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WO1999039700A1 - Compositions pharmaceutiques se presentant sous forme de nanoparticules comprenant des substances lipidiques et des substances amphiphiles, et procede de preparation connexe - Google Patents

Compositions pharmaceutiques se presentant sous forme de nanoparticules comprenant des substances lipidiques et des substances amphiphiles, et procede de preparation connexe Download PDF

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Publication number
WO1999039700A1
WO1999039700A1 PCT/EP1999/000782 EP9900782W WO9939700A1 WO 1999039700 A1 WO1999039700 A1 WO 1999039700A1 EP 9900782 W EP9900782 W EP 9900782W WO 9939700 A1 WO9939700 A1 WO 9939700A1
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Prior art keywords
nanoparticles
compositions
lipidic
composite
composite material
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PCT/EP1999/000782
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English (en)
Inventor
Pierandrea Esposito
Italo Colombo
Nicoletta Coceani
Maria Dorly Del Curto
Fabio Carli
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Eurand International S.P.A.
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.)
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Application filed by Eurand International S.P.A. filed Critical Eurand International S.P.A.
Priority to CA002319565A priority Critical patent/CA2319565A1/fr
Priority to BR9907683-7A priority patent/BR9907683A/pt
Priority to JP2000530200A priority patent/JP2002502813A/ja
Priority to AU27238/99A priority patent/AU747129B2/en
Priority to KR1020007008610A priority patent/KR20010040726A/ko
Priority to EP99907510A priority patent/EP1051160A1/fr
Publication of WO1999039700A1 publication Critical patent/WO1999039700A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the polyalkylcyanoacrylates are metabolized by the organism in a 24 hours interval and release formaldehyde, a potentially toxic derivative; the PLA and PLA-PLGA polymers do not produce toxic metabolites but they have long degradation times ranging from some weeks to some months, and then they may show dangerous accumulation phenomena.
  • the preparation methods of these systems need the use of potentially toxic organic solvents which may remain in traces in the final form.
  • the size of the majority of said systems exclude their use for intravenous way because extraneous bodies having size higher than 5 ⁇ m injected in vein may cause embolisms.
  • lipidic colloidal systems such as oil/water emulsions, liposomes, lipidic micro- and nanoparticles.
  • Oil/water emulsions consisting of lipidic droplets having size in the range of nanometers, dispersed in an external aqueous phase, have been used as a vehicle for the parenteral feeding (JP Patent No. 55,476, 1979, Okamota, Tsuda and Yokoama).
  • Oil/water emulsions containing active principles have been described in the Patent WO 91/02517, 1991 , Davis and Washington. Such systems have a high capacity to incorporate active principles in the internal lipidic phase, but the active principles easily diffuse from such phase towards the external phase originating stability problems and limitations for the optional development of a protracted release form.
  • the liposomes are colloidal structures having an aqueous internal phase sorrounded by one or more layers of phospholipids.
  • the use of liposomes as vehicles for the administration of drugs is described for example in the U.S. Patent No. 3,993,754 (1976, Rahman and Cerny). However typically, such systems show stability problems during the stocking, a poorly reproducible preparation method and a low potentiality to incorporate and retain active principles.
  • Domb and others invented the LiposheresTM, insoluble particles having size about equal to 40 ⁇ m, suspended in an aqueous environment, consisting of a lipophilic internal phase surrounded by external layers of phospholipids, added to the composition and adsorbed on the surface of the particles themselves.
  • These systems were developed for the controlled release of anaesthetic drugs (Domb and others, US Patent 5227165) and of active principles having insecticide and pesticide activity (Domb and others US Patent 5227535).
  • Solid lipidic systems consisting of nanopellets were developed by Lucasr and others (US Patent 4,880,634, 1989), and destined to the oral administration of poorly absorbed drugs.
  • the lipidic pellets are prepared emulsifying lipidic substances in an aqueous environment with a high energy mixer, then cooling the emulsion at room temperature and obtaining the pellets by sonication.
  • Gasco EP 0526666A1 , 05/08/1991 invented a technique for the preparation of lipidic nanoparticles.
  • a microemulsion is prepared adding to an aqueous phase a lipid melted in the presence of surfactants and cosurfactants, which is then dispersed in an aqueous environment maintained at a temperature around 10 °C.
  • the solid nanoparticles are obtained in an aqueous suspension, but may be subsequently deprived of the residual surfactants by ultrafiltration and recovered by filtration or freeze-drying.
  • Such technique turns out to be advantageous from the point of view of the saving of energy with respect to the high energy homogenization, it allows to obtain smaller nanoparticles, having average diameters ranging from 90 nm to 900 nm, with a more uniform size distribution and a low polydispersion index.
  • the preparation of a microemulsion needs the melting of the lipidic material which is for most used lipidic substances about 70 °C, which limits the use of such technique for the thermolable substances. Summary of the invention
  • the invention relates to pharmaceutical compositions in form of nanoparticles, having a diameter lower than 1000 nm and preferably ranging from 50 to 500 nm, comprising a composite material, consisting of at least one lipidic substance and at least one amphiphilic substance, and a pharmaceutically active principle.
  • said composite material and the relative particles have characteristics not achievable by an usual mixing of a lipidic substance with an amphiphilic substance or by the adsorption of an amphiphilic substance on lipidic particles.
  • the amphiphilic substance may be preferentially distributed on the surface of the nanoparticles or it may be preferentially distributed inside the nanoparticles or it 4
  • thermolable drugs may be homogeneously distributed on the surface of and inside the nanoparticles.
  • the formation of the composite material allows to obtain nanoparticles: 1. with surface characteristics helping the oral administration absorption and the half-life time in the circulatory system; 2. with mass characteristics, as the low melting temperature, allowing to incorporate thermolable drugs;
  • the invention relates to the preparation of compositions for pharmaceutical use in form of particles having size lower than one micrometer (nanoparticles), comprising a composite material consisting of lipidic and amphiphilic substances, the latter being of lipidic or polymeric kind.
  • the nanoparticles according to the invention are prepared starting from a composite material obtained by comelting or cosolubilization of the lipidic material and the amphiphilic substances.
  • the comelted mixture at the subsequent cooling, results in a composite material having new characteristics with respect to the two starting materials, showing more hydrophilic zones and more lipophilic zones thanks to the reciprocal disposition of the components or to the segregation of the amphiphilic material towards the surface or inwards the mass of the nanoparticles.
  • These characteristics are substantially different from the surface adsorption of an amphiphilic substance on a lipophilic surface. Such properties will be described in detail in the Characterization Examples reported below.
  • the drug may be dissolved or suspended in said comelted mixture during the preparation process and, thanks to the new properties of the composite material, it may divide, according to its characteristics, preferentially inside the more hydrophilic areas or the more lipophilic areas.
  • the hydrophilic drugs for example peptides
  • the nanoparticles obtained from the comelted mixture maintain the same characteristics of the starting composite material.
  • the nanoparticles may be obtained with different preparation techniques:
  • a technique providing for the dispersion of a oil in water microemulsion (consisting of, as oil phase, lipidic and amphiphilic materials kept at a temperature higher than the melting point of the composite mixture and one or more surfactants and cosurfactants) in an aqueous medium, utilising the temperature gradient.
  • a technique providing for the high pressure homogenization of a fine emulsion of a composite material, at a temperature higher than the melting temperature of the materials forming the composite, or of a fine suspension of a composite material, below the melting temperature of the composite, in presence of surfactant agents.
  • the preparation of the invention according to the microemulsion-dispersion process provides for the initial comelting or cosolubilization of two or more lipidic and amphiphilic components, taken to the melting temperature of the components themselves or at least to the melting of one of the two components, when the latter is soluble in the former; an appropriate volume of an aqueous solution containing ore or more surfactants and cosurfactants, warmed at the same temperature of the composite material melted, under mild stirring is added to such melted composite material.
  • microemulsion it is also possible to form the microemulsion simultaneously taking to the melting temperature the lipidic and amphiphilic components in presence of the water and the surfactants and cosurfactants needed to formation of the microemulsion itself.
  • the active pharmaceutical principle may be dissolved or dispersed in the starting melted composite material or added directly to the microemulsion during the preparation of the microemulsion itself, depending on the properties of the active principle itself. The distribution of the active principle occurs into the composite material, allowing an unexpected decrease of the drug amount adsorbed on the surface and submitted to the degradating action of the enzymes and of the external environment.
  • the so formed oil/water microemulsion is subsequently dispersed in water or in aqueous medium, in controlled volume and stirring conditions, at a temperature generally ranging from +1° to +10 °C, but that may also range from -15 to -30 °C using non aqueous solvents miscible with water, originating in this way the composite nanoparticles in solid form in aqueous suspension.
  • Said nanoparticles have a diameter lower than 1000 nm.
  • the nanoparticles turn out to be different with respect to the systems obtained by the techniques of amphiphilic substances adsorption on the surface of the lipidic particles (Domb) or by the use of amphiphilic substances as surfactants for the formation of lipidic nanoparticles (Gasco).
  • the nanoparticle suspensions may be washed with water or aqueous solutions through an ultrafiltration system (or dialysis) which allows to remove the surfactant, cosurfactant and free drug excess. Therefore such process allows to remove the undesired possible effects due to the surfactants presence in the pharmaceutical form. Moreover, with such a procedure it is possible to quantitatively determine the percentage of the active principle not incorporated or adsorbed on the nanoparticles.
  • composition described above may be administered as an aqueous suspension or it is recovered as a solid by freeze-drying, filtration, evaporation of the aqueous solvent or spray-drying techniques.
  • the nanoparticles according to the present invention have the following quantitative composition by weight:
  • lipidic substances from 0.5 to 99.5%, and preferably from 10% to 90%;
  • - amphiphilic substances from 0.5 to 99.5% and preferably from 10% to 90%;
  • the component substances are used in the following proportions by weight: in the microemulsion:
  • lipidic components from 0.1% to 50% by weight and preferably from 10 to 25%
  • amphiphilic components from 0.1% to 50% by weight and preferably from 0.5% to 25%
  • the microemulsion prepared as described above is dispersed in aqueous environment (water or aqueous solutions) with volumetric dilutions from 1 :2 to 1 :200, preferably from 1 :5 to 1 :50.
  • aqueous environment water or aqueous solutions
  • - viscosizing agents of polymeric kind, from 0.05% to 5% by weight may be added.
  • the preparation according to the high pressure homogenization technique provides for the dispersion of the composite material, added with one or more adjuvant substances, in an aqueous environment.
  • the composite material is homogenized to form nanoparticles maintaining the system at the melting temperature of the material itself or just below such temperature (“softening”) or at temperatures maintaining the composite material at the solid state.
  • the composite material may be initially prepared by comelting or cosolubilization, analogously to what is reported for the technique 1 , proceeding to the comelting of two or more lipidic and amphiphilic components taken to the melting temperature of the components themselves or at least to the melting of one of the two components when the latter is soluble in the former.
  • the composite material may be preliminarly dispersed in an aqueous solution containing surfactant substances, stabilizing substances and/or viscosizing substances by dispersion or low energy homogenization techniques (for example using Silverson L2R or Ultra-Turrax kind equipments).
  • the system is submitted to high pressure homogenizator (for example of APV Gaulin, APV Rannie Mini-Lab, Microfluidizer kind) to repeated homogenization cycles which cause nanoparticle dispersions.
  • high pressure homogenizator for example of APV Gaulin, APV Rannie Mini-Lab, Microfluidizer kind
  • the high pressure homogenization treatment may occur at the composite material melting temperature, at "softening" temperature or at temperatures at which the material is present in a solid state in micronized form.
  • the active principle may be comelted, dissolved or dispersed in the composite material or in each of its constituents during the comelting of the system, or added during the subsequent process phases, as it is or in presence of surfactants which helps its incorporation in the nanoparticles or the adsorption on their surface.
  • the nanoparticle suspensions may be washed with water or aqueous solutions, analogously to what is described for the technique (1), through a ultrafiltration system.
  • composition may be administered as aqueous suspension or recovered as a solid by freeze-drying, filtration or aqueous solvent evaporation or spray-drying techniques.
  • the substances composing the invention are used in the following proportions by weight:
  • lipidic components from 0.1% to 50% by weight, preferably from 0.5 to 15%; - amphiphilic components, from 0.1 % to 50%, preferably from 0.5% to 15%;
  • - surfactants from 0.05% to 10%, preferably from 0.5% to 5%;
  • - water, or aqueous solutions of hydrosoluble components from 45% to 99.5%, preferably from 50% to 80%;
  • lipidic materials usable according to the invention we can mention both natural products and synthetic or semi-synthetic kind products definable as "fats" in that they are not miscible or only partially miscible with water:
  • natural fats either saturated or unsaturated and partially or totally hydrogenated vegetal oils, for example hydrogenated cotton oil (LubritabTM), hydrogenated palm oil (DynasanTM P60) and hydrogenated soy-bean oil (SterotexTM HM);
  • liquid waxes for example isopropyl myristate, isopropyl-caprinate, -caprylate, - laurate, -palmitate, -stearate and esters of fatty acids, such as ethyl oleate and oleyl oleate;
  • solid waxes for example carnauba wax and bees-wax
  • aliphatic alcohols for example cetyl alcohol, stearyl alcohol, lauryl alcohol, cetylstearyl alcohol and their polyhydroxyethylated derivatives
  • aliphatic carboxylic acids preferably having medium and long chain (C10-C22). saturated (decanoic acid, lauric acid, palmitic, stearic, docosanoic acid, etc.), unsaturated (oleic, linoleic, etc.) and their polyhydroxyethylated derivatives. 10
  • lipids having in their structure some hydrophilic components, such as for example: 1) phospholipids belonging to the series: phosphatidyl glycerol, phosphatidylcholine and phosphatidic acid (e.g. dimiristoyl phosphatidyl glycerol); 2) mono- and di-glycerides such as glyceril monostearate (MyvaplexTM 600) or glyceril palmitostearate (PrecirolTM);
  • triglycerides and saturated or unsaturated polyhydroxylated triglycerides e.g. series of LabrafilTM, LabrafacTM Hydro, GelucireTM;
  • esters of fatty acids such as decylester of oleic acid: CetiolTM V and isopropylmyristate;
  • medium chain fatty acids such as capric, caproic and lauric acids.
  • amphiphilic materials of polymeric kind polymers may be used such as:
  • PEG Polyethylene glycols
  • Polysaccharides of natural origin such as chitosan and derivatives, ialuronic acid and derivatives, xanthan, scleroglucan, gellan, guar gum, locust bean gum, alginate and dextran;
  • polyesters such as for example poly- ⁇ -caprolactone.
  • the composite materials according to the invention may be prepared by mixing, comelting or cosolubilization of the components selected among the lipidic materials and among the amphiphilic materials of lipidic or polymeric kind.
  • composite materials according to the invention may be formed from mixtures of fatty acids (stearic acid-decanoic acid), of fatty acids and phospholipids (stearic acid-dimihstoyl phosphatidyl glycerol or dimiristoyl phosphatidylcholine), fatty acids and triglycerides or polyhydroxylated triglycerides 11
  • aqueous phase of the microemulsion according to the technique 1 and/or dispersing phase according to the techniques 1 and 2) may be mentioned:
  • hydrophilic, hydrosoluble or hydrodispersable polymers such as polyethylene glycol, polyvinyl pyrrolidone, polyacrylic acids and derivatives (e.g. Carbopol®, Pemulen®, etc.), polymethacrylic acids and derivatives (e.g. Eudragit®), copolymers of polyoxyethylene-polyoxypropilene (e.g. Poloxamer, Lutrol®), polysaccharides of various nature such as for example dextran, xanthan, scleroglucan, gum arabic, guar gum, chitosan, cellulose and starch derivatives;
  • hydrophilic, hydrosoluble or hydrodispersable polymers such as polyethylene glycol, polyvinyl pyrrolidone, polyacrylic acids and derivatives (e.g. Carbopol®, Pemulen®, etc.), polymethacrylic acids and derivatives (e.g. Eudragit®), copolymers of polyoxyethylene-polyoxypropilene (e.g
  • aqueous solutions of saccharides e.g. sorbitol, mannitol, xylitol
  • polyethylene glycols e.g. PEG 200, PEG 400, PEG 600, PEG 1000
  • polyglycolic glycerides e.g. LabrasolTM
  • polyglycols such as for example propylene glycol, tetraglycol, ethoxydiglycol
  • non ionic surfactants with a HLB value generally but non necessarily greater than 7, such as for example: sorbitan-esters of fatty acids (e.g. Span®, Arlacel®, Brij®), polyoxyethylen sorbitan esters of fatty acids (e.g. Tween®, Capmul®, Liposorb®), copolymers of polypropileneoxide- polyethyleneoxide (Poloxamer), esters of polyethylene glycol (PEG)-glycerol (Labrasol®, Labrafil® with HLB 6-7), esters of PEG and acids or long chain aliphatic alcohols (e.g. Cremophor®), polyglycerid esters (Plurol®), esters of saccharides and fatty acids (sucro-esters). When needed, even anionic 12
  • surfactants e.g. sodium lauryl sulfate, sodium stearate, sodium oleate
  • bile salts e.g. sodium glycocholate, taurodeoxycholate, taurocholate, ursodeoxycholate
  • cationic e.g. tricetol
  • low HLB surfactants e.g. lecithins as they are (Lipoid S75) and hydrogenated (e.g. Lipoid S75, S75-3), phospholipids and their semisynthetic or synthetic derivatives may be used.
  • cosurfactants needed for the formation of the microemulsion we remember short chain alcohols such as for example ethanol, 2-propanol, n- butanol, isopropanol; short and medium aliphatic acids (e.g. butyric acid, valeric and capronic acids), aromatic alcohols (e.g. benzyl alcohol); medium chain alcohols and aliphatic acids (C8-C12) such as decanoic acid, lauric acid, caprynil alcohol and lauryl alcohol. Moreover, as cosurfactants may be used also esters or ethers of acids or medium-long chain aliphatic alcohols with mono- or polyhydroxylated alcohols.
  • short chain alcohols such as for example ethanol, 2-propanol, n- butanol, isopropanol
  • short and medium aliphatic acids e.g. butyric acid, valeric and capronic acids
  • aromatic alcohols e.g. benzyl alcohol
  • the pharmaceutical active principles usable in the invention may be both hydrosoluble (e.g. peptides or proteins) and liposoluble (e.g. steroidal hormones), as well as poorly soluble in both vehicles (e.g. acyclovir).
  • the surface and mass properties of the nanoparticles according to the invention allow important advantages such as for example: 1) the possibility of administering by oral or transmucosal way molecules usually not absorbable by such a way (e.g. polypeptides and proteins);
  • the active principle groups which may be advantaged from the invention include: non steroidal (NSAID) and steroidal (SAID) anti-inflammatories, estrogenic or 13
  • progestational hormones progestational hormones, cardiovasculars, antivirals, antimycotics, antineoplastics, hypolipidemics, peptides and proteins having different action.
  • ergot alkaloids and derivatives dihydroergotamine, didhydroergotoxine and bromocriptine.
  • Analgesics and non steroidal anti-inflammatories, and their salts diclofenac sodium, diclofenac hydroxyethil pyrrolidine, diclofenac diethylamine, ibuprofen, flurbiprofen, ketoprofen, indomethacin, mefenamic acid, naproxen, nimesulide and piroxicam.
  • Antiarrhythmics amiodarone, diisopyramide, propranolol and verapamil.
  • Antibactericals amoxicillin, flucloxacillin, gentamicin, rifampicin, erythromycin and cephalosporins.
  • Antifungins and antipsoriatics amphotericin, butoconazole nitrate, ketoconazole, econazole, etretinate, fluconazole, flucytosine, griseofulvin, itraconazole, miconazole, nystatin, sulconazole and tioconazole.
  • Antivirals Acyclovir, ganciclovir, AZT and protease inhibitors.
  • Antihypertensives amlodipine, clonidine, diltiazem, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine hydrochloride, nimodipine, nifedipine, prazosin hydrochloride and papaverine.
  • Antidepressants carbamazepine.
  • Antihistaminics diphenhydramine, chlorpheniramine, pyrilamine, chlorcyclizine, promethazine, acrivastine, cinnarizine, loratadine and terfenadine.
  • Antineoplastics and immunosuppressants cyclosporin, dacarbazine, etretinate, etoposide, lomustine, melphalan, mitomycin, mitoxantrone, paclitaxel, procarbazine, tamoxifen, taxol and derivatives and taxotere.
  • ⁇ -Blockers alprenolol, atenolol, oxprenolol, pindolol and propranolol.
  • ⁇ -Agonists salbutamol, salmeterol.
  • Cardiac and cardiovascular inotropics amrinone, digitoxin, digoxin, lanatoside C, 14
  • Corticosteroids beclomethasone, betamethasone, budesonide, cortisone acetate, desoximethasone, dexamethasone, fludrocortisone acetate, flunisolide, hydrocortisone, methylprednisolone, methylprednisone and triamcinolone.
  • Gastrointestinals and anti H2-histaminics cimetidine, cisapride, domperidone, famotidine, loperamide, mesalazine, omeprazole, ondansetron hydrochloride and ranitidine.
  • hypolipidemics bezafibrate, clofibrate, gemfibrozil, probucol and lovastatin.
  • Anti-anginals amyl nitrate, glyceryl trinitrate, isosorbide dinitrate and mononitrate and pentaerythritol tetranitrate.
  • Vitaminic and Nutritional Agents betacarotene, vitamin A, Vitamin B2, Vitamin D and derivatives, vitamin E and derivatives and vitamin K.
  • Opioid Analgesics codeine, dextropropoxyphene, diihydrocodeine, morphine, pentazocine and methadone.
  • Peptidic, proteic or polysaccharidic molecules having different activity leuprolide and LH-RH analogues, calcitonin, glutathione, somatotropin (GH), somatostatin, desmopressin (DDAVP), interferon, molgramostin, epidermic growth factor (EGF), nervous growth factor (NGF), insulin, glucagon, toxins or toxoides
  • tetanus toxin for example tetanus toxin
  • antigenic factors of proteic or polysaccharidic kind for example heparin, heparin having low molecular weight and heparinoids.
  • Molecules having specific topical activity e.g. sun protectors (UV Absorbers); skin nutrients, ceramides and glycolic acid.
  • compositions according to the invention may be evaluated by several physico chemical methods, such as for example:
  • LLC laser light scattering
  • hydrophilic drugs e.g. peptides
  • lipidic matrix helps the dissolution/dispersion of the active principle in the most hydrophilic zones of the nanoparticles themselves
  • amphiphilic compound at certain proportions of amphiphilic and lipidic substance, result in two phases, with peculiar characteristics, wherein the amphiphilic compound:
  • the nanoparticles consisting of composite materials having peculiar and different characteristics with respect to the single original materials, may melt at physiological temperatures releasing the active principle in a fast way (e.g. for topical/percutaneous treatments and flavour masking),
  • the nanoparticles may stay as they are at physiological temperatures ensuring the release of the active principle by diffusion and/or degradation of the nanoparticles themselves, - at certain proportions of lipidic and amphiphilic material, in the preparation technique (1 ), based on the oil-water microemulsion of the composite mixture, it is possible to extend the thermal interval of existence of the microemulsion itself to lower temperature values, allowing the incorporation of thermolable molecules.
  • Fundamental and innovative characteristic of the invention independently from the process of preparation of the nanoparticles, is thus the unexpected formation of a composite material having new and different surface and mass characteristics with respect to the single components.
  • the qualitative characteristics of the chosen starting materials e.g.
  • compositions according to the invention are reported, with the technique 1 (Examples 1-36), and with the 17
  • the microemulsion at about 60 °C, is dispersed in 5 volumes of water at pH 3 cooled to 3-5 °C, under constant stirring (250 rpm), to form composite solid lipidic nanoparticles consisting of stearic acid - dimyristoil- phosphatidyl glycerol containing calcitonin.
  • the suspension is washed by ultrafiltration in order to remove the surfactant excess.
  • the calcitonin incorporation efficacy in the nanoparticles determined by fluorimetric and chromatographic techniques (see characterization Examples), is about 10.5 %.
  • the average diameter of the nanoparticles is 226 nm and the polydispersion index is 0.200.
  • Example 2 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 1.0%.
  • the calcitonin incorporation efficacy is 10.2%, the average diameter of the nanoparticles 220 nm and the polydispersion 0.268.
  • Example 1 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 4.5%.
  • the calcitonin incorporation efficacy is 13.2%, the average diameter of the nanoparticles 199 nm and the polydispersion 0.212.
  • EXAMPLE 4 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 5.2%.
  • the calcitonin incorporation efficacy is 13.4%, the average diameter of the nanoparticles 195 nm and the polydispersion 0.200.
  • EXAMPLE 5 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 4.5%.
  • the calcitonin incorporation efficacy is 13.2%, the average diameter of the nanoparticles 195 nm and the polydispersion 0.200.
  • Example 6 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 9.5%. The calcitonin incorporation efficacy is 9.19%, the average diameter of the nanoparticles 231 nm and the polydispersion 0.186. EXAMPLE 6
  • Example 7 The preparation of the Example 1 is repeated, using a DMPG percentage in the composite mixture equal to 25%.
  • the calcitonin incorporation efficacy is 9.51%, the average diameter of the nanoparticles 205 nm and the polydispersion 0.275.
  • Example 2 The preparation of the Example 1 is repeated, using as an amphiphilic material the distearoil phosphatidic acid (DSPA) phospholipid in a percentage in the composite mixture equal to 1.2%.
  • the calcitonin incorporation efficacy is 9.9%, the average diameter of the nanoparticles 245 nm and the polydispersion 0.261.
  • Example 7 The preparation of the Example 7 is repeated, using a DSPA percentage in the composite mixture equal to 5.2%. The calcitonin incorporation efficacy is 14.4%, the average diameter of the nanoparticles 324 nm and the polydispersion 0.341.
  • EXAMPLE 9 The preparation of the Example 1 is repeated, using low molecular weight heparin as an active principle (average molecular weight 4000 Da) and, the dimyristoil phosphatidylcholine (DMPC) phospholipid as amphiphilic material, in a percentage in the composite mixture equal to 4.0%. The heparin incorporation efficacy is about 1.0%, the average diameter of the nanoparticles is 213 nm and the polydispersion 0.186.
  • DMPC dimyristoil phosphatidylcholine
  • Example 9 The preparation of the Example 9 is repeated, using the dimyristoil phosphatidylcholine (DMPC) phospholipid, in a percentage in the composite mixture equal to 8.0%.
  • the average diameter of the nanoparticles is 179 nm and the polydispersion 0.249.
  • Example 9 The preparation of the Example 9 is repeated, using the dimyristoil phosphatidylcholine (DMPC) phospholipid, in a percentage in the composite mixture equal to 10%.
  • the average diameter of the nanoparticles is 290 nm and the polydispersion 0.270.
  • Example 9 The preparation of the Example 9 is repeated, using the dimyristoil phosphatidylcholine (DMPC) phospholipid, in a percentage in the composite mixture equal to 14%.
  • the average diameter of the nanoparticles is 369 nm and the polydispersion 0.360.
  • Example 14 The preparation of the Example 1 is repeated, using the Labrafac HydroTM polyhydroxylated triglyceride as amphiphilic material, in a percentage in the composite mixture equal to 1.0%.
  • the average diameter of the nanoparticles is 307 nm and the polydispersion 0.234.
  • Example 15 The preparation of the Example 13 is repeated, using the Labrafac HydroTM polyhydroxylated triglyceride, in a percentage in the composite mixture equal to 2.5%. The average diameter of the nanoparticles is 307 nm and the polydispersion 0.234. EXAMPLE 15
  • Example 13 The preparation of the Example 13 is repeated, using the Labrafac HydroTM polyhydroxylated triglyceride, in a percentage in the composite mixture equal to 50%.
  • the average diameter of the lipidic nanoparticles is 310 nm and the polydispersion 0.332.
  • Example 17 The preparation of the Example 13 is repeated, using the Labrafac HydroTM polyhydroxylated triglyceride, in a percentage in the composite mixture equal to 10.0%.
  • the average diameter of the nanoparticles is 326 nm and the polydispersion 0.325.
  • Tween 20 To the so formed emulsion kept under stirring, 4 ml of Tween 20 are added, to form a transparent and anisotropic microemulsion.
  • the microemulsion, heated to about 50 °C is dispersed in 50 volumes of water at pH 3 cooled to about 3-5 °C, under constant stirring (250 rpm), to form the solid nanoparticles containing calcitonin.
  • the suspension is washed by ultrafiltration in order to remove the surfactant excess.
  • the calcitonin incorporation efficacy in the nanoparticles is about 11.5 %.
  • the average diameter of the nanoparticles is 185 nm and the polydispersion index is 0.300.
  • Example 18 The preparation of the Example 18 is repeated without the incorporation of calcitonin.
  • the average diameter of the composite nanoparticles is 182 nm and the polydispersion index 0.295.
  • Example 18 The preparation of the Example 18 is repeated, using the Labrafil 2130CS polyhydroxylated triglyceride at 8.9% in the composite mixture.
  • the composite mixture is melted at about 70 °C.
  • the average diameter of the nanoparticles is 173 nm and the polydispersion index 0.268.
  • polyhydroxylated triglyceride at 10% in the composite mixture.
  • the composite mixture is melted at 66 °C.
  • the average diameter of the nanoparticles is 216 nm and the polydispersion index 0.287.
  • EXAMPLE 22 The preparation of the Example 18 is repeated, using the Labrafil 2130CS polyhydroxylated triglyceride at 15% in the composite mixture.
  • the average diameter of the nanoparticles is 188 nm and the polydispersion index 0.247.
  • Example 18 The preparation of the Example 18 is repeated, using the Labrafil 2130CS polyhydroxylated triglyceride at 50% in the composite mixture and the composite mixture is melted at 60 °C.
  • the average diameter of the nanoparticles is 312 nm and the polydispersion index 0.424.
  • Example 18 The preparation of the Example 18 is repeated, using the Labrafil 2130CS polyhydroxylated triglyceride at 75% in the composite mixture and the composite mixture is melted at 54 °C.
  • the average diameter of the nanoparticles is 162 nm and the polydispersion index 0.315.
  • Example 18 The preparation of the Example 18 is repeated, using the Labrafil 2130CS polyhydroxylated triglyceride at 95% in the composite mixture and the composite mixture is melted at 35 °C.
  • the average diameter of the nanoparticles is 205 nm and the polydispersion index 0.281.
  • Example 26 The preparation of the Example 26 is repeated, using the decanoic acid at 50% in the composite mixture. The composite mixture is melted at 50 °C. The average diameter of the nanoparticles is 310 nm and the polydispersion index 0.280.
  • EXAMPLE 28 The preparation of the Example 26 is repeated, using the decanoic acid at 75% in the composite mixture. The composite mixture is melted at 35 °C. The average diameter of the nanoparticles is 300 nm and the polydispersion index 0.250.
  • EXAMPLE 29 1.8 g of stearic acid and 0.2 g of polyethylene glycol PEG 4000 (PEG 4000 percentage in the mixture: 10.0%) are mixed, and they are heated to about 75 °C with the formation of the composite mixture.
  • Example 29 The preparation of the Example 29 is repeated using the polyethyleneglycol PEG 4000 at 20% in the composite mixture.
  • the composite mixture is melted at 50 °C.
  • the average diameter of the nanoparticles is 263 nm and the polydispersion index 0.334.
  • Example 29 The preparation of the Example 29 is repeated, using the poly-(propyleneoxide) poly-(ethyleneoxide) copolymer as amphiphilic material, LutrolTM 188 at 10% in the composite mixture.
  • the composite mixture is melted at 50 °C.
  • the average diameter of the nanoparticles is 353 nm and the polydispersion index 0.314.
  • Example 29 The preparation of the Example 29 is repeated, using LutrolTM 188 at 20% in the composite mixture.
  • the composite mixture is melted at 50 °C.
  • the average diameter of the nanoparticles is 375 nm and the polydispersion index 0.300.
  • EXAMPLE 33 1.4 g of stearic acid and 607 mg of LabrafilTM M2130CS polyhydroxylated triglyceride (Labrafil percentage in the mixture: 30.1%) are mixed, and they are heated to about 70 °C with the formation of the composite mixture.
  • To such a mixture 1.06 g of partially hydrogenated soybean lecithin (Lipoid S75-35) are added.
  • the average diameter of the nanoparticles containing ciclosporin is 304 nm and the polydispersion index 0.365.
  • EXAMPLE 34 The preparation of the Example 33 is repeated, incorporating in the microemulsion 100 mg of etoposide. The composite mixture is melted at 50 °C. The average diameter of the composite nanoparticles is 288 nm and the polydispersion 0.211.
  • EXAMPLE 35 The preparation of the Example 29 is repeated, using LutrolTM 188 at 20% in the composite mixture. The composite mixture is melted at 50 °C and added with acyclovir in an amount equal to 100 mg per gram of composite mixture. The 24
  • average diameter of the nanoparticles containing acyclovir is 360 nm and the polydispersion index 0.302.
  • Tween 20 To the so formed emulsion, kept under stirring, 6 ml of Tween 20 are added to form a transparent and anisotropic microemulsion.
  • the microemulsion, heated to about 50 °C is dispersed in 50 volumes of water at pH 3, at about 3-5 °C, under constant stirring (250 rpm), to form the solid nanoparticles containing ubidecarenone.
  • the suspension is washed by ultrafiltration in order to remove the surfactant excess.
  • the ubidecarenone incorporation percentage in the nanoparticles is 99%, the average diameter of the nanoparticles is 195 nm and the polydispersion index 0.214.
  • EXAMPLE 37 6 g of stearic acid and 0.9 g of LabrafilTM M2130CS polyhydroxylated triglyceride (15% of the mixture) are mixed, which are melted at a temperature about equal to 70 °C. To the melted composite mixture 1.5 g of soybean lecithin (Lipoid S75-35) are added, and 300 ml of an aqueous solution at pH 5.5 containing 3 g of Tween 20. The so formed emulsion is passed in a high pressure Rannie-MiniLab 8.30 homogenizer, at a temperature equal to 70 °C and a pressure equal to 750 bar for times ranging from 0 to 15 min. The dispersions are recovered and instantaneously cooled to 4 °C, by constant stirring at 250 rpm in a thermostated bath, giving origin to solid nanoparticles. The average diameters are: 25
  • Example 37 The preparation of the Example 37 is repeated, maintaining the temperature of the system, once prepared the composite material by comelting, below the melting temperature of the composite itself (T ⁇ 50 °C).
  • the obtained dispersion is pre- homogenized for 5 minutes in a low energy (Silverson mod. L2R) homogenizer- mixer, and subsequently homogenized at high pressure (750 bar) at constant T° (45 °C).
  • L2R Low energy homogenizer- mixer
  • Example 39 The preparation of the Example 39 is repeated, maintaining the temperature of the system, once prepared the composite material by comelting, under the melting temperature of the composite itself (T ⁇ 35 °C).
  • the obtained dispersion is pre- homogenized in a low energy (Silverson mod. L2R) homogenizer-mixer, and subsequently homogenized at high pressure (750 bar) at constant T (30 °C).
  • L2R Low energy homogenizer-mixer
  • Example 41 The preparation of the Example 41 is repeated, maintaining the temperature of the system, once prepared the composite material by comelting, under the melting temperature of the composite itself (T ⁇ 45 °C).
  • the obtained dispersion is pre- homogenized in a low energy (Silverson mod. L2R) homogenizer-mixer, and subsequently homogenized at high pressure (750 bar) at constant T (45 °C).
  • EXAMPLE 43 The preparation of the Example 41 is repeated, with a PEG percentage equal to 15% in the composite mixture and incorporating in the composite mixture itself 300 mg of salmon calcitonin. The efficiency of the calcitonin incorporation in the PEG-stearic acid mixture is equal to 35%.
  • Example 45 The preparation of the Example 42 is repeated maintaining the temperature of the system, once prepared the composite material by comelting below the melting temperature of the composite itself (T ⁇ 45 °C).
  • the obtained dispersion is pre- homogenized in Silverson and subsequently homogenized at high pressure (750 bar) at constant T (45 °C).
  • a composite mixture containing 5% stearic acid and 95% LabrafilTM M2130CS polyhydroxylated triglyceride is prepared by comelting and cooling.
  • To the melted composite mixture (75 °C) 1 g of ibuprofen and 240 mg per gram of mixture of soybean lecithin (Lipoid S75-35) and an aqueous solution containing 1.2% of Tween 20 in an amount of 40 ml of aqueous solution at pH 5.5 per gram of composite mixture + drug are added.
  • the so formed emulsion is treated in a high pressure Rannie-MiniLab 8.30 homogenizer, at a temperature equal to 70 °C and a pressure equal to 750 bar, for times ranging from 0 to 10 min.
  • the dispersions are instantaneously cooled to 4 °C by constant stirring at 250 rpm in a thermostated bath, giving origin to solid nanoparticles.
  • the average diameters are:
  • Example C The procedure of the Example A is repeated, adding 3.85 mg of salmon calcitonin. The incorporation efficacy of the calcitonin in the nanoparticles is 1.82%. The average diameter of the nanoparticles is 193 nm and the polydispersion index is 0.235.
  • Example B The procedure of the Example B is repeated. To the so prepared nanoparticles an amount of amphiphilic material (dimyristoil phosphatydil glycerol, DMPG) is added, under stirring in a mixer, in a ratio equal to 1 :10 with respect to the lipidic mass of the stearic acid, which is adsorbed on the surface of the nanoparticles themselves. The incorporation efficacy of the calcitonin on the nanoparticles is equal to 1.75%.
  • Such composition according to the prior art is directly comparable with the Example 5 of the invention, deferring only for having the adsorbed amphiphilic component on the surface and not as a component of the composite material forming the nanoparticles.
  • the suspension is washed by ultrafiltration in order to remove the surfactant excess.
  • the average diameter of the nanoparticles is 215 nm and the polydispersion index is 0.175.
  • stearic acid and 300 mg of ubidecarenone are mixed and they are melt heated to about 70 °C.
  • 0.5 ml of n-butanol, 1.30 g of sodium taurodeoxycholate in 10 ml of aqueous solution at pH 3, heated to 70 °C are added to the comelted.
  • 3.25 g of Tween 20 are added to form a microemulsion.
  • the microemulsion heated to about 70 °C is dispersed in 50 volumes of water at pH 3 at about 3-5 °C under constant stirring (250 rpm), to form the lipidic nanoparticles according to the EP 0526666A1 technique.
  • the suspension is washed by ultrafiltration to remove the surfactant excess.
  • the incorporation percentage of ubidecarenone in the nanoparticles is about 80%, the 29
  • average diameter of the nanoparticles is 205 nm and the polydispersion index is
  • stearic acid 7.5 g of stearic acid are melted at a temperature equal to 75 °C. 3 g of soybean lecithin (Lipoid S75-35) are added and 300 ml of aqueous solution at pH 5.5 containing 6 g of Tween 20.
  • the so obtained emulsion is treated in a high pressure Rannie-MiniLab 8.30 homogenizer at a temperature equal to 70 °C and a pressure equal to 750 bar, for times ranging from 0 to 10 min.
  • the dispersions are instantaneously cooled to 4 °C giving origin to solid nanoparticles according to the technique described in WO 93/05768.
  • the average diameters are:
  • One of the innovative characteristics of the invention is the possibility to improve the efficacy of the incorporation of hydrophilic drugs (peptides) and to improve the distribution inside the composite nanoparticles. Such aspect has been shown by the fluorescence techniques.
  • the calcitonin peptide has been marked by a fluorophor (7-nitrobenz-2oxa- 1,3diazol, NBD), according to a known technique (Biochem. J., 272, 713-719, [1990]), and subsequently incorporated in the nanoparticles as described in the Examples 1-8 of the invention and the Comparative Examples B-C.
  • the samples have been washed according to the ultrafiltration procedures described in the Examples. • The percentage of peptide incorporated in the nanoparticles 30
  • Another innovative characteristic of the invention product is the modification of the mass properties of the composite materials forming the nanoparticles.
  • the modifications of the mass properties are quantitatively evaluated by thermal analysis techniques by a differential scanning calorimeter, DSC, Perkin Elmer mod. DSC 7.
  • the nanoparticles according to the invention may be formed either by an homogenous composite material, or by a composite material presenting separated phases with different properties. In the former case it is possible for example to observe that the homogeneous composite material shows the modification of a thermal event (melting temperature) as a function of the composition (Example G) (Table 2).
  • thermodynamical behaviour of the composite nanoparticles as a function of the component percentage is observable also on the nanoparticles in suspension, for example by techniques of laser light scattering ("laser light scattering").
  • laser light scattering The phase transitions of the composite nanoparticles are noticeable from the intensity variation of the scattering as a function of the temperature, measured by a Brookhaven mod. BI-90 Particle Sizer.
  • Labrafil 2130 CS polyhydroxylated triglyceride corresponding to the Examples 18-
  • Phase transitions of the composite nanoparticles determined by the scattering techniques, corresponding to the described products in the Examples 3-5 and the Comparative Example A.
  • the phase transition (melting) is pointed out by the decrease of the intensity of the laser light scattering ("scattering"), as a function of the temperature.
  • the beginning of such a variation corresponds to the beginning of the transition. It is clear how, in the compositions according to the invention, such a transition may be changed and controlled varying the composition of the material forming the nanoparticles.
  • the melting temperature of the particles 63 °C in the Example 35
  • One of the innovative characteristics of the product of the invention is the possibility to control the surface properties of the composite materials forming the nanoparticles and, consequently, of the nanoparticles themselves.
  • the surface characteristics of the nanoparticles obtained according to the techniques and the materials of the invention differ in substantial way with respect to the surface adsorption of amphiphilic components described in the state of art, because they are dependent from the formation of the composite material.
  • an advantage of the invention is the possibility to obtain composite nanoparticles having favourable characteristics of biocompatibility, hydrophobicity, hydropilicity and polarity according to the therapeutical aim to achieve.
  • the surface properties of the composite materials forming the nanoparticles may 36
  • ⁇ sv ⁇ si + ⁇ iv (cos ⁇ ) (1 )
  • indexes sv, si, Iv refer respectively to the surface energy ( ⁇ ) of the solid-vapour, solid-liquid and liquid-vapour surfaces
  • ⁇ is the angle of contact of the liquid with the solid surface.
  • Figure 5 Trend of the surface energy of the stearic acid-Labrafac Lipo composition.
  • the invariant trend shows a homogeneous distribution of the amphiphilic component Labrafac Lipo in the composite mixture.
  • the variation of the surface properties of the composite nanoparticles as a function of the used composite materials composition is quantifiable also by Zeta potential measures carried out by a laser light scattering electrophoretic analyzer, ZetaMaster (Malvern, UK), on the aqueous suspensions of the composite nanoparticles.
  • the Zeta potential (shear plane potential) is a measure of the surface charge of the nanoparticles in suspension.
  • Composite nanoparticles suspensions according to the invention (20 ml) containing calcitonin (specific activity: 4000 Ul/mg; nominal dose: 600 Ul/kg, incorporated effective dose in the nanoparticles: 60-80 Ul/kg), have been administered per os to 4 Rhesus macaques. Samples of blood (1.5 ml) were taken at determined times and immediately analyzed after the taking.

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Abstract

L'invention porte sur des compositions pharmaceutiques se présentant sous forme de nanoparticules comprenant un matériau composite constitué d'au moins une substance lipidique et d'au moins une substance amphiphile, et d'un principe pharmaceutiquement actif. Ces compositions, grâce aux propriétés de surface et de masse du matériau composite, présentent une amélioration dans l'incorporation des principes actifs et un accroissement de la biodisponibilité des principes actifs à faible pouvoir d'absorption.
PCT/EP1999/000782 1998-02-06 1999-02-05 Compositions pharmaceutiques se presentant sous forme de nanoparticules comprenant des substances lipidiques et des substances amphiphiles, et procede de preparation connexe WO1999039700A1 (fr)

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CA002319565A CA2319565A1 (fr) 1998-02-06 1999-02-05 Compositions pharmaceutiques se presentant sous forme de nanoparticules comprenant des substances lipidiques et des substances amphiphiles, et procede de preparation connexe
BR9907683-7A BR9907683A (pt) 1998-02-06 1999-02-05 Composições farmacêuticas na forma de nanopartìculas, compreendendo substâncias lipìdicas e substâncias anfifìlicas e processo de preparação correlacionado
JP2000530200A JP2002502813A (ja) 1998-02-06 1999-02-05 脂質物質及び両親媒性物質より成っているナノ粒子の形態の薬学的組成物と関連する調製工程
AU27238/99A AU747129B2 (en) 1998-02-06 1999-02-05 Pharmaceutical compositions in form of nanoparticles comprising lipidic substances and amphiphilic substances and related preparation process
KR1020007008610A KR20010040726A (ko) 1998-02-06 1999-02-05 지질성 물질 및 양친매성 물질을 포함하는 나노입자형태의 약학적 조성물 및 관련 제조방법
EP99907510A EP1051160A1 (fr) 1998-02-06 1999-02-05 Compositions pharmaceutiques se presentant sous forme de nanoparticules comprenant des substances lipidiques et des substances amphiphiles, et procede de preparation connexe

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IT98MI000234A IT1298575B1 (it) 1998-02-06 1998-02-06 Composizioni farmaceutiche in forma di nanoparticelle comprendenti sostanze lipidiche e sostanze antifiliche e relativo processo di
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CA2319565A1 (fr) 1999-08-12
BR9907683A (pt) 2000-11-14
IT1298575B1 (it) 2000-01-12
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AU2723899A (en) 1999-08-23
JP2002502813A (ja) 2002-01-29

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