastically processable polymers for the polymer matrix according to the invention are amorphous, thermoplastic polymers
• Suitable polymers are all those which are pharmaceutically acceptable.
• water-soluble or water-dispersible polymers are used.
• amphiphilic copolymers are suitable as matrix material for the foamed molding compositions.
• Particularly suitable amphiphilic copolymers are polyether-containing graft polymers. These are obtained by radical polymerization of vinyl monomers in the presence of a polyether component, which serves as a grafting base.
• polyether graft polymers which are obtained by free-radically initiated polymerization of a mixture of i) 30 to 80% by weight of N-vinyllactam, ii) 10 to 50% by weight of vinyl acetate and iii) 10 to are suitable for the preparation of the foamed preparations 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight.
• the polyether copolymers are readily soluble in water, which means that 1 part of copolymer dissolves in 1 to 10 parts of water at 20 ° C.
• preferred polyether copolymers obtained from: i) 30 to 70% by weight of N-vinyllactam
• Particularly preferably used polyether copolymers are obtainable from: i) 40 to 60 wt .-% N-vinyl lactam
• polyether copolymers are obtainable from i) 50 to 60 wt .-% N-vinyl lactam
• iii) from 10 to 20% by weight of a polyether. It is also true for the preferred and particularly preferred compositions that the sum of components i), ii), and iii) is equal to 100% by weight.
• N-vinyllactam are N-vinylcaprolactam or N-vinylpyrrolidone or mixtures thereof. Preference is given to using N-vinylcaprolactam.
• the graft is polyether.
• Suitable polyethers are preferably polyalkylene glycols.
• the polyalkylene glycols may have molecular weights of from 1000 to 100,000 D [daltons], preferably from 1500 to 35,000 D, more preferably from 1,500 to 10,000 D. The molecular weights are determined on the basis of the measured according to DIN 53240 OH number.
• polyalkylene glycols are polyethylene glycols. Also suitable are polypropylene glycols, polytetrahydrofurans or polybutylene glycols obtained from 2-ethyloxirane or 2,3-dimethyloxirane.
• Suitable polyethers are also random or block copolymers of polyalkylene glycols obtained from ethylene oxide, propylene oxide and butylene oxides, such as, for example, polyethylene glycol-polypropylene glycol block copolymers.
• the block copolymers may be of the AB or ABA type.
• the preferred polyalkylene glycols also include those which are alkylated at one or both OH end groups.
• Suitable alkyl radicals are branched or unbranched C to C22-alkyl radicals, preferably C 1 -C 6 -alkyl radicals, for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl , Dodecyl, tridecyl or octadecyl radicals.
• General processes for the preparation of the polyether copolymers according to the invention are known per se.
• the preparation is carried out by free-radically initiated polymerization, preferably in solution, in nonaqueous, organic solvents or in mixed nonaqueous / aqueous solvents.
• Suitable production processes are described, for example, in WO 2007/051743 and WO 2009/013202, the disclosure of which is expressly referred to with regard to the preparation process.
• amphiphilic copolymer used is preferably a copolymer commercially available under the brand name Soluplus®, from BASF SE.
• graft polymers which consist of polyethers as the graft base and grafted polyvinyl alcohol units.
• suitable polymers are, for example, water-soluble, melt-processable homopolymers or random copolymers of N-vinylpyrrolidone or mixtures thereof
• the polymers usually have glass transition temperatures in the range of 80 to 190, preferably 90 to 175 ° C. Suitable homopolymers
• polymers having Fikentscher K values are in the range of 10 to 30.
• Suitable copolymers may include as comonomers unsaturated carboxylic acids, e.g. Methacrylic acid, crotonic acid, maleic acid, itaconic acid, and esters thereof with alcohols having 1 to 12, preferably 1 to 8 carbon atoms,
• Preferred comonomers are acrylic acid and, most preferably, vinyl acetate.
• the comonomers may be present in amounts of from 20 up to 70% by weight
• copolymers which are obtained from 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate.
• Suitable polymers are, for example, homopolymers or copolymers of vinyl chloride, polyvinyl alcohols, polystyrene, polyhydroxybutyrates or copolymers of ethylene and vinyl acetate.
• water-soluble or water-dispersible block copolymers are also suitable, for example those with vinyllactam blocks.
• the polymer matrix may also contain polymers which are sparingly soluble in water.
• water sparingly soluble polymers in the context of the invention are either neutral poorly soluble polymers (slow release polymers), anionic poorly soluble polymers (enteric polymers) or basic poorly soluble polymers to understand.
• sparingly soluble polymers are meant those polymers which are water-sparingly soluble over the entire pH range of 1 to 14 or only swellable in water. As a rule, only one water-insoluble polymer is contained in the pharmaceutical composition. However, if appropriate, two or more water-insoluble polymers may also be present next to one another or in a mixture. Suitable sparingly soluble polymers are, for example:
• Neutral or substantially neutral methacrylate copolymers may in particular consist of at least 95, in particular at least 98, preferably at least 99, in particular at least 99, particularly preferably at 100% by weight.
• Suitable (meth) acrylate monomers with neutral radicals are, for. B.
• Residues, z For example, acrylic acid and / or methacrylic acid.
• Eudragit NE is a copolymer of 30% by weight of ethyl acrylate and 70% by weight.
• sparingly soluble (meth) acrylate copolymers are, for example, polymers which are soluble or swellable independently of the pH and which are suitable for pharmaceutical coatings.
• the sparingly soluble polymer can be a polymer of 98 to 85% by weight of C1 bis
• the sparingly soluble polymer can also be a polymer of 97 to more than 93% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 3 to less than 7% by weight of (meth) acrylate monomers having a quaternary
• 2-trimethylammoniumethyl methacrylate chloride is particularly preferred.
• An exemplarily suitable copolymer contains 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonium ethyl methacrylate chloride (Eudragit RS).
• the sparingly soluble polymer may be a polymer of 93 to 88% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7 to 12% by weight of (meth) acrylate monomers having a quaternary ammonium group (Eudragit RL type).
• a concrete suitable copolymer contains z. B. 60 wt .-% methyl methacrylate, 30 wt .-% ethyl acrylate and 10 wt .-%
• the water-insoluble polymer may be a mixture of polymers of the type
• Eudragit RS and type Eudragit RL in the ratio 20 to 1 to 1 to 20.
• the pharmaceutical composition may also contain a polyvinyl acetate as a sparingly soluble polymer.
• Suitable polyvinyl acetates are, for example, the homopolymers of vinyl acetate.
• sparingly soluble polyvinyl acetate copolymers for example water-insoluble copolymers of vinyl acetate and N-vinylpyrrolidone.
• Commercially available suitable polyvinyl acetates are, for example, Kollicoat® SR 30D or Kollidon® SR.
• alkylcelluloses such as, for example, ethylcellulose.
• hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose acetate phthalate.
• anionic sparingly soluble polymers can also be used.
• anionic polymers are preferably polymers with at least 5%,
• Suitable commercially available (meth) acrylate copolymers having anionic groups are the Eudragit® grades L, L100-55, S and FS.
• Suitable anionic (meth) acrylate copolymers are, for. B. Polymers of 25 to 95, wt .-% C1 to C4 alkyl esters of acrylic or methacrylic acid and 5 to 75 wt .-% of (meth) acrylate monomers having an anionic group. Depending on the content of anionic groups and the character of the further monomers, corresponding polymers are water-soluble at pH values above pH 5.0 and thus also intestinal juice-soluble. As a rule, the proportions mentioned add up to 100% by weight.
• a (meth) acrylate monomer having an anionic group may e.g. As acrylic acid, but preferably be methacrylic acid.
• anionic (meth) acrylate copolymers of 40 to 60, wt .-% methacrylic acid and 60 to 40 wt .-% methyl methacrylate or 60 to 40 wt .-% ethyl acrylate. (Types Eudragit L or Eudragit L1 00-55).
• EUDRAGIT L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid.
• Eudragit L1 00-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.
• Eudragit L 30D-55 is a dispersion containing 30% by weight.
• anionic (meth) acrylate copolymers of from 20 to 40% by weight of methacrylic acid and from 80 to 60% by weight of methyl methacrylate (type Eudragit® S).
• Eudragit FS is a copolymer of 25% by weight, methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid.
• Eudragit FS 30 D is one
• Dispersion containing 30% by weight of Eudragit® FS.
• copolymers preferably consist essentially or exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the above
• copolymers can be prepared by conventional methods of radical
• the average molecular weight M w (weight average, determined, for example, by measuring the solution viscosity) can be determined by e.g. In the range of 80,000 to 1,000,000 (g / mol).
• the emulsion polymerization in the aqueous phase is preferably in the presence of water-dissolved initiators and (preferably anionic) emulsifiers.
• the copolymer may be processed in solid form by crushing, extrusion, granulation or hot stamping.
• Basic sparingly soluble polymers It is also possible to use basic polymers such as basic meth (acrylates) or chitosan.
• An example of a corresponding commercially available polymer is Eudragit® E or EPO, which is a copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate.
• nanoporous foamed active substance preparations according to the invention can contain as active ingredients all biologically active substances which can be incorporated undecomposed into the polymer melt under the processing conditions.
• active ingredients are, for example:
• Levothyroxine Lidocaine, Lipase, Lisinopril, Loperamide, Lorazepam, Lovastatin, Medroxyprogesterone, Menthol, Methotrexate, Methyldopa, Methylprednisolone, Metoclopramide, Metoprolol, Miconazole, Midazolam, Minocycline, Minoxidil, Misobrostol, Morphine, Multivitamins and Minerals, Nystatin, N-Methylephedrine, Naftidrofuril, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, ofloxacin, omeprazole, ondans
• Vitamins can also be formulated according to the invention. These include the vitamins of the A group, the B group, which in addition to B1, B2, B6 and B12 and nicotinic acid and nicotinamide including compounds with vitamin B properties are understood, such.
• Folic acid orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and alpha-lipoic acid, furthermore vitamins of the C group, D group, E group, F group, H group, I and J group, K group and P group.
• active ingredients are also pesticides, other biocides or veterinary substances into consideration.
• the preparations according to the invention are preferably suitable for embedding active ingredients which are sparingly soluble in water.
• the term "sparingly soluble in water” is understood according to the invention as follows:
• the term "sparingly soluble in water” according to the invention comprises sparingly soluble to virtually insoluble substances and means that for a solution of the substance to be dissolved in water at 20 ° C at least 100 g Water per g of substance is needed. In the case of practically insoluble substances, at least 10,000 g of water are required per g of substance.
• the active compound preparations may also contain starches, degraded starches, casein, pectin, chitin, chitosan, gelatin or shellac as matrix components, which can be processed in the melt with the addition of customary plasticizers.
• preparations according to the invention may contain the usual pharmaceutical auxiliaries, such as fillers, lubricants, mold release agents,
• examples of fillers which may be mentioned are the oxides of magnesium, aluminum, silicon and titanium and lactose, mannitol, sorbitol, xylitol, pentaerythritol and its derivatives, the amount of filler being in the range from 0.02 to 50, preferably 0.2 to 20,% by weight .-% lies.
• flow control agents e.g. the mono-, di- and triglycerides of the long-chain fatty acids such as C12, C14, C16 and C18 fatty acids, waxes such as carnauba wax and the lecithins mentioned, wherein the amount in the range of 0.1 to 30, preferably 0.1 to 5% by weight.
• plasticizers e.g. in addition to low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol also
• polyhydric alcohols such as propylene glycol, glycerol, pentaerythritol and sorbitol, and sodium diethylsulfosuccinate, mono-, di- and triacetate of glycerol and polyethylene glycol stearate.
• the amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 wt .-%.
• lubricants e.g. Stearates of aluminum or calcium and talc and silicones mentioned, wherein their amount is in the range of 0.1 to 5, preferably 0.1 to 3 wt .-%.
• stabilizers for example, light stabilizers, antioxidants, free-radical scavengers and stabilizers against microbial attack may be mentioned, wherein
• the active ingredient component can either be mixed in advance with the polymer and then extruded, or else metered in during the extrusion of the blowing agent-containing polymer melt.
• the proportions of the individual components in the preparation can be varied within wide limits. Depending on the effective dose and release rate
• the active ingredient may amount thereof 0.1 to 90 wt .-% of the active ingredient preparation.
• the amount of the polymer may be 10 to 99.9 wt .-%.
• 0 to 50 wt .-% of one or more auxiliaries may be included.
• the foamed forms can also be provided with a conventional drug-permeable Ü-coating, so easily floating
• swimming forms can be obtained. Such swimming forms can be used for pharmaceutical purposes or for veterinary or agricultural purposes
• Products are used, for example, for the production of slowly sinking fish food.
• the solid, foamed active substance preparations obtained according to the invention which contain the active ingredient homogeneously dispersed in the polymeric matrix, dissolve very rapidly and thus allow the rapid release of the active ingredient.
• Active ingredient preparations can be obtained in a simple and economical manner. It is also advantageous that can be extruded at significantly lower temperatures than without blowing agent by the viscosity-reducing effect of the blowing agent, so that the active ingredients are thermally less stressed.
• the active substance is embedded in amorphous form.
• Amorphous means that no more than 3% by weight of the active ingredient, measured by DSC, is in crystalline form.
• the DSC measurement is carried out at a heating rate of 20 K / min.
• the foamed active ingredient preparation is then shaped into the respectively desired active substance forms, for example by pelleting, granulation or tableting by known processes.
• the foamed preparations can be comminuted for example by grinding and then filled into capsules.
• the foamed sample was ground after cooling with an analytical mill (IKA A10) for 30 s.
• IKA A10 analytical mill
• the sieve fraction was used, which was smaller than 250 ⁇ after grinding.
• the produced polymer foams were examined by XRD (X-ray diffractometry) and DSC (Differential Scanning Calorimetry) for crystallinity or amorphicity using the following equipment and conditions:
• Measuring instrument Diffractometer D 8 Advance with 9-fold sample changer (Fa.Bruker / AXS)
• the milled foams were filled into hard gelatin capsules.
• the release of active ingredient was in accordance with USP. Apparatus (paddle method) 2, 37 ° C, 50 rpm (BTWS 600, Pharmatest) in 0.1 molar hydrochloric acid for 2 h.
• the detection of the released active ingredient was carried out by UV spectroscopy (Lamda-2, Perkin Elmer).
• the drawn samples were diluted with methanol immediately after filtration to prevent crystallization of the sparingly soluble drug.
• polymer 1 a graft copolymer of polyethylene glycol 6000 / N-vinylcaprolactam and vinyl acetate in a weight ratio of 13/57/30 (Soluplus®, BASF) was used.
• the K value was 31-41, measured 1 wt .-% strength in ethanol.
• the glass transition temperature of the polymer was 75 ° C as determined by DSC.
• the polymer was in the form of granules.
• polymer 2 was a random copolymer of methacrylic acid / ethyl acrylate in the weight ratio 1: 1 with an average molecular weight M w in the range of
• Example 1 (according to the invention):
• polymer 1 was used. 200 mg of polymer in the form of a sample pressed at 180 ° C (diameter of 4.5 mm in a brass mold for 5 minutes at 180 ° C and a pressing force of 50 kN) were placed in a temperature-controllable vertical steel autoclave with an internal volume of 2.5 ml brought to the foaming temperature listed below. This autoclave was equipped with a pressure sensor at the top which measures the internal pressure at a rate of 1 / ms. Pressure and temperature were recorded continuously via a computer.
• the foaming temperature was determined as the directly measured temperature of the rupture disk attached to the underside of the autoclave. de, with the polymer lying on the rupture disk.
• an automatic screw press pump SITEC Model C
• the stated propellant was then pumped in the supercritical state and applied the respective loading pressure.
• the pressure was readjusted within the first hour until a stable equilibrium state and a stable temperature of the rupture disk had set.
• the sample was saturated for 22 h under constant conditions, even if a state of equilibrium is established after a shorter time.
• the pressure of the supercritical propellant in the chamber was then increased over the spindle press pump over a period of a few seconds until the failure pressure of the rupture disk was reached.
• the pressure relaxation rate according to the invention was subsequently determined by evaluating the pressure data of the sensor. Here, a linear pressure drop was assumed. The foam experiment showed an almost complete pressure drop in the range of 2 ms, whereby the undershooting of the saturation pressure determining the cell nucleation took place even faster.
• the foamed sample was collected after exiting the pressure chamber through the hole forming in the rupture disk in a sponge and could be stably handled and examined directly after the foaming process.
• the density of the foamed shaped bodies was determined mathematically from the mass to volume ratio, while the cellular parameters such as the mean cell diameter were determined by evaluation of scanning electron micrographs at at least 2 locations in the foam. For the statistical evaluation, images with at least 10 whole cells in the image section were used.
• Example 2 (according to the invention):
• Polymer 1 was also used for Example 2 according to the invention.
• 30 g of polymer were premixed with 4.5 g of itraconazole (melting point of 166 ° C) (corresponding to a loading of 15 wt.% Based on the mass polymer) and melted in a high pressure capillary rheometer (Rheograph 2003) and by a punch through a extruded static mixer (Sulzer SMXS with a length of 18 mm) and a round die at a temperature of 150 ° C.
• 200 mg of the polymeric molding composition containing 15% by weight of itraconazole was in the form of a pressed at 180 ° C (diameter of 4.5 mm in a brass mold for 5 minutes at 180 ° C and a pressing force of 50 kN).
• a pressed at 180 ° C diameter of 4.5 mm in a brass mold for 5 minutes at 180 ° C and a pressing force of 50 kN.
• 20 h at 50 ° C dried in a vacuum oven in a specially made, temperature-controlled vertical steel autoclave with an internal volume of 2.5 ml on the below listed foaming temperature.
• This autoclave is equipped with a pressure sensor at the top, which measures the internal pressure at a rate of 1 / ms. Pressure and temperature were recorded continuously via a computer and could then be evaluated. It should be noted that the foaming temperature was taken as the directly measured temperature of the bottom rupture disk on which the polymer lay.
• the sample was saturated for 22 h under constant conditions, even if a state of equilibrium is established after a shorter time.
• the density of the foamed moldings was determined mathematically from the mass to volume ratio, while the cellular parameters such as the average cell diameter were determined by evaluation of scanning electron micrographs at least 2 locations in the foam. For the statistical evaluation, images with at least 10 whole cells in the image section were used.
• FIG. 1 shows a representative scanning electron micrograph of the foamed preparation, from which the bicontinuous open-cell structure emerges.
• the foamed sample was examined by XRD and DSC and found to be amorphous.
• Example 2 200 mg of the polymeric molding composition were processed and foamed analogously to Example 2. The characterization was carried out as described in Example 2. Polymer PropellantTemperaSattiVersagensPerformanceRequency Mean Pressurization Time [GPa / s] Pressure Burst [h] [MPa]
• the foamed sample was examined by XRD and DSC and found to be amorphous.
• the foamed sample was examined by XRD and DSC and found to be amorphous.
• polymer 2 was used. 30 g of polymer were extruded with 6 g of itraconazole (corresponding to a loading of 20% by weight, based on the mass polymer) and analogously to Example 2 at a temperature of 180 ° C.
• FIG. 2 shows a representative scanning electron micrograph of the foamed preparation, from which the bicontinuous open-cell structure emerges.
• a solid foamed preparation of active compound which contained the active ingredient homogeneously dispersed in the polymeric matrix, was prepared in a continuous extrusion process.
• step 1 of the foaming process the polymer-active molding compound was melted in an extruder (Leistritz 18 mm) at a throughput of 2.5 kg / h and homogenized.
• a mass flow in the range of 0.800 kg / h of CO2 was set, resulting in a loading in the range of 32 wt .-%, based on the mass polymer and active ingredient, resulted. (800 g / h C02 / 2500 g / h polymer + active ingredient).
• the loaded molding compound was then lowered over mixing and cooling elements to a temperature in the range of 50 ° C in front of the nozzle.
• the pressure along the process line after the propellant injection was kept above a minimum value of 35.0 MPa by the use of melt pumps.
• This process according to the invention resulted in a continuously extruded optically homogeneous nanoporous foam having an average density of 380 kg / m 3 and an average cell diameter of 270 nm.
• the foamed sample was examined by XRD and DSC and found to be amorphous.
• FIG. 3 shows a representative scanning electron micrograph of the foamed preparation, from which the bicontinuous open-cell structure emerges.

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