WO2012101242A1 - Nouvelle suspension pharmaceutique pour administration parentérale - Google Patents

Nouvelle suspension pharmaceutique pour administration parentérale Download PDF

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Publication number
WO2012101242A1
WO2012101242A1 PCT/EP2012/051288 EP2012051288W WO2012101242A1 WO 2012101242 A1 WO2012101242 A1 WO 2012101242A1 EP 2012051288 W EP2012051288 W EP 2012051288W WO 2012101242 A1 WO2012101242 A1 WO 2012101242A1
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Prior art keywords
drugs
injectable pharmaceutical
suspension
pharmaceutical suspension
eudragit
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PCT/EP2012/051288
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English (en)
Inventor
Lutz KRÖHNE
Christoph Dunmann
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Capsulution Pharma Ag
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Publication of WO2012101242A1 publication Critical patent/WO2012101242A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • 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
    • A61K9/5089—Processes

Definitions

  • the present invention is in the field of drug formulation.
  • the present invention relates to improved nanoparticulate suspensions of poorly soluble compounds and nanoparticulate pharmaceutical compositions. More particularly the present invention relates to injectable nanoparticular suspensions of poorly soluble compounds comprising a methacrylate polymer.
  • an injectable pharmaceutical suspension according to the present invention overcomes these problems.
  • the inventors especially found that the use of methacrylate polymers allows the provision of a stable, injectable and highly concentrated pharmaceutical suspension.
  • the injectable pharmaceutical suspensions according to the present inventions exhibit a high bioavailability of the pharmaceutically active compound after injection and moreover serve as a depot, resulting in a release of the drug over a longer period after single administration.
  • the present invention relates to an injectable pharmaceutical suspension comprising a polyelectrolyte and a nanoparticular, poorly soluble pharmaceutically active compound, wherein said polyelectrolyte comprises a methacrylate polymer.
  • the present invention further relates to a method for stabilizing a poorly soluble active pharmaceutical compound in a n injectable anoparticulate pharmaceutical suspension comprising the steps of: a) suspending in a liquid dispersion medium a poorly soluble pharmaceutically active compound without the presence of a detergent,
  • the present invention relates to a method for stabilizing a poorly soluble active pharmaceutical compound in a injectable nanoparticulate pharmaceutical suspension comprising the steps of:
  • the present invention also relates to a method for stabilizing two or more poorly soluble pharmaceutically active in an injectable pharmaceutical suspension comprising the steps of: a) contacting two or more poorly soluble pharmaceutically active compound with a solution of methacrylate polymer without the presence of a detergent;
  • an injectable pharmaceutical suspension according to the present invention derivable by a method according to the present invention as disclosed herein. Furthermore the present invention relates to an injectable pharmaceutical suspension according to the present invention, for use in the treatment of a disease in a subject, wherein the composition is provided in a form to be administered parenterally to said subject.
  • the present invention also relates to a dosage form comprising an injectable pharmaceutical suspension according to the present invention.
  • the present invention relates to a method of treating comprising the parenteral application of an injectable pharmaceutical suspension according to the present invention.
  • “Injectable” in the context with the present invention means that the suspension can be easily handled and applied using syringes and needles.
  • the skilled artisan is aware of the properties such a suspension has to have. He knows that the suspension has to be of a viscosity that allows application event through thin needles, e.g. a 28 gauge needle. Even nanosuspensions with 10% solid content are of a viscosity similar to water and therefore i.v. injectable. Viscosities range from 1-20 mPas for very low viscous systems, up to 100 mPas for nanosuspensions with similar viscosity to injectable oils.
  • the injectable pharmaceutical suspension has a viscosity of 1 to 30,000 mPas, preferably of 1 to 1,000 mPas, more preferably 1 to 100 mPas, even more preferably 1 to 20 mPa s. Since the suspension is to be applied parenterally, the skilled artisan will recognize that the suspension also has to possess properties that allow the direct application into the animal or human body. Theses properties may vary for different routes of application, e.g. intravenous or intramuscular application. Among these properties the pH and osmolarity are relevant, they are preferably physiological. In one embodiment of the present invention the injectable pharmaceutical suspension has a pH between 5 and 9, preferably between 6 and 8, more preferably between 7,0 and 7,5. The osmolarity of the injectable pharmaceutical suspension according to the present invention is in one embodiment isotonic, preferably 308 mosmol/1.
  • the average size of the particles is preferably less than about 5000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm, most preferably less than about 800 nm.
  • a polyelectrolyte according to the present invention is a polymer whose repeating units bear an electrolyte group. These groups will dissociate in aqueous solutions, making the polymers charged. Methacrylate polymers are examples of such polyelectrolytes.
  • Metalate polymer in the context with the present invention is a polymer comprising a methacrylate and/or methacrylate derivative as a repeating unit.
  • the polymer may be a homopolymer or copolymer.
  • Preferred methacrylate polymers in context of the present invention are selected from the group of poly-(methyl methacrylate), poly-(methyl acrylate), poly-(methacylic acid-co-methyl methacrylate), poly-(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate), and poly-(dimethylaminoethyl methacrylate.
  • the methacrylate polymer is Eudragit, preferably selected from the group comprising Eudragit L 100-55®, Eudragit L- 100®, Eudragit S-100®, Eudragit E-100®, and Eudragit E PO®.
  • the poorly soluble pharmaceutically active compound has preferably a solubility in the liquid dispersion medium, e.g. in water of less than 10 g/L, preferably 1 g/L, more preferably less than about 250 mg/L, most preferably less than 100 mg/L at processing temperature, e.g. room temperature.
  • the preferred liquid dispersion medium is water; however other liquid media in which the active compound is poorly soluble and dispersible including aqueous salt solutions or aqueous mixtures of solvents such as ethanol, benzyl alcohol, dimethyl sulfoxide, chlorobutanol, glycerin, thioglycerol and polyethylene glycol, preferably ethanol.
  • aqueous salt solutions or aqueous mixtures of solvents such as ethanol, benzyl alcohol, dimethyl sulfoxide, chlorobutanol, glycerin, thioglycerol and polyethylene glycol, preferably ethanol.
  • solvents such as ethanol, benzyl alcohol, dimethyl sulfoxide, chlorobutanol, glycerin, thioglycerol and polyethylene glycol, preferably ethanol.
  • the pH of the aqueous dispersion media can be adjusted by techniques known in the art.
  • the poorly soluble active compound is a poorly soluble drug according to groups II or IV of the Biopharmaceutics Classification System (BCS) (FDA).
  • the nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
  • Atorvastatin Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
  • Cisplatin Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs used in oncology; Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
  • Clozapine Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone, Carbamazepine and other drugs for CNS indications;
  • Bosentan Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications;
  • Dronabinol Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafmil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
  • the injectable pharmaceutical suspension may comprise a solubilizer selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, miglyol.
  • solublizers are absent.
  • the injectable pharmaceutical suspension may comprise additional compounds to confer desired properties to the suspension, e.g. the desired osmolality.
  • the suspension further comprises excipients selected from the group comprising NaCl.
  • the injectable pharmaceutical suspension comprises a second or further polyelectrolyte(s) in addition to the methacrylate polymer.
  • the second or further polyelectrolyte(s) are selected for the group consisting of water-soluble cationic or anionic polysaccharides, peptides, proteins, nucleic acids and corresponding salts thereof, xylan polysulfates, dextran sulfates, poly(amino acids) such as polyaspartic acid, poly-arginine, poly-lysine or polyglutamic acid, polysaccharide polysulfates such as sulfates of starch hydrolysates, inulin, hydroxyethylstarches, polysaccharide polysulfonates, polysaccharide polyphosphates, polyphosphates, methacrylate polymers, Eudragits, Eudragit L 100-55®, Eudragit L-100® and Eudragit S-100®
  • the second polyelectrolyte is oppositely charged to the methacrylate polymer, i.e. since methyl acrylic acid compounds are polyanions, the second polyelectrolyte is a polycation and vice versa.
  • the third (and if applicable the other odd-numbered polyelectrolytes) polyelectrolyte have the same charge as the methacrylate polymer, i.e. they are polyanions, and the second (and if applicable the other even-numbered polyelectrolytes) have opposite charges as compared to the methacrylate polymer.
  • the suspension is contacted with a second polyelectrolyte and no further polyelectrolytes.
  • the second polyelectrolyte is a further methacrylate polymer.
  • the second polyelectrolyte is human serum albumin (HSA) or bovine serum albumin (BSA).
  • HSA human serum albumin
  • BSA bovine serum albumin
  • the methacrylate polymer is Eudragit S and the second polyelectrolyte is Eudragit E.
  • the methacrylate polymer is Eudragit E and the second polyelectrolyte is Eudragit S.
  • first polyelectrolyte is Eudragit S and the second polyelectrolyte is Eudragit E.
  • methacrylate polymer is Eudragit and the second polyelectrolyte is bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • methacrylate polymer is Eudragit.
  • methacrylate polymer and/or the second or further polyelectrolytes according to the present invention in the methods for stabilizing may be provided in a solution.
  • methacrylate polymer has a concentration in the solution of between 5% and 0,5%, preferably between 5% and 2,5%.
  • the solution comprising methacrylate polymer or polyelectrolyte is liquid.
  • the solution is an aqueous solution, optionally comprising excipients or solubilizers.
  • the aqueous solution further comprises Lipoid.
  • the aqueous solution comprises NaCl, preferably in a concentration of 0,2M.
  • the method for stabilizing a poorly soluble active pharmaceutical compound comprises the step of: contacting said suspension with a one or more further polyelectrolytes during, before and/or after mechanically treating. It might be desireable to dilute the suspension obtained by the method according to the present invention, due to the high concentrations of pharmaceutically active compounds in the suspension obtainable by using the method according to the present invention. Hence, in one embodiment of the present invention, the method for stabilizing a poorly soluble active pharmaceutical compound comprises the step of diluting the suspension to the desired concentration.
  • a typical wet mill configuration involves slurry circulated through a high shear mixer (ULTRA-TURRAX® and Mills from IKA® Werke GmbH&Co.KG), or using beads or basket mills (DISPERMAT® and TOROUSMILL® from VMA-Getzmann GmbH), or planetary micro mills (PULVERISETTE 7, 6, 5, 4, 0, Classic Line/Premium Line from Fritsch GmbH) at rotation speeds of up to 1100 rpm.
  • 2.5 mm zirconium oxide milling beads, 2.0 mm zirconium oxide milling beads, 1.8 mm zirconium oxide milling beads, 1.5 mm zirconium oxide milling beads and/or 0.5 mm zirconium oxide milling beads are used (diameters of the beads).
  • milling beads with a diameter of from about 1.5 mm to about 1.8 mm are used.
  • the beads may be exchanged, for instance when adding the further (e.g. second) polyelectrolyte the beads are changed from 2.5 to 0.5 mm zirconium beads.
  • the milling beads are not exchanged during the milling process. Milling times may be varied. Preferred milling times are for example 10, 20, 30, 40, 50 or 60 minutes independently for each milling step.
  • the method according to the present invention is carried out without any intermediate washing steps.
  • the method comprises a dilution step at the end of the process to obtain the formed injectable pharmaceutical suspension.
  • step a) suspending a poorly soluble active compound is carried out without the presence of a detergent.
  • the method is carried out without a detergent selected from the group comprising soaps, fatty acid salts, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfate salts, sodium lauryl sulfate, sodium laureth sulfate (also known as sodium lauryl ether sulfate (SLES)), Alkyl benzene sulfonate, cetyl trimethylammonium bromide (CTAB) also known as (a.k.a.) hexadecyl trimethyl ammonium bromide, and other alkyltrimethylammonium salts, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzethonium chloride (BZT), dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine,
  • a detergent selected from the group comprising
  • mechanically treating is selected from the group comprising wet milling, high-shear mixing and high-pressure homogenization. Most preferred is wet milling as mechanically treating.
  • wet milling as mechanically treating.
  • several improvements may be applied to the milling process as outlined in the following.
  • the skilled artisan knows that the hydrodynamics during milling can be influenced by the addition of methacrylate polymer, improving the yield of milling and thus the control of the particle size.
  • the inventors now unexpectedly found that the addition of a methacrylate polymer greatly improves the hydrodynamics and allows the provision of injectable suspension with a high concentration of the nanoparticular, poorly soluble pharmaceutically active compound.
  • the methacrylate polymer or methacrylate polymer and a second or further polyelectrolyte(s) may serve as additional nanoparticulate abrasive agents during milling.
  • the presence of methacrylate polymer or methacrylate polymer and a second or further polyelectrolyte(s) during the milling process may lead to transitional coating of the grist, the walls of the mill and the grinding balls, respectively, thereby improving the grinding process and the milling results.
  • the methacrylate polymer and/or the second or further polyelectrolyte(s) also serve as lubricants during milling resulting in a reduction of abrasion of the milling equipment and a decrease in contamination of the grist.
  • the injectable pharmaceutical suspension comprises two or more nanoparticular, poorly soluble, pharmaceutically active compound.
  • the injectable pharmaceutical suspension comprises a second nanoparticular, poorly soluble, pharmaceutically active compound.
  • the second nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
  • Atorvastatin Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
  • Cisplatin Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs used in oncology; Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
  • Clozapine Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone, Carbamazepine and other drugs for CNS indications;
  • Bosentan Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications;
  • Dronabinol Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafinil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
  • one or more solubilizer and/or excipient selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, miglyol, and NaCl is present in said suspension.
  • the one or more solubilizers and/or excipients is present during mechanical treatment of the suspension.
  • a solubilizer and one excipient is present, preferably Lipoid and NaCl.
  • the concentration of NaCl, present in the injectable pharmaceutical suspension is 0.2M.
  • parenteral application in the context with the present invention means subcutaneous administration, intramuscular administration, intraorbital administration, intracapsular administration, intraspinal administration, intrasternal administration, intravenous administration, intradermal administration, intraperitoneal administration, and intraportal administration.
  • the injectable pharmaceutical suspension for use in the treatment of a disease the suspension is provided in a form to be administered by injection, preferably by subcutaneous, intramuscular, intraarterial or intravenous injection to said subject.
  • the injectable pharmaceutical suspension for use in the treatment of a disease according to the present invention is suited for the application of poorly soluble pharmaceutically active compounds to different animals and humans.
  • methacrylate polymers are not biodegradable.
  • the injectable pharmaceutical suspension is only administered to non-human animals.
  • the inventors unexpectedly found that even if the non-human animal is an animal for slaughter and subsequent consumption, the residual methacrylate polymer in the meat of the animal is passaged through the intestinal tract without interfering with the human organism.
  • the subject is selected from the group of human and non-human animals, preferably non-human animals.
  • Non-human animals include but are not limited to pets, zoo animals, farm animals and animals for production; preferably selected from the group comprising alpacas, including mules, miniature donkeys, donkeys, burros, cats, dogs, ferrets, hedgehogs, horses, goats, pygmy goats, llamas, pigs, rabbits, rodents (including hamsters, guinea pigs, mice, gerbils, chinchillas, plains viscachas, and rats), sheep (including ewes and lambs), skunks or any pets, cattle, elephants, camels, lions, tigers, rhinoceroses or any other zoo animals.
  • alpacas including mules, miniature donkeys, donkeys, burros, cats, dogs, ferrets, hedgehogs, horses, goats, pygmy goats, llamas, pigs, rabbits, rodents (including hamsters,
  • the present invention relates to dosage forms of the injectable pharmaceutical suspension.
  • the skilled artisan knows forms suited for dosage.
  • the injectable pharmaceutical suspension is primarily used for parenteral application, preferably through injection by syringes, in one embodiment of the dosage form according to the present invention the injectable pharmaceutical suspension is provided in a syringe or transferable to a syringe, preferably provided in a pharmaceutical phial.
  • the present invention relates to a method for treating a disease, comprising administering an injectable pharmaceutical suspension according to the present invention to a subject, wherein the administration is performed parenterally.
  • the injectable pharmaceutical suspension exhibits a zeta potential of between -10 mV and -80 mV, preferably between -30 mV and - 70 mV. If the second or further polyelectrolyte is a polykation, the skilled artisan will recognize that the zeta potential may also be positive. Hence, in one embodiment of the present invention the injectable pharmaceutical suspension exhibits a zet potential of between 10 mV and 80 mV, preferably between 30 mV and 70 mV.
  • the mean distance between individual particles of active agent is increased by the presence of polyelectrolyte complexes adsorbed to the drug surface and in the dispersion medium, thereby increasing their surface stability and preventing aggregation. Also the stability of the suspension is increased during sterilisation procedures (e.g. autoclaving, gamma radiation treatment) when the methacrylate polymer is present.
  • sterilisation procedures e.g. autoclaving, gamma radiation treatment
  • the purpose of this example was to prepare an injectable nanoparticular suspensions of a poorly soluble pharmaceutically active compound (API 1) exclusively stabilized by a charged methacrylate polyelectrolyte.
  • API 1 a poorly soluble pharmaceutically active compound
  • Eudragit S an anionic polymer with methacrylate as a functional group
  • An alkaline aqueous solution of 5 % Eudragit S was prepared in water containing 0.2 M sodium chloride with a pH of 8.5 g of API 1 was transferred to the 45 ml chamber of a planetary mill (Pulverisette 7 premium line, manufactured by Fritsch GmbH, Germany). 12 ml of the Eudragit S solution was added.
  • the resulting suspension was diluted with the Eudragit S solution as described above to a target concentration of 12.5 % (w/v) of API 1.
  • the characterized data remained unchanged. And no aggregation of particles could be observed macro- and microscopically.
  • the suspension was administered subcutaneously to mammalians and performance was measured with regard to the concentration of the API 1 in blood, indicating a fast onset of action showing the high bioavailability.
  • the results are shown in Figure 1.
  • the concentration of API 1 in the blood was constant over a longer period, i.e. for several days. This clearly shows that the injected suspension has very good properties as a depot.
  • An alkaline aqueous solution of 5 % Eudragit S was prepared in water containing 0.2 M sodium chloride with a pH of 8.
  • An aqueous solution of BSA with a concentration of 5 % was prepared with MilliQ-water. This solution contains of 0.5 % Lipoid SI 00.
  • 0.4 g of API 2 was transferred to the 45 ml chamber of a planetary mill (Pulverisette 7 premium line, manufactured by Fritsch GmbH, Germany). 3 ml of the Eudragit S solution and 3 ml of BSA solution were added to the solid substance. Suspension and milling of the API 2 were performed with 2.5 mm zirconium oxide beads for 2 10 min at 800 rpm. After the second lO min milling another 2 ml of the Eudragit S solution and 2 ml of BSA solution were added. The milling process was continued for another 2 10 min at 800 rpm.
  • the resulting suspension was removed from the bowls and characterized regarding particle size (laser diffraction), zeta potential, drug content (HPLC) and microscopy.
  • LD values were: dg 0 of 2.6 ⁇ , d 50 of 1.1 ⁇ and d 10 of 486 nm.
  • Zeta potential measured at -42.7 mV.
  • Drug contents in the high concentrated suspension were 2.85 % (w/V) API 2.
  • the resulting dispersion was diluted with Eudragit solution as described above to a target concentration of 1 % (w/v) API 2. When stored at room temperature, the characterized data remained unchanged. And no aggregation of particles could be observed macro- and microscopically.
  • the suspension was administered subcutaneously to a non-human mammal and compared to the performance of a control formulation of API 2 from prior art (without polyelectrolytes) with regard to the concentrations of the API 2 in blood.
  • the results are shown in Figure 2.
  • the fast onset of high concentrations of API 2 in the blood indicates a high bioavailability.

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Abstract

Cette invention concerne une suspension pharmaceutique injectable comprenant un polyélectrolyte et un principe pharmaceutiquement actif nanoparticulaire, peu soluble, ledit polyélectrolyte comprenant un polymère de méthacrylate. Cette invention concerne, en outre, un procédé pour stabiliser un principe pharmaceutique actif, peu soluble, dans une suspension pharmaceutique injectable comprenant les étapes consistant à : a) mettre en suspension dans un milieu de dispersion liquide un principe pharmaceutiquement actif peu soluble, hors la présence d'un détergent, b) traiter mécaniquement ladite suspension pour obtenir des particules contenant le principe actif, lesdites particules ayant une taille moyenne efficace inférieure à environ 5 000 nm, de préférence, inférieure à environ 4 000 nm, plus préférablement, inférieure à environ 3 000 nm, voire plus préférablement, inférieure à environ 1 000 nm et idéalement, inférieure à environ 800 nm, c) mettre ledit principe actif ou ladite suspension en contact avec un polymère de méthacrylate ou avec un complexe polyélectrolytique comprenant un polymère de méthacrylate pendant et/ou avant le traitement mécanique. Cette invention concerne également la suspension pharmaceutique injectable selon l'invention destinée à être utilisée pour traiter une maladie.
PCT/EP2012/051288 2011-01-27 2012-01-27 Nouvelle suspension pharmaceutique pour administration parentérale WO2012101242A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103239399A (zh) * 2013-05-30 2013-08-14 苏州普罗达生物科技有限公司 一种西罗莫司纳米混悬剂及其制备方法
CN103263385A (zh) * 2013-05-17 2013-08-28 江苏正大清江制药有限公司 一种塞来昔布长效纳米注射剂及其制备方法
US20150335753A1 (en) * 2012-12-19 2015-11-26 Kashiv Pharma, Llc Supersaturated stabilized nanoparticles for poorly soluble drugs
US20170128380A1 (en) * 2014-07-03 2017-05-11 Pfizer Inc. Targeted Therapeutic Nanoparticles And Methods Of Making And Using Same
CN107216445A (zh) * 2017-05-03 2017-09-29 南京大学 一种纳米复合物及其制备方法与应用
WO2018055615A1 (fr) * 2016-09-22 2018-03-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Implants injectables
CN109310643A (zh) * 2016-05-12 2019-02-05 株式会社柳柳制药 含甘油脂肪酸酯衍生物或丙二醇脂肪酸酯衍生物的度他雄胺和他达拉非复合制剂及包含其的口服胶囊制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070082838A1 (en) * 2005-08-31 2007-04-12 Abraxis Bioscience, Inc. Compositions and methods for preparation of poorly water soluble drugs with increased stability
EP2172193A1 (fr) 2008-10-02 2010-04-07 Capsulution Nanoscience AG Compositions de nanoparticules améliorées de composés faiblement solubles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070082838A1 (en) * 2005-08-31 2007-04-12 Abraxis Bioscience, Inc. Compositions and methods for preparation of poorly water soluble drugs with increased stability
EP2172193A1 (fr) 2008-10-02 2010-04-07 Capsulution Nanoscience AG Compositions de nanoparticules améliorées de composés faiblement solubles

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150335753A1 (en) * 2012-12-19 2015-11-26 Kashiv Pharma, Llc Supersaturated stabilized nanoparticles for poorly soluble drugs
US10500282B2 (en) * 2012-12-19 2019-12-10 Kashiv Biosciences, Llc Supersaturated stabilized nanoparticles for poorly soluble drugs
CN103263385A (zh) * 2013-05-17 2013-08-28 江苏正大清江制药有限公司 一种塞来昔布长效纳米注射剂及其制备方法
CN103239399A (zh) * 2013-05-30 2013-08-14 苏州普罗达生物科技有限公司 一种西罗莫司纳米混悬剂及其制备方法
RU2706791C2 (ru) * 2014-07-03 2019-11-21 Пфайзер Инк. Направленно доставляемые терапевтические наночастицы и способы их получения и использования
US10182996B2 (en) * 2014-07-03 2019-01-22 Pfizer Inc. Targeted therapeutic nanoparticles and methods of making and using same
CN107072962A (zh) * 2014-07-03 2017-08-18 辉瑞公司 靶向治疗性纳米颗粒以及其制备和使用方法
US20170128380A1 (en) * 2014-07-03 2017-05-11 Pfizer Inc. Targeted Therapeutic Nanoparticles And Methods Of Making And Using Same
CN109310643A (zh) * 2016-05-12 2019-02-05 株式会社柳柳制药 含甘油脂肪酸酯衍生物或丙二醇脂肪酸酯衍生物的度他雄胺和他达拉非复合制剂及包含其的口服胶囊制剂
WO2018055615A1 (fr) * 2016-09-22 2018-03-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Implants injectables
US11439587B2 (en) 2016-09-22 2022-09-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Injectable implants
CN107216445A (zh) * 2017-05-03 2017-09-29 南京大学 一种纳米复合物及其制备方法与应用
CN107216445B (zh) * 2017-05-03 2020-02-21 南京大学 一种纳米复合物及其制备方法与应用

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