EP1137404A2 - Systemes noyau-coque nanoparticulaires et leur utilisation dans des preparations pharmaceutiques et cosmetiques - Google Patents

Systemes noyau-coque nanoparticulaires et leur utilisation dans des preparations pharmaceutiques et cosmetiques

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Publication number
EP1137404A2
EP1137404A2 EP99963399A EP99963399A EP1137404A2 EP 1137404 A2 EP1137404 A2 EP 1137404A2 EP 99963399 A EP99963399 A EP 99963399A EP 99963399 A EP99963399 A EP 99963399A EP 1137404 A2 EP1137404 A2 EP 1137404A2
Authority
EP
European Patent Office
Prior art keywords
core
active ingredient
shell
preparations
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP99963399A
Other languages
German (de)
English (en)
Inventor
Robert Heger
Helmut Auweter
Jörg Breitenbach
Heribert Bohn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
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Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP1137404A2 publication Critical patent/EP1137404A2/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • Nanoparticulate core-shell systems and their use in pharmaceutical and cosmetic preparations
  • the present invention relates to nanoparticulate preparations of active pharmaceutical ingredients with a core-shell structure, the active ingredient being present in the core in X-ray amorphous form together with at least one polymer and the shell consisting of a polymeric shell matrix.
  • EP-A 425 892 discloses a process for improving the bioavailability of active pharmaceutical ingredients with peptide bonds, a solution of the active ingredient in a water-miscible organic solvent being rapidly mixed with an aqueous colloid, so that the active ingredient precipitates in a colloidally dispersed form .
  • EP-A 276 735 describes protective colloid-coated active ingredient particles in which the active ingredient is dispersed in an oil phase. However, compatibility problems often occur in oil phases.
  • Particulate pharmaceutical preparations of poorly water-soluble substances are known from EP-A-0169, the preparations being obtained by precipitation from a solution of the active ingredient after addition of a precipitation solution.
  • WO 93/10767 describes oral administration forms for peptide medicaments in which the medicament is incorporated into a gelatin matrix in such a way that the colloidal particles which form are present in a charge-neutral manner.
  • a disadvantage of such forms, however, is their tendency to flocculate.
  • EP-A 0605 497 describes nanoparticles in which the active substance is stabilized in a lipid matrix.
  • lipid matrices are unstable against shear forces, which can cause problems during further processing.
  • DE-A 4440337 describes the production of nanosuspensions stabilized with surfactants. However, high surfactant concentrations can be physiologically questionable.
  • crystalline nanoparticles by special grinding processes is described in US Pat. No. 5,145,684 and US Pat. No. 5,399,363.
  • crystalline nanoparticles generally have one poorer bioavailability and can also cause problems due to the polymorphism of some active ingredients.
  • No. 4,826,689 describes a precipitation process in which amorphous spherical particles are obtained which are stabilized by no further addition or only slight additions of surfactants. The shear stability of such systems and the possibility of sterilization is low.
  • EP-A 275,796 describes the production of colloidal dispersible systems with spherical particles smaller than 500 nm, which is not a core-shell structure but a matrix structure.
  • WO 97/14407 describes the production of nanoparticles by expansion from a solvent into a compressed gas, liquid or a supercritical fluid in the presence of an amphiphile.
  • hydrosols of solid particles of a cyclosporin and a stabilizer which maintains the degree of division of the particles The particle size of these hydrosols is in the colloidal range.
  • the hydrosol particles described consist of active substance.
  • a disadvantage of these hydrosols is that the particle size of the hydrosol particles increases significantly over time. This applies in particular when the dispersing phase of the hydrosol contains active ingredient solvents. This active ingredient solvent is used in the manufacture of the hydrosol particles and must then be removed as quickly as possible.
  • the growth of the hydrosol particles can be attributed to the so-called Ostwald maturation, in which active substance molecules are transported from small hydrosol particles to large hydrosol particles via the dispersing phase. That smaller particles slowly dissolve and larger particles grow slowly. Since the active ingredient cyclosporin has a low residual solubility even in solvent-free water, an increase in the hydrosol particles cannot be prevented there either.
  • the nanoparticulate preparations of active pharmaceutical ingredients according to the invention have been found which have a core-shell structure, the core of the active ingredient being in X-ray amorphous form in a polymer matrix and the shell consisting of a stabilizing shell matrix of a polymer with protective colloid properties.
  • At least two separate phases are preferably present in the core, one phase consisting of discrete, X-ray amorphous particles of the active substance in, while the other phase represents a molecularly disperse distribution of the active substance in one or more polymers.
  • the core is single-phase or two-phase depends essentially on the quantity ratio of core polymer to active ingredient.
  • the release pressure of the substance increases with decreasing particle size of the active substance. This results in an increased saturation solubility. According to Noyes-Whitney, the increased saturation solubility leads to an increase in the dissolution rate.
  • the biologically active substance is present in an energetically unstable, metastable state in the formulations according to the invention. If the nanoparticle is not sufficiently stabilized, this can lead to spontaneous crystallization in some cases, the active substance precipitates out of the stabilized form.
  • the colloidal active substance preparations according to the invention in contrast to known active substance preparations, which essentially consist exclusively of active substance mass in the core of the colloidal particles, show a significantly lower growth of the hydrosol particles.
  • the particle growth is reduced by a factor of 1.5 - 5.
  • the colloidal particles present in the active substance preparation according to the invention have a polymer shell which envelop the core of the particles.
  • the purpose of this polymer shell is to stabilize the colloidal state against heterogeneous particle growth (aggregation, flocculation etc.).
  • colloidal particles present in the active substance preparation according to the invention have a core
  • the active substance inside this core is in X-ray amorphous form. It is essential that no crystalline active ingredient components are detectable in the active ingredient preparation (X-ray diffraction).
  • the polymers inside the particles help to maintain the active substance in its non-crystalline state and to stabilize the colloidal structures with regard to homogeneous particle growth (Ostwald ripening).
  • Suitable polymeric stabilizers for the shell matrix of the shell are, according to the invention, swellable protective colloids such as, for example, beef, pork or fish gelatin, starch, dextrin, pectin, gum rabicum, lignin sulfonates, chitosan, polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, carboxymethyl cellulose, and hydroxyl methyl cellulose , Milk powder, dextran, whole milk or skimmed milk or mixtures of these protective colloids.
  • swellable protective colloids such as, for example, beef, pork or fish gelatin, starch, dextrin, pectin, gum rabicum, lignin sulfonates, chitosan, polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, carboxymethyl cellulose, and hydroxyl methyl cellulose , Milk powder, dextran
  • Homo- and copolymers based on the following monomers are also suitable: ethylene oxide, propylene oxide, acrylic acid, maleic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, ⁇ - and ⁇ -aspartic acid.
  • gelatin types mentioned is particularly preferably used, in particular acidic or basic degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 as well as low molecular weight, enzymatically degraded gelatin types the Bloom number 0 and molecular weights of 15,000 to 25,000 D such as Collagel A and Gelitasol P (from Stoess, Eberbach) and mixtures of these types of gelatin.
  • the preparations also contain low molecular weight surface-active compounds.
  • amphiphilic compounds or mixtures of such compounds are particularly suitable. Basically, all surfactants with an HLB value of 5 to 20 can be used.
  • surface-active substances are, for example: esters of long chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their ethoxylation products, esters of monofatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyltartaric acid, polyglycerol fatty acid esters such as the monostearate of Triglyce- rins, sorbitan fatty acid esters, Propylenglykolfettklasteder , 2- (2'-stearoyllactyl) lactic acid salts and lecithin.
  • Ascorbyl palmitate is preferably used.
  • all polymers which are in the core of the particles of the active substance preparation according to the invention are suitable as polymer constituents which are in a temperature range between 0 and 240 ° C, a pressure range between 1 and 100 bar, a pH range from 0 to 14 or ionic strengths up to 10 mol / 1 are not or only partially soluble in water or aqueous solutions or water-solvent mixtures.
  • insoluble or only partially soluble means that the second virial coefficient for the polymer or polymers in water or a mixture of water and an organic solvent can assume values of less than zero.
  • the 2nd virial coefficient which provides information about the behavior of a polymer in a solvent (mixture), can be determined experimentally, for example by measuring light scattering or determining the osmotic pressure. The dimension of this coefficient is (mol-l) / g 2 .
  • One or more polymers can be used.
  • the molar masses of the polymers used are in the range from 1000 to 10000000 g / mol, preferably in the range from 1000 to 1000000 g / mol. Basically, all polymers suitable for the pharmaceutical and cosmetics application field can be considered.
  • polymers which are soluble in organic, water-miscible solvents and which are not or only partially soluble in water or aqueous solutions or water-solvent mixtures at temperatures between 0 and 240 ° C.
  • the following polymers are mentioned by way of example, but are not restrictive:
  • Poly (vinyl ethers) such as poly (benzyloxyethylene), poly (vinyl acetals), poly (vinyl ketones), poly (allyl alcohol), poly (vinyl esters such as poly (vinyl acetate), poly (oxytetramethylene), poly (glutaraldehyde), Poly (carbonate), poly (ester), poly (siloxane), D, L-poly (lactide), poly (lactide), poly (glycolide), poly (D, L-lactide-co-glycolide), poly (amide ), Poly (piperazines), poly (anhydrides) such as poly (metharylanhydride), Gutta Percha, cellulose ethers such as methyl cellulose (3% to 10% substitution), ethyl cellulose, butyl cellulose, cellulose esters such as cellulose acetate or starches
  • copolymers and block copolymers of the monomers of the abovementioned polymers furthermore copolymers and block copoly
  • polymers which have an upper and / or lower mixture gap at temperatures between 0 and 240 ° C. in water or aqueous solutions or water-solvent mixtures, ie by increasing or lowering the temperature, these polymers can be precipitated from corresponding solutions .
  • the following polymers are mentioned as examples, but are not restrictive:
  • AB or ABA block copolymers based on ethylene oxyiod and propylene oxide, e.g. Poloxamers such as Poloxamer 188 and Poloxamer 407.
  • polymers which can be precipitated from corresponding solutions at temperatures between 0 and 240 ° C. in water or aqueous solutions or water-solvent mixtures by varying the pH or the ionic strength.
  • the following polymers are mentioned as examples, but are not restrictive:
  • the amounts of the various components are chosen according to the invention so that the preparations 0.1 to 70% by weight, preferably 1 to 40% by weight, of active ingredient, 1 to 80% by weight, preferably 10 to 60% by weight. % of one or more polymeric stabilizers (shell polymer), 0.01 to 50% by weight, preferably 0.1 to 30% by weight of one or more polymers for the core, and 0 to 50% by weight, preferably 0.5 to 10 wt .-% of one or more low molecular weight Contains stabilizers. The percentages by weight relate to a dry powder.
  • the preparations may also contain antioxidants and / or preservatives to protect the active ingredient.
  • Suitable antioxidants or preservatives are, for example, ⁇ -tocopherol, t-butylhydroxytoluene, t-butylhydroxyanisole, lecithin, ethoxyquin, methylparaben, propylparaben, sorbic acid, sodium benzoate or ascorbyl palmitate.
  • the antioxidants or preservatives can be present in amounts of 0 to 10% by weight, based on the total amount of the preparation.
  • the preparations may also contain plasticizers to increase the stability of the end product.
  • plasticizers are, for example, sugars and sugar alcohols such as sucrose,
  • Lactose is preferably used as the plasticizer.
  • the plasticizers can be contained in amounts of 0 to 50% by weight.
  • auxiliaries such as binders, disintegrants, flavors, vitamins, colorants, wetting agents, additives influencing the pH value (cf. H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978) can also be used via the organic solvent or aqueous phase are introduced.
  • a solution of the active ingredient is first prepared in a suitable solvent, solution in this context meaning a true molecularly disperse solution or a melt emulsion.
  • a suitable solvent solution in this context meaning a true molecularly disperse solution or a melt emulsion.
  • Suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, oxygen, nitrogen and sulfur. Expediently, they are at least 10% by weight miscible with water and have a boiling point below 200 ° C. and / or have less than 10 carbon atoms.
  • Corresponding alcohols, esters, ketones, ethers and acetals are preferred.
  • ethanol, n-propanol, isopropanol, butyl acetate, ethyl acetate, tetrahydrofuran, acetone, 1, 2-propanediol-1-n-propyl ether or 1, 2-butanediol-methyl ether are used.
  • Ethanol, isopropanol and acetone are very particularly preferred.
  • a molecularly disperse solution of the active ingredient in the selected solvent together with the polymer that in the active ingredient preparation in Core of the particles should be made.
  • This polymer has the property of being insoluble or only partially soluble in water in a certain temperature, pH or salt range.
  • the concentration of the active ingredient-polymer solution prepared in this way is generally 10 to 500 g of active ingredient per 1 kg of solvent and 0.01 to 400 g of polymer, the polymer-active ingredient weight ratio being between 0.01 to 1 and 5 to 1.
  • the low molecular weight stabilizer is added directly to the active substance-polymer solution.
  • the active substance-polymer solution is mixed with an aqueous solution of the polymeric shell material.
  • concentration of the polymeric shell material is 0.1 to 200 g / 1, preferably 1 to 100 g / 1.
  • a molecularly disperse solution of the active ingredient in the selected solvent is prepared without the polymer that should be in the core of the particles in the active ingredient preparation.
  • the concentration of the active ingredient solution thus prepared is generally 10 to 500 g of active ingredient per 1 kg of solvent.
  • this solution is mixed with an aqueous molecular solution of the polymer that should lie in the core of the particles in the active substance preparation.
  • concentration of the polymer solution thus prepared is generally from 0.01 to 400 g of polymer.
  • the temperatures, pH values and salt concentrations of the two solutions to be combined are selected so that the active ingredient and the polymer are insoluble after the solutions have been combined.
  • the low molecular weight stabilizer is added directly to the active ingredient solution.
  • the active substance-polymer precipitate is mixed with an aqueous solution of the polymeric shell material.
  • concentration of the polymeric shell material is 0.1 to 200 g / 1, preferably 1 to 100 g / 1.
  • a high mechanical energy input is recommended when mixing the cyclosporin solution with the solution of the coating material.
  • Such energy input can take place, for example, by vigorous stirring or shaking in a suitable device, or by injecting the two components with a hard jet injects a mixing chamber so that it mixes violently.
  • the mixing process can be carried out batchwise or, preferably, continuously. As a result of the mixing process, precipitation occurs.
  • the suspension or colloid obtained in this way can then be converted into a dry powder in a manner known per se, for example by spray drying, freeze drying or drying in a fluidized bed.
  • the person skilled in the art can determine which conditions are to be selected in the specific case when carrying out the method according to the invention with regard to varying the water / organic solvent system, the pH values, the temperatures or the ionic strengths by carrying out a few simple preliminary tests for the corresponding Determine polymer.
  • the primary dispersion can be subjected to drying processes known to the person skilled in the art.
  • the nanoparticulate systems according to the invention can also be dried after production, e.g. by spray drying or lyophilization and then redispersing again with almost the same particle size distribution.
  • This is of great advantage for all applications in which the preparation may have to be stored for a long time, is exposed to extreme loads such as heat or cold, or is to be converted from an aqueous carrier into other carriers as solvents.
  • the preparations according to the invention are therefore no longer bound to the solvent with which they were produced.
  • cryoprotective substances such as e.g. Trehalose or Polyvinypyrrolidone can be added.
  • dry powders can thus be obtained which no longer lose their properties obtained in the primary dispersion. That means the amorphous character of the active ingredient and the core-shell structure are retained. It is also a property according to the invention that, when redissolved, these dispersions, with a deviation of 20%, preferably ⁇ 15%, have the same particle size distribution that they had as the primary dispersion.
  • the interfacial tension of the nanoparticulate dispersions according to the invention is between 20-40 mN / m, preferably 10-30 nM / m.
  • the particle sizes of the core-shell structures are in the range from 0.1 to 2 ⁇ m, preferably 0.05 to 0.9 ⁇ m.
  • Suitable active ingredients are, for example:
  • Analgesics / anti-rheumatic drugs such as codeine, diclofenac, fentanyl, hydromorphone, ibuprofen, indomethacin, levomethadone, morphine, naproxen, pritramide, piroxicam, tramadol
  • Antiallergic agents such as astemizole, dimetinden, doxylamine, loratidine, meclozin, pheniramine, terfenadine
  • Antibiotics / chemotherapeutics such as erythromycin, framycetin, fusidic acid, rifampicin, tetracycline, thiazetazone, tyrothricin
  • Antiepileptics such as carbamazepim, clonazepam, mesuximide, phenytoin, valproic acid
  • Antifungals such as clotrimazole, fluconazole, itraconazole
  • Calcium antagonists such as darodipine, isradipine
  • Corticoids such as aldosterone, betametasone, budesonide, dexametasone, fluocortolone, fludrocortisone, hydroxycortisone, methyl prednisolone, prednisolone
  • Hypernicum Urtica folia, Artichoke, Agnus Castus, Cimicifuga, Devil's Claw, Broom, Broom, Peppermint Oil, Eucalyptus, Celandine, Ivy, Kava-Kava, Echinacea, Valerian, Sabalex tract, Hypericum, Milk Thistle, Ginkgoaden- soba, Aloe Allium sativum, Panax Ginseng, Serenoa Repens, Hydrastis canadensis, Vaccinium macrocarpon or mixtures thereof
  • Protease inhibitors e.g. B. saquinavir, indinavir, ritonavir, nelfinavir, palinavir or combinations of these protease inhibitors
  • Anabolic steroids, androgens, antiandrogens, estradiols, progestogens, progesterone, estrogens, antioestrogens such as tamoxifen
  • Vitamins / antioxidants such as carotenoids or carotenoid analogs, e.g. ß-carotene, canthaxanthin, astaxanthin, lycopene or lipoic acid
  • Busulfan carmustine, chlorambucil, cyclophosphamide, dacarbacin, dactinomycin, estramustine, etoposide, flurouracil, ifosfamid, methotrexate, paclitaxel, vinblastine, vincristine, vindisol
  • nanoparticulate preparations according to the invention are suitable in principle for the production of all pharmaceutical dosage forms: oral dosage forms, topical dosage forms such as dermatica, ophthalmica, pulmonary or nasal forms, buccal forms, anal or intravaginal forms, enteral and parenteral forms.
  • the preparations according to the invention can thus be processed into tablets, pellets, sachets, drinking formulations, suppositories, injection solutions or as capsule fillings.
  • Such formulations then represent examples of multiparticulate systems in which the nanoparticles, one phase, the preparation of the soft gelatin matrix, is another phase, which can also contain another or the same active ingredient.
  • the systems according to the invention can also be introduced into other matrices and thereby represent a separate phase from the rest of the matrix.
  • Such matrices can also be introduced into other matrices and thereby represent a separate phase from the rest of the matrix.
  • Tablets, suppositories or systems for pulmonary administration or transdermal application are particularly preferred.
  • amorphous active substance embedding a special special property of active substances, the polymorphism, should also be mentioned.
  • Many active ingredients exist in more than one crystalline form. In general, it can be assumed that more than 50% of all active substances exist in several crystalline forms. All these polymorphic modifications of an active substance are chemically identical, but have different physical properties such as melting point, density and solubility. The different modifications also have an impact on processability and, in the most critical case, on bioavailability.
  • the preparations according to the invention make it possible in a simple manner to convert active substances into the amorphous state and can also use products of the most varied particle size distribution and amorphous bulk materials as starting materials and thus the problem of different polymorphic forms and the associated possible disadvantages with regard to solubility, storage stability and Bypass bioavailability.
  • the nanoparticles according to the invention enable aseptic production and sterile filtration. Since solid tumors have the ability to filter particles from the blood stream, the preparations according to the invention are suitable for achieving tumor targeting. In this way, locally highly concentrated accumulations of cytotoxic substances can be achieved. Therapy of cancer diseases by the nanoparticulate systems according to the invention is therefore particularly preferred.
  • Cytostatics which are preferably suitable for the technology according to the invention are taxols such as paclitaxel, cis-platinum but also non-intercalating famesyl transferase inhibitors.
  • nanoparticulate systems can cross the blood-brain barrier and can therefore be used in particular in the field of therapy for CNS diseases.
  • nanoparticles according to the invention which are therefore particularly suitable for use in the treatment of diseases in the CNS area.
  • the polymer weight is significantly lower than in the forms described in EP-A 425 892, it is possible to obtain stable products adapted to the requirements.
  • the small number of auxiliaries is advantageous compared to other processes.
  • the preparations according to the invention of the amorphous core-shell nanoparticles often consist only of the polymeric carrier and the biologically active substance.
  • the amorphous core-shell nanoparticles according to the invention have a further advantage due to the method.
  • the intensive mixing of the biologically active substance from a solvent into a non-solvent enables small amounts of the polymer, which later aggregates by adsorption on the surface, to be introduced into the matrix during the formation of the spherical structure. This contributes to the stabilization of the amorphous and thus metastable state.
  • it is a multi-phase system with an outer shell composed of the polymeric additive responsible for the dispersion and an amorphous structure which, when dissolved, also contains the same polymeric or another additive as a crystallization inhibitor.
  • a special situation is the appearance of liquid crystalline systems in the amorphous phase of the preparations according to the invention.
  • Preparations of low molecular weight peptides such as the LMWH, can be administered orally and advantageously with the same formulation as an injection, the standard route of application currently used for deep vein thrombosis.
  • the preparations according to the invention are also suitable for colon targeting.
  • the preparations according to the invention can also be used in parenteral nutrition.
  • the preparation according to the invention can be used in particular for the formulation of vitamins and amino acids.
  • the preparations according to the invention can e.g. the necessary plasma peaks can be achieved with nicotine tartrate or nicotine base, which are of particular importance in the weaning process.
  • Topical application for hair growth agents such as minoxidil is also advantageous with the preparation according to the invention. Due to the structure, the hair follicles can be reached more easily.
  • the pulmonary application of the preparations according to the invention is particularly intended for the administration of protein and peptide therapeutic agents.
  • examples are vasopressin analog, LHRH antagonists, glucagon, parathyroid hormone, calcitonin, insulin, LHRH analog leuprolipids, granuloctye-colony stimulating factor and somatropin.
  • the application can also be carried out as an atomized aqueous suspension. It can be applied via the nose, bronchi or lungs. In the case of nasal application, it is particularly advantageous to choose an aqueous suspension, since this prevents irritation of the nasal mucous membranes and the sensation of burning by organic solvents.
  • the active substance class of leukotriene antagonists is particularly suitable as an area of application for the technology.
  • the preparations according to the invention can also be used to bring antisense active substances, ie oligonucleotides with a complementary base sequence to messenger RNA, into formulations that can be applied. Phosphorothioate oligonucleotides are preferred.
  • subcutaneous or intravenous administration as an infusion or injection can also be used for oral administration. However, dermal application and inhalation are also conceivable.
  • the forms according to the invention can be used in oral forms which can be used both from preparations in conventional tablets and in capsules.
  • the possibility of being able to produce suppositories which is ensured by the stability of the nanoparticles according to the invention when stirred into the carrier matrices, opens up this field of application. It is advantageous here that only a limited volume of liquid is available for rectal administration and that the preparations according to the invention can be dispersed and absorbed extremely well in the small volume of liquid.
  • mucoadhesive preparations with a nanoparticulate size can also be produced.
  • nanoparticulate preparations can ultimately lead to an increase in bioavailability. This can be of particular interest for nasal application.
  • the adherence of the nanoparticulate particles to the mucosa of the nasal mucosa has a positive effect on the otherwise too short dwell time and can thus contribute to increasing bioavailability.
  • the preparations according to the invention can also be used on the eye.
  • the nanoparticulate systems according to the invention form a separate phase which can guide the active ingredient in nanoparticulate amorphous form to the eye and is distributed homogeneously during the gel formation in the matrix.
  • Contrast agents for medical imaging diagnostics such as X-ray methods, scintigraphy, ultrasound, magnetic resonance imaging, fluorescence giography and ophthalmology can also be produced with the preparations according to the invention.
  • the nanoparticulate core-shell nanoparticles according to the invention can be used in cosmetics and dermatics to protect active substances sensitive to hydrolysis. Such preparations are also able to facilitate penetration between the stratum corneum cells due to the small particle size.
  • the preparations according to the invention can be used in the formulation of perfumes and decorative cosmetics, such as the introduction of dyes or pigments into lipsticks, eyeliner, eye shadows or nail polishes.
  • the preparations can also be used in creams, gels and ointments.
  • this coarsely disperse solution was mixed with 120 g of water at a mixing temperature of 200 ° C. for 0.3 s.
  • the average particle size was determined to be 260 nm with a variance of 42% by quasi-elastic light scattering. The average particle size only increased by one hour
  • Spray drying of the product la gave a nanoparticulate dry powder.
  • the active substance content in the powder was determined by chromatography to be 19.84% by weight.
  • the dry powder dissolves in drinking water to form a gelblieh-cloudy dispersion (hydrosol) with an average particle size of 306 nm with a variance of 48%.
  • the mean particle size increased by only approx. 30 nm to 349 nm within one hour.
  • An analogously produced colloidal ritonavir dispersion without collicoat shows an increase in the particle size by approx. 350 nm within one hour. This is summarized in Table 2.
  • Table 2 Table 2
  • this coarsely disperse solution was mixed with 120 g of water at a mixing temperature of 200 ° C. for 0.3 s.
  • Spray drying of the product 2a gave a nanoparticulate dry powder.
  • the active substance content in the powder was determined by chromatography to be 20.03% by weight.
  • the dry powder dissolves in drinking water to form a white, cloudy dispersion
  • Example 5 Analogously to Example 1, a micronizate which contained propafenone as active ingredient was produced. 5
  • Example 2 Analogously to Example 2, a micronized, which instead of the polymer Kolliciat ® MAE polymer as a poly (D, L-lactide-co-glycolide 10) (49 mole% D, L-lactide, 51 mol% glycolide) was manufactured.
  • this coarsely disperse solution was used with a mass flow of 1.8 kg / h
  • the mean particle size was found to be 796 nm with a variance of 81% by quasi-elastic light scattering.
  • the mean particle size was determined to be 256 nm with a variance of 56% by quasi-elastic light scattering.
  • the mean particle size was found to be 178 nm with a variance of 22% by quasi-elastic light scattering.
  • the following dosage forms can be produced:
  • nanoparticulate preparation (supported on lactose) are mixed with 10% by weight sucrose, 28% by weight microcrystalline cellulose, 3% by weight Kollidon VA 64 and 0.2% by weight Aerosil and then pressed directly.
  • the tablet weight is 250 mg.
  • the diameter is 8 mm.
  • a patch with a reservoir made of 17.5% by weight of polystyrene and 17.5% by weight of polyvinyl acetate and 30% by weight of the nanoparticles according to the invention was produced.
  • Cremophor is dissolved in the fat phase and water is added to this mixture with vigorous stirring. The mixture is stirred until it cools down and then the nanoparticle preparation is added and homogenized.
  • a preparation for topical use with the nanoparticulate core-shell preparations was obtained as follows: (in g / lOOg)
  • Aerosol 10 g of micronisate according to Example 1, 14 g of Kollidon K 25, preservative q.s., water ad 100 g. 7. Aerosol
  • 0.25% by weight of a nano-part budesonide preparation is mixed with a mixture of 4% by weight of ethanol and water (50:50) and 5.95.75% by weight of 1.1.1.2 tetrafluoroethane in an aluminum vessel under pressure bottled.
  • nanoparticle powder according to the invention is stirred into the mixture and the mass is applied on a non-woven plaster basis.
  • nanoparticles according to the invention 10% by weight. of the nanoparticles according to the invention, 30% by weight of a lactic acid-glycol copolymer, 10% by weight of ethanol, 50% by weight of isotonic saline solution 25

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Abstract

L'invention concerne des préparations nanoparticulaires de principes actifs pharmaceutiques et cosmétiques, comportant une structure noyau-coque et dans lesquelles le principe actif est présent sous forme amorphe aux rayons X dans le noyau, conjointement avec une matrice polymère, et la coque est constituée d'une matrice enveloppante à effet stabilisant.
EP99963399A 1998-12-08 1999-12-07 Systemes noyau-coque nanoparticulaires et leur utilisation dans des preparations pharmaceutiques et cosmetiques Ceased EP1137404A2 (fr)

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DE19856432 1998-12-08
DE19856432A DE19856432A1 (de) 1998-12-08 1998-12-08 Nanopartikuläre Kern-Schale Systeme sowie deren Verwendung in pharmazeutischen und kosmetischen Zubereitungen
PCT/EP1999/009545 WO2000033820A2 (fr) 1998-12-08 1999-12-07 Systemes noyau-coque nanoparticulaires et leur utilisation dans des preparations pharmaceutiques et cosmetiques

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