EP1487415A2 - Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive - Google Patents

Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive

Info

Publication number
EP1487415A2
EP1487415A2 EP03724926A EP03724926A EP1487415A2 EP 1487415 A2 EP1487415 A2 EP 1487415A2 EP 03724926 A EP03724926 A EP 03724926A EP 03724926 A EP03724926 A EP 03724926A EP 1487415 A2 EP1487415 A2 EP 1487415A2
Authority
EP
European Patent Office
Prior art keywords
substance
solvent
nanoparticles
particles
microparticles
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.)
Withdrawn
Application number
EP03724926A
Other languages
German (de)
English (en)
Inventor
Bernd W. MÜLLER
Norbert Rasenack
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.)
Pharmatech GmbH
Original Assignee
Pharmatech GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pharmatech GmbH filed Critical Pharmatech GmbH
Publication of EP1487415A2 publication Critical patent/EP1487415A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/14—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
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the invention relates to a process for the production of micro- and nanoparticles of solid substances by constructive micronization by means of dissolution and precipitation, and the use of these small particles.
  • Parrot describes the comminution using gas jet mills as "ineffective" (Parrot, EL, 1990. Comminution. In: Swarbrick, J., Boylan, JC (ed.), Encyclopedia of Pharmaceutical Technology, Vol. 3, Marcel Dekker Inc., New York, pp. 101-121).
  • water-soluble should mean that the water solubility is greater than 1 g / 100 ml.
  • drugs for use in a powder inhaler should show a low tendency to agglomerate, good flow properties and high batch conformity [York, P., Powdered raw materials: Characterizing batch uniformity. Proc. Resp. Drug del. IV (1994) 83-91]. These requirements often conflict with the properties of a material crushed by grinding. When grinding larger particles there is only a small possibility, the particle size and shape as well as the To influence surface properties and the electrostatic charge [Malcolmson, R. and Embleton, JK, Dry powder formulations for pulmonary delivery. PSTT 1 (1998) 394-399]. Alternative micronization processes are therefore available that do not require grinding, but rather provide the active ingredient with the required properties directly during its production.
  • Small spherical particles can be formed by spray drying a solution.
  • spray-dried active ingredients are mostly amorphous.
  • spray-dried, amorphous disodium cromoglycic acid (DNCG) only results in a fine particle fraction between 15% (Rotahaler ® ) and 36% (Dinkihaler ® at 90 1 / min) depending on the particle size used, air flow and inhaler [Chew, NYK] due to incomplete dispersibility , Bagster, DF and Chan, HK, Effect of particle size, air flow and inhaler device on the aerolization of disodium cromoglycate powders. Int. J. Pharm. 206 (2000) 75-83].
  • This technique is rarely used for poorly water-soluble active ingredients, since the organic solvents required here cause environmental toxicological problems and require a lot of equipment. It plays in the field of dye chemistry
  • Crystal size also plays an important role. For example, dispersions with coarsely crystalline beta-carotene are not colored. Colloidal systems are required to achieve staining.
  • Micronization by comminution of poorly soluble drugs is a widely used method to increase the rate of dissolution.
  • the most common way in pharmacy to produce small particles is comminution using various mills.
  • due to the formation of high-energy lipophilic breaking edges, among other things, such a method does not lead to the desired optimal products. Flotation frequently occurs as a problem and hinders a considerable dissolution of the active substance.
  • Tablets should be as small as possible. This means that an optimal tablet formulation should have the highest possible proportion of active ingredient.
  • the preparation should be designed so that it has the highest possible bioavailability. This means that a tablet should disintegrate quickly in the gastrointestinal tract and release the active ingredient quickly.
  • the active substance has to be required to have a high dissolution rate after the release. This is particularly important for those drugs in which the dissolution rate is the step determining absorption.
  • the loss due to the deposition of the particles outside the lungs, which can also lead to undesirable drug effects, must be avoided. The main part of the applied active substance should therefore reach its active site or absorption site in the lungs.
  • US-A-5 021 242 reports particle size reduction by means of a grinding process without auxiliary substances. It describes an increase in bioavailability through micronization.
  • US-A-5622938 describes an "unexpected bioavailability" as a result of a micronization process.
  • wet grinding is reported in the presence of a grinding medium that contains surface-active additives (surfactants based on sugar).
  • US-A-5747001 describes beclometazone nanoparticles which have been produced by a grinding process in the presence of surface-modifying substances.
  • US-A-5 091 187 and US-A-5 091 188 provide an overview of various methods for producing nanocrystals for intravenous application, the particles being coated with phospholipids. Only stabilization of nanocrystals by phospholipids is reported. Degrading processes (ultrasound, air jet mill, high-pressure homogenization) for reducing the particle size are described, but also constructive processes. In the case of the constructive methods, drug and phospholipid are combined in one organic
  • Solvent dissolved and then precipitated together by spray drying An "in-flight crystallization" is specified for this: A solution of the drug and lipid is spray-dried. The precipitation takes place during the spray drying of the solution. The particle size is thus determined by the spray drying process since there are no solid particles beforehand. Another method described is "solvent dilution". Here, an organic solution of the lipid and the drug is placed in water, causing the drug and the lipid to precipitate. The precipitated crystals are obtained by filtration or sedimentation. The two building processes mentioned are a water-insoluble coating of the crystals by a lipid. In this process, the lipophilic active ingredient is dissolved in the organic solvent together with a lipophilic auxiliary. Both, ie the active ingredient and the auxiliary, are precipitated out by adding water.
  • Pace et al. also describe micronization in the presence of phospholipids. (Pharmaceutical Technology, 1999 (3), pages 116-134). Comminution by means of shear forces or impaction by means of homogenization techniques or grinding techniques are described.
  • NanoCrystals are by a
  • the prerequisite is in any case the solution of the drug in an alkali and the addition of an anionic surfactant that has a molecular structure that is at least 75% consistent with the drug.
  • the precipitation is brought about by a pH shift into the acidic range.
  • US-A-5 700 471 describes the preparation of an amorphous dye or amorphous drug preparation.
  • the fabric is melted and the melt obtained is then emulsified in water and spray dried.
  • US-A-5133 908 describes a precipitation which leads to matrix formation.
  • the precipitation of a protein forms a colloidal preparation, the precipitation liquid having a temperature which is higher than the coagulation temperature of the protein.
  • Spherical particles of the matrix type are formed.
  • US Pat. No. 5,932,245 describes the production of nanoparticles from poorly water-soluble drugs. However, this requires a surface charge of the drug. Gelatin is used as an adjuvant and the pH is adjusted so that the drug is negative and the gelatin is positively charged.
  • Spray drying for the production of micronized carotene is described in EP-A-0 410 236 and US-A-5 364 563.
  • An emulsion of carotene is dried by spray drying.
  • Gelatin is mainly reported as a stabilizer, and the ratio of carotene to gelatin at 1: 2.5 must be rated as extremely unsatisfactory. If the other necessary auxiliary substances are taken into account, a preparation is described which contains only 12.5% by weight of carotene. So there is more of an embedding. The carotene is amorphous. The high proportion of auxiliary substances prevents crystallization.
  • Another patent (US-A-4726955) describes the use of milk as a precipitant, the coagulation of which is used in the presence of alcohols.
  • budesonide particles in the micrometer range is described by Ruch and Matijevic (J. Coll. Interf. Sei 229, 207-211, 2000), some of which are carried out using ultrasound.
  • the budesonide particles obtained are not sufficiently stabilized against particle size growth.
  • the precipitated dispersions show particle size growth and the dry product cannot be redispersed without changing shape and size. A broad particle size distribution and an agglomeration of the particles are described.
  • US-A-4 826 689 describes the production of amorphous particles of poorly soluble drugs by precipitation processes.
  • the problem of stability generally arises with amorphous products. No crystallization may occur over the period of use, at different temperatures or during further processing.
  • high amounts of auxiliary substances are necessary for stabilization.
  • Esumi et al. (Colloids and Surfaces B: Biointerfaces 11, 1998, pages 223-229) describe a fine, aqueous suspension.
  • the drug CT 112 forms suspensions that are difficult to stabilize.
  • the method described describes a way of stabilization, the suspension being formed by adding acid to an alkaline solution which, in addition to the medicinal substance, also contains PVP and cellulose.
  • the polymers act as dispersants and also prevent crystallization. There is therefore a suspension with an amorphous solid phase.
  • micronized substances Another way of constructing micronized substances is by precipitation from supercritical gases (Kerc, J., Srcic, S., Knez, Z., Sencar-Bozic, P., 1999. Micronization of drugs using supercritical carbon dioxide. Int. J Pharm. 182, 33-39; Steckel, H., Thies, J., Müller, BW, 1997. Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide. Int. J. Pharm. 152, 99-110).
  • a disadvantage of this technique is the high expenditure on equipment due to the high pressure required to reach the supercritical gas.
  • the present invention has for its object to provide a method with which the production of particles with a size in the micro and nanometer range is possible quickly, inexpensively and with little technical effort. At the same time, the disadvantages associated with the usual degrading (comminuting) processes should be avoided. Further the aim is to offer a possibility of producing rapidly soluble pharmaceutical preparations which contain the pharmaceutical substance in finely divided size. It should also be possible to use it in other fields in which it is desirable to use finely divided, poorly soluble solids. The resulting powder should have good properties, for example be flowable and not show strong cohesion, which is important, for example, in pulmonary use, especially in powder inhalers.
  • This object is achieved according to claim 1 by a process for the production of micro- and / or nanoparticles of a substance, which is characterized in that the substance is solved in a solvent system for this and then a non-solvent for this substance, which with the solvent system is in principle miscible for this substance, is added, one or more crystal growth inhibitor (s) being present and a rapid combination of solvent and non-solvent being carried out, as a result of which the substance precipitates to form a dispersion of particles which is a Have size in the micro or nanometer range.
  • the substance can form a temporary hybrid gap in the solvent, so that the primary crystallization takes place in a two-phase system.
  • production is possible by adding the substance solution to the non-solvent or by mutual mixing, for example in a mixer.
  • the precipitation preferably with crystallization, takes place due to a rapidly occurring supersaturation.
  • Precipitation preferably occurs in the presence of one or more additives which reduce the crystal size growth of the resulting particles, ie crystal growth inhibitors.
  • the solvent system can comprise one or more solvents for the substance.
  • Suitable solvents can be selected from the group of aliphatic or aromatic alcohols, ketones, nitriles and ethers, in particular they can be one of isopropanol, ethanol, methanol, acetone and acetonitrile, tetrahydrofuran (THF), propylene glycol, glycerol and dimethylformamide (DMF) include.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • a solution in acidic or alkaline water is also possible if the substance is pH-dependent.
  • the method can be applied to all substances with low solubility in the non-solvent used (precipitation medium).
  • water as a precipitant, it is therefore applicable to all poorly water-soluble substances (poorly soluble, very poorly soluble, practically insoluble; corresponding to a water solubility of less than 1 g / 100 ml, preferably less than ⁇ 0.1 g / 100 ml), such as poorly soluble drugs and vitamins.
  • This poor solubility can also be characterized by the octanol / water partition coefficient, which should preferably be> 1.5.
  • Suitable non-solvents are, of course, depending on the substance, for example one or more selected from water, ketones, short-chain alcohols, DMF, THF, nitriles, glycerol and propylene glycol.
  • non-solvents for water-soluble substances.
  • Suitable non-solvents can, for example, linear or branched Ci -C 10 alcohols such as isopropanol, methanol or ethanol, or C 3 - C 10 - etone as acetone, or aldehydes such as acetaldehyde hyd, or nitriles such as acetonitrile or amides such as dirnethylformamide.
  • the process according to the invention enables the production of crowned or colloidal powders with an auxiliary content of well below 50% by weight. If desired, however, higher proportions of auxiliary can also be used. However, this is not necessary for the stability of the particles of the final product
  • ⁇ are characterized by an average particle size of 100 ⁇ m to 10 n, preferably 50 ⁇ m to 20 nm, in particular 30 ⁇ m to 30 nm and particularly preferably 15 ⁇ m to 100 nm,
  • ⁇ have a narrow particle size distribution (this distinguishes them from particles crushed by an air jet mill, for example, which usually have such a wide particle size distribution that a fractionation of the product is necessary),
  • ⁇ crystalline or amorphous, - are preferably crystalline, ⁇ as a solid in solid dosage forms such as capsules,
  • Tablets or coated tablets can be used
  • ⁇ which have an accelerated dissolution characteristic as well as an improved wettability, the reason being an enlarged wettable surface, ⁇ can be used partially,
  • ⁇ can be incorporated into semi-solid systems (e.g. for therapeutic, cosmetic, stabilizing or dyeing purposes),
  • ⁇ can be administered by inhalation (powder inhalation or suspension aerosol from a pressure container),
  • ⁇ can be used in liquid preparations after redispersion without particle size growth taking place.
  • a flotation as often occurs with a mechanically comminuted drug, cannot be observed.
  • the saturation solubility is increased with a significant reduction in the particle size (especially with a particle size of ⁇ 1 ⁇ m).
  • the drug is released faster due to the higher release pressure. Since it can then be distributed in a larger compartment or transported away, recrystallization cannot occur.
  • the invention also relates to the use of the products thus produced for the production of pharmaceutical dosage forms.
  • an application in food technology, cosmetics, crop protection or in the field of coloring techniques is included according to the invention.
  • the use in liquid preparations can serve, for example, coloring or therapeutic purposes.
  • a dispersion of colloidal dye pigments preferably 10 nm - 500 nm
  • an ink for example for use in inkjet printers.
  • the method used is based on a solution of the substance which is sparingly or slightly soluble in the non-solvent or precipitant in a solvent system which is miscible with this precipitant.
  • the solvents used are, for example, alcohols such as ethanol, methanol, isopropanol, glycerol and propylene glycol, ketones such as acetone, ethers such as THF, DMF and nitriles such as aeetonitrile in question. It is also possible to use hydrophobic solvents both as solvents and as precipitants, such as dichloromethane, ether, or hydrofluoroalkanes. A dispersion is prepared from this solution by adding the precipitant, such as water.
  • crystal growth inhibitors or stabilizers are optionally added.
  • the dispersion can then be converted into a powder by drying (for example spray drying, solvent evaporation or freeze drying), a filtration step or a combination of several of these processes.
  • the process according to the invention can be carried out either batchwise (ie firstly a batch is prepared, which is subsequently converted into a dry powder) or continuously (ie simultaneously adding solution and precipitant in a suitable ratio and mixing them, for example in a static mixer.
  • a batch is prepared, which is subsequently converted into a dry powder
  • continuously ie simultaneously adding solution and precipitant in a suitable ratio and mixing them, for example in a static mixer.
  • auxiliaries for inhibiting crystal growth / stabilizing the dispersion which are preferably water-soluble in the case of water as the precipitant, are: ⁇ Polyvinyl alcohol, PVA
  • HPC hydroxypropyl cellulose
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • MC methyl cellulose
  • MHEC methyl hydroxyethyl cellulose
  • Caseinates such as calcium caseinate
  • casein casein
  • Polyvinyl alcohol-polyethylene glycol graft copolymer e.g.
  • HES Hydroxyethyl starch
  • Polyoxypropylene-polyoxyethylene block polymers (poloxamers) (to be preferred because there is no micelle formation), partial fatty acid esters of polyoxyethylene sorbitan, such as, for example, polyethylene glycol (20) sorbitan monolaurate, monopalmitate, monostearate, monooleate; Polyethylene glycol (20) sorbitan tristearate and trioleate; Polyoxyethylene (5) sorbitan monooleate; Polyoxyethylene (4) - sorbitan monolaurate (also referred to as polysorbate) polyoxyethylene fatty alcohol ethers, such as, for example, polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (10) stearyl ether,
  • Polyoxyethylene fatty acid esters such as, for example, polyoxyethylene stearate, ethoxylated triglycerides, such as polyoxyethylene glycol fatty acid esters, such as, for example, polyoxyethylene glycerol monoisostearate,
  • Sugar esters such as, for example, sucrose monolaurate, sucrose monopalmitate, sucrose monostearate, sucrose monomyristate, sucrose monooleate
  • Alkaline soaps fatty acid salts
  • fatty acid salts such as sodium laurate, palmitate, stearate, oleate, ionic and zwitterionic surfactants, e.g. B. betaines, such as cocobetaine
  • Stabilizers can also be added in relation to other functions, e.g. B. when using substances sensitive to oxidation.
  • the additives are preferably dissolved in the precipitant, but can also be dissolved or suspended in the solvent or non-solvent.
  • the concentration of crystal growth inhibitor, based on the substance to be precipitated, is usually in the range from 0.01 to 50% by weight, preferably 0.1 to 30% by weight and preferably 0.5 to 20% by weight.
  • the invention provides a method for forming crystals with a significantly reduced crystal size.
  • the crystals can be called icronized to colloidal.
  • the process does not mechanically crush larger crystals, but limits the crystal size growth by means of suitable measures. It deals is therefore a constructive process.
  • the resulting crystals have, for example, a crystal size of 100 ⁇ m to 10 nm, preferably 50 ⁇ m to 20 nm, in particular 30 ⁇ m to 30 nm and particularly preferably 15 ⁇ m to 100 nm.
  • the crystals produced in this way show an accelerated dissolution, so that when used in the pharmaceutical sector for drugs in which the dissolution rate is the step limiting the bioavailability, the result is an accelerated flooding in the blood plasma and an increase in the bioavailability.
  • the crystals produced in this way also show a low level of cohesion compared to degrading comminution processes. Furthermore, they are not electrostatically charged. This enables them to be used in areas where an easily dispersible powder is required, for example in pharmaceutical forms for pulmonary use.
  • thermolabile substances With a particle size of ⁇ 400 nm, preferably ⁇ 200 nm, sterile filtration is possible. This enables the preparation of preparations of thermolabile substances to be administered parenterally or ophthalmologically, since heat sterilization can be replaced by sterile filtration.
  • Itraconazole, ketoconazole, ibuprofen, beclometasone dipropionate and other drugs that meet the above-mentioned criteria of poor solubility are suitable as poorly or poorly soluble drugs. Such drugs can also be used.
  • suitable sparingly or poorly soluble substances are, for example, carotenoids such as beta-carotene, lycopene, lutein, canthaxanthin, astaxanthin or zeaxanthin.
  • carotenoids such as beta-carotene, lycopene, lutein, canthaxanthin, astaxanthin or zeaxanthin.
  • the particles produced, in particular crystals, are also suitable for use in colloidal solutions (for example aqueous dye solutions of poorly soluble dyes).
  • the product is obtained by filtration techniques or reverse osmosis and ⁇ if necessary, redispersion.
  • the particle size is determined directly when the particles are precipitated and thus when the dispersion is produced. Spray drying does not affect the size of the individual particles.
  • the dispersion initially only dries. Since the particle size and the particle size distribution are not determined by the spray drying process, the spray drying process can be carried out using the direct current method. This is particularly preferable for thermolabile fabrics.
  • spray towers operating according to the countercurrent method can also be used. Additional processing aids can be added, such as lactose or mannitol. In general, however, spray drying of the dispersion is possible without further additives.
  • Another suitable method for drying is freeze drying or the solvent evaporation method or a combination of several methods.
  • other drying processes can also be used.
  • Product extraction using filtration techniques is also suitable.
  • the method according to the invention is thus a method that can be used very easily with extremely little technical effort, almost anywhere and leads to a high degree of loading of the end product. Since the product is preferably crystalline, its stability is given, especially when compared to the amorphous products described in the literature. There is no thermal stress as in grinding processes.
  • An advantage of the method according to the invention is the production of a micronized drug preparation (or substance preparation) with a (medicinal) substance content of over 50% by weight (m / m).
  • the process according to the invention has the advantage that no input of mechanical energy is necessary for comminution.
  • all crystal surfaces are of natural origin, no areas of different energy (as they result from mechanical comminution) exist.
  • Mechanical crushing results in breaking edges, which are usually non-polar.
  • Another commonly used method to increase the rate of dissolution is to encapsulate a poorly soluble drug in cyclodextrins.
  • solids containing cyclodextrin have only a very low drug content, generally well below 50% by weight (m / m).
  • Another disadvantage of complexing with the aid of cyclodextrins is that this method cannot be used universally, since the drug has to have an affinity for the cyclodextrin.
  • a certain molecular geometry is required. Effective encapsulation can be prevented, for example, by large substituents. There is usually no connection between the tendency towards complex formation and the physicochemical properties of the drug.
  • the use of the method according to the invention described here is tied to the physicochemical properties of the medicinal substance (for example solubility in the solvent and insolubility in the precipitant).
  • the insolubility Wise in water therefore also represents the problem of the slow dissolution rate (and thus the low bioavailability) as well as the problem solving.
  • the method according to the invention is based on the physicochemical properties of the medicinal product and consequently on all (medicinal) substances which have mentioned problematic physicochemical properties, universally applicable.
  • Figure 1 clearly shows that effective stabilization has been achieved: the particle size distribution is shown 24 hours after precipitation. The stabilization of the colloidal state becomes particularly clear when comparing the particle size growth if only water is used without auxiliary substances (Fig. 2).
  • the dispersion is spray dried (as soon as possible after the precipitation; however, as the particle size distributions show, intermediate storage is also possible).
  • the particle size is therefore already determined during the preparation of the dispersion. Spray drying does not affect the particle size.
  • the submitted dispersion only dries. The accelerated dissolution rate is shown in Fig. 4.
  • ibuprofen 2.5 g are dissolved in 50 ml of isopropyl alcohol. A 0.1% by weight solution of HPMC 15 (200 ml) in water is used for the precipitation. The solutions are quickly combined.
  • the particle size distribution in the resulting dispersion is determined by laser diffractometry. It is clear from the figures Fig. 9, Fig. 10 and Fig. 11 that an effective stabilization has been achieved: The particle size distribution after precipitation is shown, with an average particle size of 1800 nm (Fig. 9).
  • the dispersion is spray dried immediately after production.
  • the spray-dried product has a particle size distribution that corresponds to that of the dispersion, as can be seen from the SEM image (Fig. 10).
  • a dispersion After redispersion in water, a dispersion is obtained whose particle size distribution corresponds to the spray-dried product, which underlines the stability. There is no increase in particle size.
  • the increase in solution speed is illustrated in Fig. 12.
  • Example 5 Beta Carotene:
  • DPI powder inhaler
  • the itraconazole powder from Example 1 is redispersed in water. The result is a uniform dispersion which remains unchanged even after 60 days.
  • cromoglycic acid disodium salt 4 g are dissolved in 100 ml of a 1% solution of HPMC in water. The precipitation is carried out with isopropanol with rapid combination in a ratio of 1: 8. The resulting dispersion is spray dried. The spray-dried product shows an even, homogeneous, narrow particle size distribution. The powder shows a very low tendency to agglomerate, a very low cohesiveness and is not electrostatically charged.
  • the building micronized drug is compared with drug that has been micronized using a gas jet mill.
  • a gas jet mill Here there is a strong agglomeration and an electrostatic charge, which leads to problems during the micronization process.
  • Both the build-up micronized and the drug micronized with the help of the Jet-mill are analyzed to determine the respirable fraction with the help of a multi-stage liquid impactor (Multi-Stage Liquid Impinger, MSLI) (without the addition of other auxiliaries). This shows dramatic differences:
  • the Jet-mill micronized product has a fine particle fraction (based on the amount of drug made available in the applicator), FPF of 7.3% by weight.

Abstract

L'invention concerne un procédé pour produire des microparticules et/ou des nanoparticules d'une substance, ledit procédé consistant à former des particules à partir d'une substance à distribution moléculaire et, simultanément, à stabiliser cette dernière dans une suspension. A cet effet, on dissout la substance dans un système de solvant approprié, puis on ajoute un agent ne dissolvant pas la substance, qui peut être mélangé au système de solvant pour ladite substance. On ajoute ensuite un ou plusieurs inhibiteur(s) de cristallisation et on réunit rapidement le solvant et l'agent non solvant. Cette opération provoque la précipitation de la substance qui forme une dispersion de particules présentant une taille de l'ordre du micromètre ou du nanomètre.
EP03724926A 2002-03-27 2003-03-21 Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive Withdrawn EP1487415A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10214031A DE10214031A1 (de) 2002-03-27 2002-03-27 Verfahren zur Herstellung und Anwendung von Mikro- und Nanoteilchen durch aufbauende Mikronisation
DE10214031 2002-03-27
PCT/EP2003/002984 WO2003080034A2 (fr) 2002-03-27 2003-03-21 Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive

Publications (1)

Publication Number Publication Date
EP1487415A2 true EP1487415A2 (fr) 2004-12-22

Family

ID=28050958

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03724926A Withdrawn EP1487415A2 (fr) 2002-03-27 2003-03-21 Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive

Country Status (6)

Country Link
US (1) US20050139144A1 (fr)
EP (1) EP1487415A2 (fr)
JP (1) JP2005527536A (fr)
AU (1) AU2003227540A1 (fr)
DE (1) DE10214031A1 (fr)
WO (1) WO2003080034A2 (fr)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040121003A1 (en) * 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
GB0300427D0 (en) * 2003-01-09 2003-02-05 Univ Strathclyde Pharmaceutical composition
ES2297461T3 (es) 2003-09-09 2008-05-01 Fumapharm Ag Uso de derivados del acido fumarico para tratar la insuficiencia cardiaca y el asma.
DE10355400A1 (de) 2003-11-25 2005-07-07 Noack, Andreas, Dr. Multikomponenten Mineralstoffpräparate und Verfahren zur Herstellung von Multikomponenten-Mineralstoffpräparaten
ES2523796T1 (es) 2004-10-08 2014-12-01 Forward Pharma A/S Composición farmacéutica de liberación controlada que comprende éster de ácido fumárico
GB0501835D0 (en) * 2005-01-28 2005-03-09 Unilever Plc Improvements relating to spray dried compositions
US8679341B2 (en) 2005-05-06 2014-03-25 Fujifilm Corporation Method of concentrating nanoparticles and method of deaggregating aggregated nanoparticles
JP4870383B2 (ja) * 2005-05-06 2012-02-08 富士フイルム株式会社 ナノ粒子の濃縮方法
DE102005027333B4 (de) 2005-06-13 2017-04-13 Terra Nano Ltd. Nanoskalische Reaktivdesorption - ein Verfahren zur Herstellung kolloidalisierter Wirkstoff- oder Vitalstoffspezies, insbesondere entsprechender Wirkstoff- oder Vitalstoffkonzentraten sowie Vorrichtungen zur Durchführung derselben
EP1915387B1 (fr) 2005-07-07 2010-01-20 Aditech Pharma AG Nouveaux esters de glucopyranose et esters de glucofuranose d'alkyl-fumarates et leur utilisation pharmaceutique
CN101272848B (zh) * 2005-07-28 2013-03-13 Isp投资有限公司 改进喷雾干燥的粉末和颗粒材料性质的方法，以及由此生产的产品
EP1782797A1 (fr) * 2005-11-02 2007-05-09 Pharmatex Italia Srl Procédé de préparation de composés pharmaceutiques stériles pulvérulents
DE102005053862A1 (de) * 2005-11-04 2007-05-10 Pharmasol Gmbh Verfahren und Vorrichtung zur Herstellung hochfeiner Partikel sowie zur Beschichtung solcher Partikel
US8158152B2 (en) * 2005-11-18 2012-04-17 Scidose Llc Lyophilization process and products obtained thereby
US9393215B2 (en) * 2005-12-02 2016-07-19 Novartis Ag Nanoparticles for use in immunogenic compositions
WO2007070843A2 (fr) * 2005-12-15 2007-06-21 Acusphere, Inc. Procédés de préparation de formulations pharmaceutiques à base de particules destinées à une administration orale
CN101415395B (zh) * 2006-03-29 2012-02-08 富士胶片株式会社 酪蛋白纳米粒子
WO2007127380A2 (fr) * 2006-04-28 2007-11-08 Schering Corporation Procédé de précipitation et d'isolement de 6,6-diméthyl-3-aza-bicyclo[3.1.0]hexane-amides par précipitation contrôlée et formules pharmaceutiques les contenant
US8420122B2 (en) 2006-04-28 2013-04-16 Merck Sharp & Dohme Corp. Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US20080098900A1 (en) * 2006-11-01 2008-05-01 Babatunde Aremu Beverage manufacture using a static mixer
WO2008076780A2 (fr) * 2006-12-14 2008-06-26 Isp Investments Inc. Valsartan amorphe et production de celui-ci
US8613946B2 (en) * 2006-12-21 2013-12-24 Isp Investment Inc. Carotenoids of enhanced bioavailability
EP2125938A2 (fr) * 2007-01-26 2009-12-02 Isp Investments Inc. Procédé de traitement de formulation pour produire des produits séchés pour une pulvérisation
WO2008092046A2 (fr) * 2007-01-26 2008-07-31 Isp Investments Inc. Oxcarbazépine amorphe et sa préparation
GB0707938D0 (en) * 2007-04-25 2007-05-30 Univ Strathclyde Precipitation stabilising compositions
GB0724498D0 (en) * 2007-12-15 2008-01-30 Univ Strathclyde Slow release compositions
EP2095816A1 (fr) * 2008-02-29 2009-09-02 Schlichthaar, Rainer, Dr. Nanosuspension avec médication antifongique à administrer via inhalation avec une sécurité et un profil d'impureté améliorés
GB0806873D0 (en) * 2008-04-16 2008-05-21 Breath Ltd Steroid nebuliser formulation
DE102008037025C5 (de) * 2008-08-08 2016-07-07 Jesalis Pharma Gmbh Verfahren zur Herstellung kristalliner Wirkstoff-Mikropartikel bzw. einer Wirkstoffpartikel-Festkörperform
NZ592861A (en) * 2008-11-04 2013-01-25 Cipla Ltd Pharmaceutical aerosol composition
CN102369000A (zh) 2009-01-09 2012-03-07 前进制药公司 包含一种或多种富马酸酯的药用组合物
DK2564839T3 (en) 2009-01-09 2016-07-25 Forward Pharma As A pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix
DE102009008478A1 (de) 2009-02-11 2010-08-19 PHAST Gesellschaft für pharmazeutische Qualitätsstandards mbH Vorrichtung und Verfahren zur Herstellung pharmazeutisch hochfeiner Partikel sowie zur Beschichtung solcher Partikel in Mikroreaktoren
US8834965B2 (en) 2009-02-12 2014-09-16 Xerox Corporation Organoamine stabilized silver nanoparticles and process for producing same
GB0914231D0 (en) * 2009-08-14 2009-09-30 Breath Ltd Dry powder inhaler formulations
WO2011116763A1 (fr) 2010-03-22 2011-09-29 Mjr Pharmjet Gmbh Procédé et dispositif pour la fabrication de micro- ou de nanoparticules
US8835363B2 (en) 2010-06-16 2014-09-16 Saudi Arabian Oil Company Drilling, drill-in and completion fluids containing nanoparticles for use in oil and gas field applications and methods related thereto
JP5977062B2 (ja) * 2011-03-30 2016-08-24 興和株式会社 カフェイン含有液状組成物及び該組成物を充填したカプセル剤
EP2782561A1 (fr) 2011-11-24 2014-10-01 Synthon BV Libération contrôlée de particules comprenant du diméthylfumarate
EP2601973A1 (fr) * 2011-12-09 2013-06-12 Laboratoires SMB SA Formulation de poudre sèche de dérivé d'azole pour inhalation
SG11201404705YA (en) 2012-02-07 2014-10-30 Biogen Idec Inc Pharmaceutical compositions containing dimethyl fumarate
EP2836204B1 (fr) 2012-04-13 2020-07-08 GlaxoSmithKline Intellectual Property Development Limited Particules agrégées
JP5827178B2 (ja) * 2012-06-05 2015-12-02 北越紀州製紙株式会社 セルロース多孔質体及びその製造方法
DE102012221219B4 (de) * 2012-11-20 2014-05-28 Jesalis Pharma Gmbh Verfahren zur Vergrößerung der Partikelgröße kristalliner Wirkstoff-Mikropartikel
KR101466908B1 (ko) * 2013-05-20 2014-12-03 한국표준과학연구원 유리지방산 입자 분산액 및 유리지방산 입자 분산액의 제조방법
PT108368B (pt) * 2015-03-31 2018-11-05 Hovione Farm S A Produção contínua de partículas

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897256A (en) * 1986-11-25 1990-01-30 Abbott Laboratories LHRH analog formulations
DE4327063A1 (de) * 1993-08-12 1995-02-16 Kirsten Dr Westesen Ubidecarenon-Partikel mit modifizierten physikochemischen Eigenschaften
DE4342625A1 (de) * 1993-12-14 1995-06-22 Max Planck Gesellschaft Pulverförmige Meliazeen-Extrakte
DE69509210T2 (de) * 1995-01-31 1999-09-16 Mitsubishi Chem Corp Verfahren zur Herstellung von pulverisiertem carboxylgruppenhaltigem Polymerisat
SE9501384D0 (sv) * 1995-04-13 1995-04-13 Astra Ab Process for the preparation of respirable particles
US20030148024A1 (en) * 2001-10-05 2003-08-07 Kodas Toivo T. Low viscosity precursor compositons and methods for the depositon of conductive electronic features
GB9919693D0 (en) * 1999-08-19 1999-10-20 Rhone Poulenc Rorer Ltd Process
ATE336231T1 (de) * 2001-08-29 2006-09-15 Dow Global Technologies Inc Verfahren zur herstellung kristalliner arzneimittelteilchen durch ausfällung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03080034A3 *

Also Published As

Publication number Publication date
JP2005527536A (ja) 2005-09-15
US20050139144A1 (en) 2005-06-30
WO2003080034A2 (fr) 2003-10-02
AU2003227540A1 (en) 2003-10-08
WO2003080034A3 (fr) 2003-11-27
DE10214031A1 (de) 2004-02-19
AU2003227540A8 (en) 2003-10-08

Similar Documents

Publication Publication Date Title
EP1487415A2 (fr) Procede pour produire et utiliser des microparticules et des nanoparticules par micronisation constructive
EP1073426B1 (fr) Formulation pharmaceutique de ciclosporine presentant de meilleures proprietes biopharmaceutiques, une meilleure qualite et stabilite en termes de physique, et procede permettant de la preparer
DE69630207T2 (de) Beclomethazon-nanopartikel dispersionen enthaltende aerosole
DE60020732T2 (de) Verfahren zur herstellung von nanometer partikeln durch fliessbett- sprühtrocknung
DE69633222T2 (de) Nanopartikel-dispersionen enthaltende aerosole
DE69916733T3 (de) Stabile Komplexe schwer löslicher Substanzen
EP1868574B1 (fr) Procédé de production de suspensions de particules très fines en conditions modérées, particules très fines correspondantes et leur utilisation
EP1868573B1 (fr) Procede de production de suspensions de l'ordre du micron ultrafines
DE60214012T2 (de) Verfahren zur herstellung kristalliner arzneimittelteilchen durch ausfällung
EP2326307B1 (fr) Procédé de fabrication de microparticules de substance active cristallines
EP1180062B1 (fr) Procede de production de microparticules et nanoparticules morphologiquement homogenes a l'aide d'un micromelangeur
DE60222898T2 (de) Orlistat und eine fettsäure oder eines ihrer salze enthaltende pharmazeutische zusammensetzung
DE69914742T2 (de) Gegen hitzeeinwirkung geschützte mikropartikel und verfahren zur terminalen dampfsterilisation derselben
DE69831677T2 (de) Nanokristalline zubereitungen von menschlichen immunschwächevirus (hiv)-protease-in-hibitoren unter verwendung von zellulose-oberflächenstabilisatoren und verfahren zu deren herstellung
US20120231093A1 (en) Method for preparing nano-scale or amorphous particle using solid fat as a solvent
US8828445B2 (en) Method for preparing nano-particles utilizing a saccharide anti-coagulant
DE3013839A1 (de) Verfahren zur herstellung einer aktivierten pharmazeutischen zusammensetzung
WO2010003762A1 (fr) Particules contenant une substance active
WO1993010768A1 (fr) Nanosol utilisable en pharmacie et son procede de preparation
DE102005062270A1 (de) Geschmacksmaskierung von Pulvern
DE60103865T2 (de) Arzneizubereitungen und deren herstellungsverfahren
EP1631373B1 (fr) Micropellets, leurs procedes de production et leur utilisation
DE60121574T2 (de) Festes dispersionssystem von pranlukast mit verbesserter auflösung und methode zu dessen herstellung
DE602004006000T2 (de) Verringerung der teilchengrösse von bioaktiven verbindungen
DE102006053375A1 (de) Verfahren zur Mischung von Pulvern

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041019

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

17Q First examination report despatched

Effective date: 20080205

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080617