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    • 专利摘要:
    The present invention is directed to a matrix material, which is subjected to a high pressure homogenization process at medium and / or low temperature, preferably at room temperature (20 ° C.), in particular at a temperature below the freezing point of water, in an anhydrous or water content. Ultra-precision micros while excluding water, minimizing water and / or excluding plasticizers and / or reducing temperature (heat) loads, characterized by a gentle reduction in particle size while minimizing damage to the chemical stability of the material It relates to a method for producing particles and nanoparticles gently, and to such ultra-precision microparticles and nanoparticles.
    公开号:KR20020037027A
    申请号:KR1020027000466
    申请日:2000-07-10
    公开日:2002-05-17
    发明作者:뮬러라이너헬무트；카르스텐 클라우스；카르스텐 먀데르
    申请人:파르마솔 게엠베하；
    IPC主号:
    专利说明:

    METHOD FOR CONTROLLED PRODUCTION OF ULTRAFINE MOCROPARTICLES AND NANOPARTICLES}
    [2] Microparticles and nanoparticles, depending on their composition, can be divided into three large groups, particles consisting of:
    [3] I. pure drugs,
    [4] II. Pure matrix materials (e.g. polymers, natural macromolecules, lipids),
    [5] III. Matrix material loaded with active ingredient.
    [6] Particles larger than 10 μm in size are readily available by conventional size reduction techniques, optionally with a nitrogen cooling process, for example by a polishing process using a pestle. It is more difficult to produce ultra-precision particles smaller than 10-20 μm in size, in particular nanoparticles smaller than 1 μm in size, in particular nanoparticles in the range of several 100 nm.
    [7] An air-jet grinding process was used to obtain particle distributions up to 25 μm in size [Peters, K., “Nanosuspensions for the iv administration of poorly soluble drugs-stability during sterilization and long- term storage ", 22 nd Int. Symp. CRS, 1995, 2212; In addition, heat loads and exposure to oxygen can damage the chemical stability of sensitive active ingredients.
    [8] Water wet grinding process: long to Reference List, PH, Arzneiformenlehre, 3 rd Edition, 1982, WVG, Stuttgart] The reduced temperature load the appropriate cooling, however, these processes are suitable for use on sensitive active ingredients to hydrolysis I can't.
    [9] An alternative manufacturing method is the method of precipitating particles, for example, the preparation of drug nanoparticles (so-called hydrosols). Sucker, H., Hydrosole-eine Alternative fur die parenterale Anwendung von schwer wasserloslichen Wirkstoffen, in Muller, RH, Hildebrand, GE, (Eds.), Pharmazeutische Technologie: Modern Arzneiformen, 2 nd Edition, 1998, WVG, Stuttgart. The disadvantage of this method is that generally organic solvents must be used (residues in the product). A further problem is that the drug must be at least soluble in the solvent. At the same time, in order to precipitate the particles by adding the solvent to the non-solvent according to Ostwald-Mier, the solvent must also be miscible with the non-solvent. The particles thus produced must then be proficiently selected for the stabilizing surfactant mixture to prevent such particles from growing during the precipitation process and to stabilize them even for long term storage.
    [10] Other methods of making microparticles and nanoparticles include, for example, spray-drying methods (Wagenaar, BW, Muller, BW, Piroxicam release from spray-dried biodegradable microspheres, Biomaterials 1994, 15, 49-53), Solvent evaporation [Nihant, N., et al., Polylactide Microparticles Prepared by Double Emulsion Evaporation Technique. I. Effect of Primary Emulsion Stability, Pharm. Res., 1994, 11, 1479-1484], solvent deposition and phase separation methods [Speiser, PP, Nanopartikel, in: Muller, RH, Hildebrand, GE, (Eds.), Pharmazeutische Technologie: Modern Arzneiformen, 2 nd edition, 1998, WVG, Stuttgart, 339-357. However, all of them usually contain organic solvents, and also contact with water is unavoidable [Farhr, A. Kissel, T., Mikropartikel und Implantate: Arzneiformen zur parenteralen Applikation, in: Muller, RH, Hildebrand, GE, (Eds.), Pharmazeutische Technologie: Modern Arzneiformen, 2 nd Edition, 1998, WVG, Stuttgart, 243-259].
    [11] As an alternative method for producing microparticles and nanoparticles through particle size reduction without using toxicologically problematic organic solvents, a high pressure homogenization method was used. Polymers to be reduced [Muller, B.W., Verfahren zur Herstellung von Pseudolatices und Mikroder Nanopartikeln und diese enthaltenden pharmazeutischen Praparaten, EP 0 605 933 B1, 1998] or drugs [Liversidge, G.G. Surface-modified drug nanoparticles, USA-A-5 145 684, 1991; Haynes, D. H., Phospholipid-coated microcrystals; injectable formulations of water-insoluble drugs, US-A-5 091 187, 1992; Westesen, K., Solid lipid particles, particles of bioactive agents and methods for the manufacture and use, International Patent Applications WO 94/20072, 1994], are then dispersed in water and then the suspension is passed through a high pressure homogenizer. The disadvantage of this method is that for all processes, the particles to be reduced are exposed to water. In particular, in the case of polymers, it is expected to add toxicologically undesirable plasticizers, since the temperature load must also be increased, for example 0.3 to 10% of ethyl cellulose. , BW, Verfahren zur Herstellung von Pseudolatices und Mikroder Nanopartikeln und diese enthaltenden pharmazeutischen Praparaten, EP 0 605 933 B1, 1998]. In addition to melting the drug (Westes, K., Solid lipid particles, particles of bioactive agents and methods for the manufacture and use eg, International Patent Application WO 94/20072, 1994), in addition to damaging chemical stability, There is a tendency to not recrystallize after the homogenization process [Siekmann, B., Westesen, K., Preparation and physicochemical characterization of aqueous dispersions of coenzyme Q10 nanoparticles, Pharm. Res., 1995, 12, 201-208.
    [12] Thus, in general, for a method of reducing the size more gently, depending on the nature of the material to be homogenized, the following is necessary:
    [13] -Minimize or exclude contact with water,
    [14] Eliminating the use of toxicologically undesirable organic solvents (eg dichloromethane),
    [15] -Minimize or avoid temperature loads,
    [16] Avoiding the addition of toxicologically undesirable additives (such as plasticizers),
    [17] Minimize or exclude exposure to oxygen,
    [18] It is necessary to avoid melting and to keep the material to be treated in a solid state.
    [1] The present invention relates to ultra-precision microparticles and nanoparticles, and to a method of producing the particles gently while excluding water, minimizing water and / or excluding plasticizers and / or reducing temperature (heat) loads.
    [222] 1: Microparticle dispersant from Example 9 prepared by adding plasticizer (top) and plasticizer-free dispersant (bottom) according to the invention as a function of the number of cycles of homogenization process (2-10 times, 1500 bar). 50%, 90% and 95% LD diameters.
    [223] 2: 50%, 90% and 95% LD diameter of the plasticizer-free dispersant according to the invention from Example 10, prepared at different temperatures (20, 40, 60 and 85 ° C.).
    [224] Figure 3: 50%, 90% of the microparticle dispersant (A) from Example 11 with plasticizer added and the plasticizer-free dispersant (O) according to the invention prepared at 20 ° C (left) and 40 ° C (right) % And 95% LD diameters.
    [225] 4: Microparticle dispersant from Example 3 prepared by homogenization in anhydrous (water-free) medium (WF) and microparticle dispersant from Example 3 prepared by homogenization in water (W) for comparison Particle size distribution curve.
    [19] The present invention realizes a gentle size reduction method by the homogenization process that simultaneously meets one or more or all of these parameters, depending on the particular of the material to be treated. If it is not essential to meet certain parameters (for example, it is not necessary to exclude oxygen), then what has been avoided for practical reasons has been withheld to make the process as economical as possible.
    [20] The principle of the size reduction of the high pressure homogenization process is cavitation (Muller, R.H., Bohm, B.H.L., Grau, M.J., Nanosuspensions-Formulierungen fur schwerlosliche Arzneistoffe mit geringer Biovefugbarkeit: I. Herstellung und Ph. Ind., 1999, 74-78. Water boils when the stop pressure (eg air pressure) acting on the water is below the vapor pressure. In a high pressure homogenizer, the liquid flows at extremely high speeds, so that the stop pressure drops below the vapor pressure of the water, which is converted to a gaseous state to form gas bubbles. When gas bubbles disintegrate (eg, when leaving the homogenization gap), these implosions generate a strong shock wave that reduces particle size. Thus, the reduction in the size of the material by the high pressure homogenization process was previously performed in water, but not in liquids with lower vapor pressures. It is even advisable to carry out a high pressure homogenization process at elevated temperatures (temperatures considerably higher than room temperature, for example 60 to 90 ° C.), which makes it easier for the difference between the stop pressure of the water (eg the pressure within the homogenization gap) and the vapor pressure. Because it can be overcome. In particular, the homogenization process was not carried out at lower temperatures because the vapor pressure of the water is lower at lower temperatures, so that the difference between the stop pressure and the vapor pressure increases and no cavitation occurs. In particular, in the case of reducing the polymer size, even temperature rises have been reported to be insufficient for effective reduction, and plasticizers have to be added to the polymer (see Muller, BW, Verfahren zur Herstellung von Pseudolatices und Mikroder Nanopartikeln und diese). enthaltenden pharmazeutischen Praparaten, EP 0 605 933 B1, 1998].
    [21] In the present invention, what is used in the homogenization process is not water but a non-aqueous liquid, in particular a non-aqueous liquid with lower vapor pressure (liquid polyethylene glycol, anhydrous glycerin). Surprisingly, it has been found that ultra-precision microparticles and nanoparticles can be produced (Examples 1 to 6). Compared to the particles homogenized in water, a negligible level difference appeared (Example 3). Homogenization processes in anhydrous media are carried out not only on pure active ingredients (eg drugs, cosmetic active ingredients, etc.), synthetic polymers and natural macromolecules, but also on polymers filled with active ingredients.
    [22] Depending on the hydrolysis sensitivity of the active ingredient, small amounts of water are allowed in the dispersion medium. Thus, a proportion of water was added to the dispersion medium to improve the uniformity of the particle dispersant (Example 7). The average diameter of the particle dispersant appears to be almost unchanged compared to the anhydrous dispersion medium (Example 6). However, the 95% diameter drops slightly, indicating that slightly larger particles exist outside the main population of particles (Example 13). Regardless, a certain proportion of water is often desired for further treatment of the particle dispersant (eg, PEG 400 when packing into soft gelatin capsules, which contain a specific proportion of humectant, thus providing gelatin Making the capsule brittle by not removing any water from the capsule wall itself). However, the conditions for this are at least low water solubility or miscibility in the dispersion medium. The proportion of water added is, for example, 1%, 5% and 10% (eg Example 7). Surprisingly, this water ratio had no effect on enhancing size reduction (as opposed to theoretical considerations) (little change in 50% diameter).
    [23] Higher proportions of water were also used (maximum amount of water used was 80% or 99%) with little or no reduction in particle size compared to the anhydrous medium (eg Examples 7 and 8). For most products, this minimal difference is independent of product quality. In the case of an intravenous suspension, it is necessary to avoid capillary blockage, whether or not the average diameter is 0.6 μm or 0.7 μm, as long as it is clear that the smallest size of the capillary remains below 5-6 μm to avoid capillary blockage (embolism). Is irrelevant. These results confirm that no external water phase is required to obtain a product with sufficient fineness.
    [24] The proportion of microparticles whose size is clearly above the average 50% diameter is a function of the number of homogenization process cycles. This decreases as the number of homogenization process cycles increases (ie, D95% or D90% as a measure of this ratio decreases) (Example 13). For example, to reduce the proportion of microparticles in terms of intravenous administration, it is generally possible to increase the number of cycles so that it is not necessary to add water to the dispersion medium for this purpose.
    [25] Although not dissolved or sufficiently dissolved in an anhydrous solvent, it is also preferred to add water so as not to impair the stability of the active ingredient when the substance or polymer desired for the final formulation is dissolved in water. When microparticles or nanoparticle dispersants need to be converted to anhydrous formulations such as tablets or pills, PEG 6000 as a mold release agent or hydroxypropyl methylcellulose (HPMC) as a structural excipient is exemplified. Preference is also given to gelling agents such as migliol gels [solutions of aerosil with a low moisture content to promote gelation in oils via hydroxyl groups of water].
    [26] 1.74% (to examine the effects of plasticizers in a manner comparable to the method described in Muller, BW, Verfahren zur Herstellung von Pseudolatices und Mikroder Nanopartikeln und diese enthaltenden pharmazeutischen Praparaten, EP 0 605 933 B1, 1998). Ethyl cellulose with m / m) plasticizer based on polymer was homogenized at elevated temperature and compared with microparticle suspension prepared without addition of plasticizer (Example 9). The difference in particle size is small, or the dispersant containing no plasticizer surprisingly exhibited even smaller particle size, so that, unlike the expected results based on the literature, it is possible to avoid using toxicologically undesirable plasticizers. have.
    [27] For polymers such as ethyl cellulose (Muller, BW, Verfahren zur Herstellung von Pseudolatices und Mikroder Nanopartikeln und diese enthaltenden pharmazeutischen Praparaten, EP 0 605 933 B1, 1998), due to the homogenization process at higher temperatures, Small particles should be produced. This takes into account the theoretical considerations that the difference between the stop pressure in the homogenizer and the vapor pressure of the dispersion medium is smaller and approaching the softening point of the polymer. Thus, ethyl cellulose was homogenized at different temperatures and then particle size was compared (Example 10). The difference is minimal, which is largely independent of product quality. Thus, it is also possible to operate these materials at temperatures from 40 to 60 ° C. or at room temperature (20 ° C.) or higher instead of 85 ° C. without losing product-related quality or particle size.
    [28] The high pressure homogenization process involves dissipation of thermal fluid energy [Jahnke, S., Theorie der Hochdruckhomogenisation, Workshop Dispergiertechnik, 4 th Expert Meeting, cdc 1999], product warming step [eg LAB 40 (APV Deutschland GmbH, Lubeck). , Germany), approximately 10-20 ° C. per cycle. For materials that are extremely temperature sensitive, the removal of heat from the product should not be waited until the product vessel stage, but preferably should be carried out in advance in the homogenization tower during the reduction process. In these cases, the process is carried out at lower temperatures (Example 14), ie, cooled at temperatures much lower than 4 ° C. or 0 ° C., for example −20 ° C. or −50 ° C., which is pure external phase with water removed. Only possible as Contrary to theoretical considerations (even at lower vapor pressures of the water at these low temperatures), the high pressure homogenization process was surprisingly effective enough to produce ultra-precision particle dispersants. A further measure is to degas the dispersion medium (eg by vacuum or by heating) and additionally generate a protective gas (eg containing nitrogen) (Example 16).
    [29] Substances to be converted into ultra-precision microparticles or nanoparticles (e.g., active ingredients, polymers or polymers loaded with active ingredients) are dispersed in a liquid medium (dispersion medium) as a powder accompanied by stirring to disperse the presuspension agent. Manufacture. The dispersing process can be carried out using mixers of various designs, such as propeller mixers, rotor- stator mixers (Ultra-Turrax), dissolver discs and the like. Alternatively, this powdery material may be gradually wetted, for example using a mortar (mortar grinder). The dispersion medium is gradually added to the material in the mortar during the mixing process.
    [30] Apart from water, any liquid with a sufficiently low viscosity can be used as the dispersion medium, for example:
    [31] Polyols such as glycerin, polyethylene glycols (PEGs) such as PEG 400 and PEG 600, polyether and polyester polyols, glycols such as propylene glycol, ethylene glycol,
    [32] Oils such as medium chain triglycerides (MCT) (eg migliol), long chain triglycerides (LCT) such as isopropyl myristate, vegetable oils such as avocado oil, cottonseed oil, safflower oil , Peanut oil, jojoba oil, coconut oil, linseed oil, walnut oil, olive oil, palm kernel oil, sesame oil, soybean oil, castor oil, wheat germ oil, animal oil, e.g. cod liver oil, halibut liver oil , Shell oil,
    [33] Liquid hydrocarbons such as liquid paraffin, viscous paraffin and hexane,
    [34] Alcohols such as methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol, pentanol, hexanol, octanol, decanol, allyl alcohol, propargyl alcohol.
    [35] If desired for the final product, a proportion of water can be added to the dispersion medium (eg, water is added to PEG 400 considering the packing side for later soft gelatin capsules). In general, the proportion of such water is in the range of 1 to 10%, but may be used at a higher ratio. The limiting factor in this case is the chemical stability of the material to be homogenized. Higher proportions of water have no or little effect on the average diameter of the prepared particle dispersant, but the proportion of larger particles is additionally minimized. In general, the 95% diameter is slightly reduced. For many products this is not relevant. However, it is useful for preparing nanoparticle dispersions for intravenous injection. If too many particles larger than 5 μm remain in the product, this may lead to capillary blockade.
    [36] If desired for the final formulation to ultimately treat the microparticles and nanoparticle dispersants, materials such as HPMC, PEG 6000 or aerosil may be dissolved in water. These are particularly important with regard to the manufacturing process of the tablets, examples of which include calcium phosphate, lactose, starch and derivatives thereof such as starch hydrolysates, cellulose, cellulose derivatives, polyethylene glycols, polyvinylpyrrolidone (PVP), Hexite, glucose; Regarding the manufacturing process of the ointment, bentonite, aerosil, cellulose ether, cellulose ester, alginate, pectinate, tragacand, polyvinyl alcohol, polyethylene glycol, gum arabic, polyacrylate, paraffin, polymethacrylate, Materials such as petroleum, plastibase, etc. may be considered; With regard to the treatment with capsules, for example polyethylene glycol, paraffin, liquid triglycerides (vegetable or animal) are important.
    [37] In order to stabilize the suspending agent and the microparticles and nanoparticles prepared therefrom, a stabilizing material may be added to the dispersion medium. An example of this is:
    [38] 1. Stereoscopically stabilized materials such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene block copolymers), ethoxylated sorbitan fatty acid esters, in particular polysorbates [e.g. polysorbates ( Polysorbate) 80 or Tween 80®), ethoxylated mono- and diglycerides, ethoxylated lipids, ethoxylated fatty alcohols or fatty acids, and esters and ethers of sugar or sugar alcohols with fatty acids or fatty alcohols (e.g., saccharose stearate) Latex, saccharose distearate, saccharose laurate, saccharose octanoate, saccharose palmitate, saccharose myristate).
    [39] 2. Charged ionic stabilizers such as diacetyl phosphate, phosphatidylglycerol, lecithin of various origins (eg egg lecithin or soy lecithin), chemically modified lecithins (eg hydrogenated lecithin), phospholipids and sphingoji Vaginal, mixtures of lecithin and phospholipids, sterols (such as stigmasterol as well as cholesterol and cholesterol derivatives), and charged and uncharged fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate or these Mixtures, amino acids or anti-condensing agents, for example sodium citrate, sodium pyrophosphate, sodium sorbate [Lucks, JS et al., Int. J. Pharm., 1990, 58, 229-235. Zwitterionic surfactants such as (3-[(3-colamidopropyl) -dimethylammonio] -2-hydroxy-1-propane sulfonate) [CHAPSO], (3-[(3 -Colamidopropyl) -dimethylammonio] -1-propane sulfonate) [CHAPS] and N-dodecyl-N, N-dimethyl-3-ammonio-1-propane sulfonate. Cationic surfactants, especially compounds used as preservatives, for example benzyldimethyl hexadecylammonium chloride, methylbenzetonium chloride, benzalkonium chloride, cetyl-pyridinium chloride.
    [40] Materials that can be used in the preparation of ultra-precision microparticles and nanoparticles are:
    [41] 1. pure substances (e.g. active ingredients in the pharmaceutical and cosmetic fields),
    [42] 2. polymer,
    [43] 3. Polymers Loaded with Active Ingredients.
    [44] Such pure substances are not limited to, for example, active ingredients in the pharmaceutical and cosmetic fields, but are derived from extremely different fields (eg agricultural business, foodstuffs). In the agricultural sector, certain ranges of pesticides are unstable in water. Thus, they dissolve in the oil phase of the emulsion, which is prepared in a highly concentrated form to minimize the proportion of water. Nevertheless, storage stability is limited. In the process of the present invention, chemically labile pesticides can be gently converted into fine nanoparticle dispersants in anhydrous processes and then sprayed onto plants. In this case, it is preferred to homogenize in a dispersion medium which is miscible with water, for example PEG 400. Before sparging, nanoparticles dispersed in PEG are mixed with water and sparging is carried out using conventional sparging equipment.
    [45] In the field of foodstuffs, for example, flavor enhancers can be considered as active ingredients.
    [46] Moreover, wood protection or abrasives are of interest as active ingredients.
    [47] In the pharmaceutical field, mainly of interest are active ingredients whose bioavailability is too low and / or chemically labile in water. A traditional example of this is cyclosporine, which is marketed as a microemulsion (critical solution) until now. The disadvantage of such microemulsions is that the initial plasma peak is high due to nephrotoxicity. By converting to nanosuspensions, the dissolution rate is increased and thus the bioavailability is increased, compared with the powdered active ingredient, and at the same time, the rapid diffusion of the active ingredient from the solution can be avoided. Another example is azodicarbonamide (ADA), which is an HIV-effective substance. Conversion of the ADA into nanoparticles using water as the dispersion medium results in the formation of an expandable dispersant. The microfoams thus formed remain stable for several weeks, and thus these foamable products cannot be further processed.
    [48] Drugs to be treated in the present invention are, for example, from the following therapeutic groups:
    [49] Analgesic / Antirheumatic
    [50] BTM bases such as morphine, codeine, pyritamide, fentanyl and fentanyl
    [51] Derivatives, levomethadone, tramadol, diclofenac, ibuprofen, indomethacin,
    [52] Naproxen, pyroxycam, penicillamine
    [53] Anti-allergic agents
    [54] Pheniramine, dimethindene, terpenadine, astemisol, loratidine, doxylamine,
    [55] Meclozin, Bamipine, Clemastine
    [56] Antibiotics / Chemotherapy
    [57] Polypeptide antibiotics such as colistin, polymyxin B. teicoplanin,
    [58] Vancomycin; Antimalarial products such as quinine, halophantrin,
    [59] Mefloquine, chloroquine; Viral proliferation inhibitors such as gancyclovir,
    [60] Foscarnet, zidobudine, acyclovir; And dapson, fosfomycin,
    [61] Fusapungin, Trimethoprim
    [62] Antiepileptic
    [63] Phenytoin, mesuccinimide, ethoximide, primidone, phenobarbital,
    [64] Valproic acid, carbamazepine, clonazepam
    [65] Antifungal agents
    [66] a) internal:
    [67] Nystatin, natamycin, amphotericin B, flucytosine, myconazole,
    [68] Fluconazole, Itraconazole
    [69] b) also external:
    [70] Clotrimazole, econazol, thioconazole, penticonazole, biponazole,
    [71] Oxyconazole, Ketoconazole, Isoconazole, Tolnafate
    [72] Corticoids (Contents)
    [73] Aldosterone, fludrocortisone, betamethasone, dexamethasone, triamcinolone,
    [74] Fluorocortolone, hydroxycortisone, prednisolone, prednillyne,
    [75] Clofrednol, Methylprednisolone
    [76] Skin disease
    [77] a) antibiotics:
    [78] Tetracycline, erythromycin, neomycin, gentamicin,
    [79] Clindamycin, pramycetin, tyrotricin, chlorotetracycline,
    [80] Mipyrosine, Fused Acid
    [81] b) such viral growth inhibitors, as well:
    [82] Grape phytotoxin, vidarabine, tromantadine
    [83] c) Corticoids as above, also:
    [84] Amcinoninide, fluprednidene, alclomethasone, clobetasol, dipulason,
    [85] Halcinolone, Fluorcinolone, Clocortolone, Flumethasone,
    [86] Diflucortolone, fluoxycortide, halomethasone, desoxymethasone,
    [87] Fluorinolide, Fluorocortinbutyl, Predniscarbate, Desonide
    [88] Diagnostics
    [89] a) covalently bound in lipids or lipoids or other molecules or complexes
    [90] Radioactive isotopes such as Te99m, In111 or I131
    [91] b) highly substituted iodine containing compounds such as lipids
    [92] Hemostatic / Anti-Bleeding Agents
    [93] Blood-coagulation factor VIII, IX
    [94] Hypnotics, Sedatives
    [95] Cyclobarbital, pentobarbital, phenobarbital, metaquaalon (BTM),
    [96] Benzodiazepines (flulazepam, midazolam, nitrazepam, lormethasepam,
    [97] Flunitrazepam, triazolam, brotizolam, temazepam, loprolazolam)
    [98] Pituitary and hypothalamic hormones, regulatory peptides and inhibitors thereof
    [99] Corticotropin, tetracosactide, coriogonadotropin, uropolytropin,
    [100] Urogonadotropin, somatropin, metergoline, bromocriptine,
    [101] Terlipressin, desmopressin, oxytocin, argipressin, ornipressin,
    [102] Reuprolinin, tryptorelin, gonadorelin, buserelin, naparelin,
    [103] High Celerine, Somatostatin
    [104] Immunotherapy and Cytokines
    [105] Dimefranol-4-acetateamidobenzoate, thymopentin, α-interferon,
    [106] β-interferon, γ-interferon, filgrastim, interleukin, azathioprine,
    [107] Cyclosporine
    [108] Local anesthetics
    [109] Content
    [110] Butanilicaine, mepivacaine, bupivacaine, ethidocaine, lidocaine,
    [111] Articaine, Prilocaine,
    [112] In addition, external preparations
    [113] Propofcaine, oxybuprocaine, tetracaine, benzocaine
    [114] Antimigraine
    [115] Proxybarval, Lisulide, Methisergid, Dihydroergotamine,
    [116] Clonidine, ergotamine, pisotifen
    [117] anesthetic
    [118] Methohexyl, propofol, ethomidate, ketamine, alfentanil, thiopental,
    [119] Droperidol, Fentanyl
    [120] Epithelial Hormones, Calcium Metabolic Regulators
    [121] Dihydrotachisterol, Calcitonin, Chlodronic Acid, Ethidronic Acid
    [122] eyewash
    [123] Atropine, cyclodlin, cyclopentholate, homatropin,
    [124] Tropicamide, Scopolamine, Poledrin, Edoksudine, Idouridine,
    [125] Tromantadine, acyclovir, acetazolamide, diclofenamide,
    [126] Carteolol, timolol, metipranolol, betaxolol, pindolol, befunolol,
    [127] Bupranolol, levobununol, carbacol, pilocarpine, clonidine, neostigmine
    [128] Psychopharmacological Agents
    [129] Benzodiazepines (lorase palm, diazepam), clomethiazole
    [130] Thyroid Drugs
    [131] 1-thyroxine, carbiazole, thiazole, propylthiouracil
    [132] Serum, Immunoglobulins, Vaccines
    [133] a) immunoglobulins, generally and specifically, for example, hepatitis type,
    [134] Rubella, Cytomegalia, Rabies, FSME, Varicella-Zoster
    [135] (varicella-zoster), tetanus, Rhesus factors
    [136] b) immune serum, eg, botulinum aemia, toxins, diphtheria,
    [137] Gas Necrosis, Deadly Poison, Scorpion Poison
    [138] c) vaccines such as influenza, tuberculosis, cholera, diphtheria, hepatitis types,
    [139] FSME, Rubella, Haemophilus Influenza, Margin, Neisseria,
    [140] Mumps, polio, tetanus, rabies, typhus
    [141] Sex hormones and their inhibitors
    [142] Anabolic, Androgen, Anti-Androgen, Zestagen, Estrogen, Anti-Estrogen
    [143] Tamoxifen, etc.
    [144] Cell proliferation inhibitors and metastasis inhibitors
    [145] a) alkylating drugs such as nimustine, melphalan, carmustine, romustine,
    [146] Cyclophosphamide, ifosfamide, trophosphamide, chlorambucil,
    [147] Busulfan, treosulfan, prednismustine, thiotepa
    [148] b) antimetabolic agents such as cytarabine, fluorouracil, methotrexate,
    [149] Mercaptopurine, thioguanine
    [150] c) alkaloids such as vinblastine, vincristine, vindesine
    [151] d) antibiotics such as aclarubicin, bleomycin, dactinomycin,
    [152] Daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin,
    [153] Plicamycin
    [154] e) complexes of subgroup elements (e.g. Ti, Zr, V, Nb, Ta, Mo, W, Ru, Pt), e.g.
    [155] For example, carboplatin, cisplatin and metallocene compounds, for example
    [156] Titanocene dichloride
    [157] f) amsacrine, dacarbazine, esturamustine, etoposide,
    [158] Hydroxycarbamide, Mitoxantrone, Procarbazine, Temiposide
    [159] g) alkylamidophospholipids (J.M. Zeidler, F. Emling, W. Zimmermann and
    [160] H.J. Roth, Archiv der Pharmazie, 324 1991, 687)
    [161] equivalence]
    [162] h) ether lipids, for example, see R. Zeisig, D. Arndt and H.
    [163] Brachwitz, Pharmazie 45 (1990) 809-818,
    [164] Hexadecylphosphocholine, monomorphine and homologues
    [165] i) taxanes such as paclitaxel.
    [166] Peptides and protein active ingredients, in particular recombinant peptides and proteins such as cyclosporine, LH-RH homologue, follicle stimulating hormone (FSH), gonadotropin releasing hormone antagonist (GnRHA), human coriogonadotropin (hCG) , Growth hormone releasing factor (GHRF), human growth hormone (hGH), interferon-beta 1a, human tumor necrosis factor-linking protein (HTBP), human interleukin-6 (HIL-6), lymphocyte activating gene 3, type 1 interferon Receptors.
    [167] Active ingredients from the following chemical groups can generally be used:
    [168] -Hydroxylated hydrocarbons
    [169] Carbonyl compounds, for example ketones (e.g. haloperidol), monosaccharides,
    [170] Disaccharide and Amino Sugars
    [171] Of carboxylic acids, for example aliphatic carboxylic acids, aliphatic and aromatic carboxylic acids
    [172] Esters, basicly substituted esters of aliphatic and aromatic carboxylic acids
    [173] (E.g. atropine, scopolamine), lactones (e.g. erythromycin), aliphatic
    [174] Amides and imides of carboxylic acids, amino acids, aliphatic aminocarboxylic acids, peptides
    [175] (E.g. cyclosporin), polypeptides, β-lactam derivatives, penicillin,
    [176] Cephalosporins, aromatic carboxylic acids such as acetylsalicylic acid, aromatic
    [177] Amide, vinyly carboxylic acid and vinyl position of the carboxylic acid
    [178] Carboxylic ester
    [179] Carbon dioxide derivatives, for example urethanes and thiourethanes, urea and urea
    [180] Derivatives, guanidine derivatives, hydantoin, barbituric acid derivatives and
    [181] Thiobarbituric acid derivatives
    [182] Nitroso compounds, for example aromatic nitroso compounds and
    [183] Heteroaromatic nitroso compounds
    [184] Amines, for example aliphatic amines, aminoglycosides, phenylalkyl amines,
    [185] Ephedrine derivatives, hydroxyphenylethanolamine, adrenaline derivatives,
    [186] Amphetamine derivatives, aromatic amines and derivatives, quaternary ammonium compounds
    [187] Sulfurous compounds such as thiols and disulfanes
    [188] Sulfones, sulfonic acid esters and sulfonic acid amides
    [189] Polycarbocycles, for example tetracycline, with aromatic ring A
    [190] The steroid, which has alpha, beta-unsaturated carbonyl functional groups on ring A,
    [191] Steroids with alpha ketol groups (or methylketo groups), C17
    [192] Steroids with butenolide rings, pentadienolide rings in C17
    [193] Steroids and second-steroids
    [194] O-containing heterocycles, for example chromman derivatives (eg chromoglic acid)
    [195] N-containing heterocycles, for example pyrazole derivatives (eg propofenazone,
    [196] Phenylbutazone)
    [197] Imidazole derivatives (eg histidine, phyllocarpine), pyridine derivatives (eg
    [198] Pyridoxine, nicotinic acid), pyrimidine derivatives (e.g. trimethoprim), indole derivatives
    [199] (E.g. indomethacin), lysergic acid derivatives (e.g. ergotamine), yohimbine derivatives,
    [200] Pyrrolidine derivatives, purine derivatives (eg allopurinol), xanthine derivatives,
    [201] 8-hydroxyquinoline derivatives, aminohydroxy-alkylated quinolines,
    [202] Aminoquinoline, isoquinoline derivatives (e.g. morphine, codeine), quinazoline derivatives,
    [203] Benzopyridazine derivatives, putridine derivatives (e.g. methotrexate),
    [204] 1,4-benzodiazepine derivatives, tricyclic N-containing heterocycles, acridines
    [205] Derivatives (e.g. etacrisdine) and dibenzazepine derivatives (e.g. trimipramine)
    [206] S-containing heterocycles, for example thioxanthene derivatives, for example
    [207] Chlorproticen)
    [208] N, O- and N, S-containing heterocycles, for example monocyclic N, O-containing
    [209] Heterocycle, monocyclic N, S-containing heterocycle, thiadiazine derivatives,
    [210] Bicyclic N, S-containing heterocycle, benzothiadiazine derivatives,
    [211] Tricyclic N, S-containing Heterocycle and Phenothiazine Derivatives
    [212] O, P, N-containing heterocycles, for example cyclophosphamide.
    [213] Synthetic, semisynthetic as well as natural polymers can be used. In particular, for example, the following may be considered:
    [214] Cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, carboxymethyl cellulose, cellulose acetate phthalate Methyl hydroxyethyl cellulose
    [215] Natural polymers such as alginate, albumin, in particular serum albumin, human albumin and bovine albumin, shellac, wax, beeswax, abrasive wax, collagen, casein, fibrin, bentonite, tragacand, xanthan, polysaccharides , For example, chitin, dextran, hyaluronic acid
    [216] Synthetic polymers such as polyacrylates, polymethacrylates, polyvinyl derivatives, polyester polymers such as polylactide, polyglycolide and copolymers thereof, polyanhydrides, polyphosphoric esters, polyethylene glycols And block polymers from polyesters, polyhydroxybutyric acid, polycyanoacrylates, polycarbonates, polycaprolactones.
    [217] For example, the active ingredient from the above-mentioned therapeutic group and / or chemical group can be pre-incorporated into the polymer prior to the homogenization process. Such active ingredients may be dissolved, dispersed, solubilized or incorporated into the polymer.
    [218] This presuspension is then further processed, for example, in one of the following dispersion systems: a piston-gap homogenizer type of high pressure homogenizer (APV Gaulin Systeme, French press, Avestin), jet-stream homogenizer (Eg microfluidizers), rotor-stator systems (Ultra-Turrax, Siverson homogenizers), ultrasonic baths, ultrasonic rods and ultrasonic homogenizers.
    [219] The presuspension thus prepared is homogenized at about 100 bar to about 2000 bar using one or more or several cycles. The pressure and number of cycles to be applied to the high pressure homogenizer are a function of the desired fineness of the particles. In general, in order to produce nanoparticles, they must be higher pressure (eg 1000 bar or more) and have more cycles. Similarly, the number of cycles also depends on the powder density of the homogenizer (for example 4 to 20 times for APV Gaulin instruments, up to 50 times in some cases, or hundreds of times for microfluidizers).
    [220] Characterization of ultra-precision microparticle dispersants and nanoparticles is accomplished by laser diffraction measurement (LD) (Coulter LS230, Coulter Electronics, Miami, USA) and photon correlation spectroscopy (PCS) (Zetasizer 4, Malvern Instruments, Malvern, United Kingdom) lost. Feature identification parameters are 50% (D50%), 90% (D90%) and 95% (D95%) LD diameters measured by LD. PCS (measurement range of approximately 3 nm to 3 μm) is a measure of PCS diameter and distribution width, giving a polydispersity index (PI) in the range of 0.000 (+ ideal monodispersant) to 0.500 (very wide distribution), 0.5 In the above, no further conclusions can be drawn about the distribution width.
    [221] The fineness of the prepared dispersant is based on the end use. Target sizes for polymer particles are often in the range of a few micrometers. Examples thereof are dispersants of ethyl cellulose to coat the tablets, or cortico-loaded polylactide glycolide particles (target size approximately 1-2 μm) for internal migration by macrophages after intra-articular injection. For drugs that hardly dissolve, such as azodicarbonamides, the target size is often in the range of approximately 1 μm or nanometers. By appropriately selecting the pressure and the number of cycles, the target size can be adjusted (controlled) in the production method.
    [226] Example 1
    [227] Drug 1-[[2,7-bis (2,6-dimethyl-4-morpholinyl) -6-phenyl-4-ptridinyl]-(2-hydroxyethyl) -amino] -2-methyl- [Cis [cis]]-propan-2-ol (1%) was dispersed in anhydrous glycerol with the addition of Tween 80 (0.5%), and the resulting predispersant was then discontinuous micron LAB40 (APV Deutschland GmbH, Lubeck, High pressure homogenization). The generation parameter is performed twice at 150 bar, twice at 500 bar, and then at six times at 1500 bar. Homogenization process was performed at room temperature. Particle size was analyzed using a laser diffractometer (Coulter LS230; Coulter Electronics, USA). After six runs at 1500 bar, D50% was 1.7 μm, D90% was 4.5 μm and D95% was 5.4 μm.
    [228] Example 2
    [229] To prepare the nanoparticles, the drug from Example 1 was homogenized as mentioned above, but performed 20 times at 1500 bar. The average PCS diameter determined by photon-correlation spectroscopy was 950 nm and PI was 0.513.
    [230] Example 3
    [231] The drug from Example 1 (1%) was dispersed in anhydrous glycerol with the addition of Tween 80 (0.5%) and a microparticle dispersant was prepared as described in Example 1 except that the homogenization process was carried out for 10 times at 1500 bar. Was performed. For comparison, the drug was homogenized in pure aqueous dispersant (glycerol replaced with water) under the same conditions. Diameters were 1.3 μm and 0.9 μm (D50%), and 3.2 μm and 2.3 μm (D90%), respectively.
    [232] Example 4
    [233] Synthetic polymer Eudragit RS PO (polyacrylic acid trimethyl-aminoethylester, Rohm GmbH, Darmstadt, Germany) 10% was dispersed in propylene glycol with the addition of 1.5% Tween 80. Determination of the particle size of the dispersed powder using ultrasonic waves showed that D50% was 79.7 μm and D95% was 185 μm. The homogenization process was performed similarly to Example 1 on a batch operated micron LAB40, where the production parameters were performed twice at 150 bar, twice at 500 bar and then twice at 1500 bar (room temperature). The PCS diameter of the nanoparticle dispersant was 123 nm and polydispersity index was 0.185. D50% LD diameter was 139 nm and D99% was 149 nm.
    [234] Example 5
    [235] 10% tragacand was dispersed in Miglyol 812 with the addition of 1% Span 80 and microparticles were prepared as described in Example 1. The average diameter determined by the light microscope was 7.54 μm after 10 runs at 1500 bar.
    [236] Example 6
    [237] Two microparticle dispersants were prepared similarly to Example 1, with the preparation parameters being performed twice at 150 bar, twice at 500 bar and then four times at 1500 bar. One dispersant was anhydrous (0% water) and another dispersant contained 1.0% water. Diameters were 1.9 μm and 2.1 μm (D50%), and 4.9 μm and 5.4 μm (D90%), respectively.
    [238] Example 7
    [239] Two microparticle dispersants were prepared similar to Example 6. One dispersant contained 10% water and another dispersant contained 30% water. Diameters were 1.7 μm and 1.7 μm (D50%), and 4.1 μm and 4.2 μm (D90%), respectively.
    [240] Example 8
    [241] Microparticle dispersants were prepared similarly to Example 7 (four times at 1500 bar), increasing the content of sweet water to 50%. Although the water content was increased compared to Example 7, the D50% and D90% diameters were 1.5 μm and 3.7 μm, respectively, unchanged.
    [242] Example 9
    [243] Determination of the Effect of Plasticizer on Homogenization Process Results: Prepared by stirring two ethyl cellulose (20 cP) dispersants. The composition of the plasticizer-free dispersant is as follows: 10.0% ethyl cellulose, 1.18% oleic acid, 0.24% caustic soda, and the remaining amount of water made of 100%. The plasticizer containing dispersant additionally contained 1.74% dibutyl sebacate.
    [244] The homogenization process was performed at 85 ° C., and the homogenization process parameters were performed twice at 150 bar, twice at 500 bar, and then at various times at 1500 bar. Five microparticle dispersants were prepared by performing two, four, six, eight and ten times at 1500 bar, respectively, and their 50%, 90% and 95% diameters were determined (FIG. 1). The diameter of the plasticizer-free dispersant according to the invention is clearly low, ie the addition of plasticizer does not enhance the dispersibility of the polymer.
    [245] Example 10
    [246] Determination of the Effect of Temperature on Homogenization Process Results: The plasticizer-free ethyl cellulose dispersant was homogenized at different temperatures. Its composition is the same as in Example 9, the homogenization process parameters are performed twice at 150 bar, twice at 500 bar, then at 10 times at 1500 bar, and the production temperatures of the four formulations are 20, 40, 60 And 85 ° C. 50%, 90% and 95% diameters were determined by laser diffraction measurement (FIG. 2), which does not change with temperature.
    [247] Example 11
    [248] Determination of the Effect of Plasticizer on Homogenization Process Results at Lower Temperatures: Two ethyl cellulose dispersants were prepared in the same manner as in Example 9 (plasticizer-free dispersants, plasticizer-containing dispersants). The homogenization process was carried out at 20 ° C. and 40 ° C. in each case, and the homogenization process parameters were performed twice at 150 bar, twice at 500 bar and then twice at 1500 bar. 3 shows 50%, 90% and 95% diameters. The diameter of the plasticizer-free dispersant according to the invention is clearly low, ie the addition of plasticizers hinders the dispersion process.
    [249] Example 12
    [250] The substance azodicarbonamide (ADA) (10%) was dispersed with stirring in polyethylene glycol 400 (PEG 400) with the addition of Tween 80 (0.5%). Microparticle dispersants were prepared as described in Example 1. The generation parameter is performed twice at 150 bar, twice at 500 bar, and then at four times at 1500 bar. 50% diameter was 3.0 μm, D90% was 6.2 μm and D95% was 7.2 μm.
    [251] Example 13
    [252] A certain percentage of microparticles are apparently reduced in size by more than 50% in diameter: the drug has 0% water (glycerol), 10%, 30%, 50% water (glycerol-water mixture) similar to Examples 6-8 Disperse in dispersion medium and 100% water (composition is the same as Examples 6-8). The homogenization process was carried out as in Examples 6-8, but only 10 times at 1500 bar. D50% hardly changed and 95% diameter decreased from 3.9 μm (in 0% water, ie pure glycerol) to 2.8 μm (in pure water) (difference is approximately 1.1 μm).
    [253] Alternatively, this effect may be achieved in anhydrous media by simply increasing the number of homogenization process cycles. In pure glycerol (0% water), D95% was reduced from 7.0 μm (after 2 runs at 1500 bar) to 3.9 μm (after 10 runs), ie the difference is approximately 3.1 μm.
    [254] Example 14
    [255] Preparation of clinical batch under poor oxygen conditions and protective gas evolution: Azodicarbonamide (1) was dispersed in 2 kg of propylene glycol with the addition of Tween 80 (0.2%), similar to Example 12, and micron LAB 60 (APV Deutschland GmbH, Lubeck, Germany) for 30 minutes in a circulating process (homogenization process pressure: 700 bar, room temperature). Propylene glycol was degassed beforehand by heating. The product vessel was kept under nitrogen. The average diameter determined by the light microscope was 5.45 mu m after the homogenization process for 30 minutes.
    [256] Example 15
    [257] 1% cyclosporine was dispersed in propylene glycol with 1% Tween 80 with stirring (Ultra-Turrax) (9500 rpm, 1 min), then homogenized twice at 150 bar at LAB 40 at room temperature The process was carried out. PCS diameter was 203 nm and polydispersity index was 0.132. Increasing the cyclosporin ratio to 5% produced particles with a size of 182 nm and a PI of 0.131. Such particles must be separated after preparation, for example by centrifugation.
    [258] Example 16
    [259] Dissolve 1% PLA / GA (Resomer RG 504, Boehringer Ingelheim, Germany) in propylene glycol with addition of 0.5% Tween 80 under stirring, then homogenize twice under 100 bar at micron LAB 40 and eight times under 150 bar The process was carried out. The 50% LD diameter was 19.0 μm.
    [260] Example 17
    [261] 1% medical grade charcoal was ground with polypropylene glycol with the addition of 1% Tween 80 and then dispersed using Ultra-Trax (9500 rpm, 1 min), followed by a temperature below room temperature of 4 ° C. at LAB 40 Homogenized at The generation parameter is performed twice at 150 bar, twice at 500 bar, and then at five times at 1500 bar. The 50% diameter was 5.6 μm, the D90% was 13.5 μm and the D95% was 16.1 μm. A second batch of the same composition was homogenized at -20 ° C. 50% diameter was 5.5 μm, D90% was 13.0 μm and D95% was 15.3 μm.
    [262] The present invention is directed to a matrix material, which is subjected to a high pressure homogenization process at medium and / or low temperature, preferably at room temperature (20 ° C.), in particular at a temperature below the freezing point of water, to achieve homogenization as such. Ultra-precision micros while excluding water, minimizing water and / or excluding plasticizers and / or reducing temperature (heat) loads, characterized by a gentle reduction in particle size while minimizing damage to the chemical stability of the material It relates to a method for producing particles and nanoparticles gently, and to such ultra-precision microparticles and nanoparticles.
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] The matrix material is subjected to a high pressure homogenization process at a medium with reduced anhydrous or water content and / or at a low temperature below 90 ° C., preferably at room temperature (20 ° C.), in particular at a temperature below the freezing point of water. Particle size (average diameter of number distribution) of less than 10 μm, in particular less than 5 μm, characterized by gentle reduction of particle size while minimizing damage to the chemical stability of such homogenized material And more preferably less than 1 μm. Ultra-precision microparticles and nanoparticles.
    [2" claim-type="Currently amended] The method of claim 1, wherein the homogenized matrix material is a drug (pharmaceutically active ingredient or veterinary drug) or an active ingredient and / or adjuvant and / or additive for cosmetics, agricultural products, foodstuffs and preservatives.
    [3" claim-type="Currently amended] The method of claim 2, wherein the homogenized matrix material is a drug cyclosporine, azodicarbonamide, paclitaxel, prednisolone, carbamazepine, taxol, morphine, diclofenac, ibuprofen, phenobarbital or chromoglycine.
    [4" claim-type="Currently amended] 2. The method according to claim 1, wherein the homogenized matrix material is a synthetic, semisynthetic or natural polymer, in particular natural macromolecules.
    [5" claim-type="Currently amended] The method according to claim 4, wherein the homogenized matrix material is a synthetic polymer, in particular polymer polylactide, polyglycolide, polylactide / polyglycolide copolymer, polyorthoester, polyhydroxybutyrate (PHB), polyhydroxy valerie (PHV), polyhydroxybutyrate / polyhydroxyvalerate copolymer, polyacrylate, polymethacrylate, polyvinyl derivative, block polymer of polyethylene glycol and polyester, polyhydroxybutyric acid, polycyanoacrylate, Polycarbonate or polycaprolactone.
    [6" claim-type="Currently amended] The method according to claim 4, wherein the homogenized matrix material comprises natural macromolecules, in particular alginate, albumin, preferably serum albumin, human albumin and bovine albumin, collagen, casein, fibrin, tragacand, xanthan, polysaccharides, In particular chitin, dextran or hyaluronic acid.
    [7" claim-type="Currently amended] The method of claim 1 wherein the homogenized matrix material is a polymer or natural macromolecule loaded with drug or active ingredient.
    [8" claim-type="Currently amended] 8. The method of claim 7, wherein the homogenized matrix material loaded with the drug or active ingredient is a polymer polylactide, polyglycolide, polylactide / polyglycolide copolymer, polyorthoester, polyhydroxybutyrate (PHB), poly Hydroxyvalerate (PHV), polyhydroxybutyrate / polyhydroxyvalerate copolymer.
    [9" claim-type="Currently amended] 8. The homogenized matrix material loaded with a drug or active ingredient according to claim 7, wherein the homogenized matrix material is loaded with natural macromolecules, in particular alginate, albumin, preferably serum albumin, human albumin and bovine albumin, collagen, casein, fibrin, bentonite, traga Kand, xanthan, polysaccharide, for example chitin, dextran or hyaluronic acid.
    [10" claim-type="Currently amended] 10. The process according to any one of the preceding claims, wherein the material to be reduced in size is dispersed in a non-aqueous or anhydrous dispersion medium.
    [11" claim-type="Currently amended] The substance according to claim 10, wherein the substance to be reduced is an oily medium, in particular medium chain triglycerides (MCT), peanut oil, avocado oil, cottonseed oil, safflower oil, long chain triglycerides (LCT), in particular soybean oil, triacetin or iso And distributed to the profile myristate.
    [12" claim-type="Currently amended] Process according to claim 10, characterized in that the substance to be reduced is dispersed in liquid hydrocarbons, in particular fluid paraffin, viscous paraffin, hexane or octane.
    [13" claim-type="Currently amended] The material according to claim 10, wherein the substance to be reduced is polystyrene glycols (PEGs), in particular PEG 100 to PEG 1000, anhydrous glycerol, anhydrous alcohols, in particular methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2 -Butanol, pentanol, hexanol, octanol, decanol, allyl alcohol, propargyl alcohol, ethanol, isopropanol and butanol, or propylene glycol.
    [14" claim-type="Currently amended] The method of claim 10 wherein the material to be reduced is dispersed in dimethyl sulfoxide.
    [15" claim-type="Currently amended] 10. The process according to any one of claims 1 to 9, characterized in that the substance to be reduced is dispersed in a dispersion medium containing a small or minimal proportion of water or a desired proportion of water with respect to the product.
    [16" claim-type="Currently amended] Method according to claim 15, characterized in that the material to be reduced is dispersed in a dispersion medium containing less than 5%, in particular less than 1% by weight of water.
    [17" claim-type="Currently amended] The method of claim 15, wherein the material to be reduced is dispersed in a dispersion medium containing less than 10% by weight of water.
    [18" claim-type="Currently amended] The method of claim 15, wherein the material to be reduced is dispersed in a dispersion medium containing less than 50% water.
    [19" claim-type="Currently amended] Method according to claim 15, characterized in that the substance to be reduced is dispersed in a dispersion medium containing less than 99%, in particular less than 80%, by weight of water.
    [20" claim-type="Currently amended] The material according to claim 15, wherein the material to be reduced is an additional material, in particular a polymer, preferably polyethylene glycol, preferably PEG 6000, or a cellulose derivative, in particular hydroxypropyl methylcellulose (HPMC), which is solid at room temperature. And is dispersed in a dispersion medium containing dissolved water.
    [21" claim-type="Currently amended] The method according to any one of claims 15 to 20, wherein the substance to be reduced is dispersed in the medium according to any one of claims 10 to 14 to which a proportion of water is added.
    [22" claim-type="Currently amended] The method according to claim 1, wherein the process temperature is above room temperature (20 ° C.), but preferably below 50 ° C., in particular below 30 ° C. 23.
    [23" claim-type="Currently amended] 22. The process according to claim 1, wherein the process temperature is at room temperature (20 ° C.), preferably below room temperature, in particular approximately 4 ° C. 23.
    [24" claim-type="Currently amended] 22. The process according to claim 1, wherein the process temperature is below the freezing point of water, preferably below −20 ° C., in particular below −50 ° C. 23.
    [25" claim-type="Currently amended] The process according to claim 1, wherein the process is carried out under the exclusion of oxygen, in particular with the generation of an inert gas, preferably nitrogen or argon gas, or under vacuum.
    [26" claim-type="Currently amended] The method according to claim 1, wherein the dispersion medium used in the process is degassed prior to use.
    [27" claim-type="Currently amended] 27. The method of any of claims 1 to 26, wherein the high pressure homogenization process is performed in a piston-gap homogenizer.
    [28" claim-type="Currently amended] 27. The process according to any of claims 1 to 26, wherein the high pressure homogenization process is carried out in a jet-stream homogenizer, in particular a microfluidizer.
    [29" claim-type="Currently amended] 27. The method of any one of claims 1 to 26, wherein the high pressure homogenization process is performed in a rotor-stator homogenizer with a high powder density.
    [30" claim-type="Currently amended] An ultrafine microparticle or nanoparticle dispersant, which may be prepared by the method according to any one of claims 1 to 27.
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    同族专利:
    公开号 | 公开日
    CA2375992A1|2001-01-18|
    ZA200200211B|2002-12-10|
    DE19932157A1|2001-01-18|
    US8202540B1|2012-06-19|
    WO2001003670A9|2001-03-01|
    CA2375992C|2014-05-27|
    AT552830T|2012-04-15|
    AU6157400A|2001-01-30|
    WO2001003670A1|2001-01-18|
    BR0013161A|2003-07-22|
    EP1194123B1|2012-04-11|
    WO2001003670A8|2001-04-19|
    CN1373657A|2002-10-09|
    EP1194123A2|2002-04-10|
    JP2003504323A|2003-02-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-07-13|Priority to DE19932157.4
    1999-07-13|Priority to DE1999132157
    2000-07-10|Application filed by 파르마솔 게엠베하
    2000-07-10|Priority to PCT/EP2000/006535
    2002-05-17|Publication of KR20020037027A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19932157.4|1999-07-13|
    DE1999132157|DE19932157A1|1999-07-13|1999-07-13|Process for the gentle production of ultra-fine microparticles and nanoparticles|
    PCT/EP2000/006535|WO2001003670A1|1999-07-13|2000-07-10|Method for controlled production of ultrafine microparticles and nanoparticles|
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