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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
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • 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
• • 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
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

• This invention relates to 2,2′,6,6′-tetraisopropyl-4,4′-biphenol lipid microsphere preparations and the preparation methods therefor, in the field of pharmaceutical preparations.
• biphenol 2,2′,6,6′-tetraisopropyl-4,4′-biphenol
• biphenol is an anti-epileptic compound newly developed (Chinese patent CN 101804043A, Uses of biphenol and its derivatives in drugs for the treatment of epilepsy) for treating many epileptic symptoms such as generalized tonic-clonic seizures (grand mal), absence seizures (petit mal), simple partial seizures, complex partial seizures (psychomotor seizures), autonomic seizures (periodic seizures) and others.
• Experimental studies have shown that biphenol has a strong affinity towards GABA receptors and is a GABA agonist, while it is an antagonist for NMDA receptors for regulating the Ca 2+ influx in Ca 2+ channels.
• the present invention provides a 2,2′,6,6′-tetraisopropyl-4,4′-biphenol lipid microsphere preparation and its preparation method.
• 0.5 ⁇ 1% of antioxidants were added to the preparation to address the issue that biphenol is easily oxidizable.
• vitamin E a potent, lipid soluble antioxidant, is used for ensuring the stability of the drug in the preparation.
• This invention uses only phospholipid emulsifiers in an amount of 1 to 1.5% without any co-solvent so as to prevent hemolysis and production of substances that may otherwise cause thrombotic inflammation.
• the emulsifiers of this invention are egg lecithin derived from the yolk of animal embryos which are easier and safer to be absorbed by the human body.
• the lipid microsphere preparations of this invention are prepared by the processing of active ingredients comprising 2,2′,6,6′-tetraisopropyl-4,4′-biphenol (hereinafter referred as biphenol), injection-grade oil, emulsifier, and injection-grade water.
• active ingredients comprising 2,2′,6,6′-tetraisopropyl-4,4′-biphenol (hereinafter referred as biphenol), injection-grade oil, emulsifier, and injection-grade water.
• biphenol 2,2′,6,6′-tetraisopropyl-4,4′-biphenol
• injection-grade oil injection-grade oil
• emulsifier injection-grade water
• injection-grade water injection-grade water.
• All units are in percentage by weight.
• the injection-grade oil is selected from one or more of soybean oil, medium chain triglyceride oil, sea buckthorn oil, and tea oil.
• the emulsifier is selected from one or more of soy lecithin, hydrogenated lecithin, synthetic lecithin, and egg lecithin.
• the antioxidant is selected from one or more of vitamin E, ascorbic acid, and sodium hydrogen sulfite.
• the lipid microsphere preparation of this invention has the following composition.
• Every 100 ml of lipid microsphere preparation comprises 1000 mg of biphenol, 10 g of soybean oil, 1.2 g of injection-grade egg lecithin for injection, 1 g of vitamin E, 2.5 g of glycerin, 0.5 g EDTA, and the remaining being injection-grade water.
• This invention also aims to provide a method for preparing biphenol lipid microsphere preparations.
• the preparation method of this invention comprises the following steps:
• said method for preparing biphenol lipid microsphere preparations comprises the following steps:
• the preparation of this invention is a lipid microsphere preparation for use in intravenous injections.
• the particle size of the lipid microspheres of this invention is in the range of 100 nm ⁇ 800 nm with the average particle size being 150 nm ⁇ 300 nm.
• biphenol is encapsulated within lipid microspheres which greatly increase its solubility in water, the amount of drug that can be loaded, and also the stability of the preparation. Further, being a novel drug carrier, lipid microspheres are non-toxic, non-immunogenic, reducing irritation due to the drug and decreasing the drug's toxic side effects.
• This invention increases the stability of the injection, extends the drug's shelf life, improves its solubility and ensures its safeness. Moreover, the simple and feasible preparation process of the present invention is time and cost effective such that it is well suited for mass production. Furthermore, the formula and preparation methods for the preparation of this invention have been scientifically screened and proven.
• the preparation of this invention relates to anti-epileptic preparations.
• the anti-epileptic preparation of this invention has significantly higher efficacy in comparison to CMCNa-biphenol.
• the method for administering the drug is switched from oral administration to intravenous injection which improves drug absorption and increases the therapeutic effect of the drug;
• the preliminary emulsion was homogenized with a high-pressure homogenizer and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• Drugs and Excipients Amount (g) Biphenol 10.0 Injection-grade Soybean oil 300 Soy lecithin 15 Vitamin E 10 Glycerin 25 EDTA 5 Injection-grade water make up to 1000 ml
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• Drugs and Excipients Amount (g) Biphenol 10.0 Injection-grade Soybean oil 100 Hydrogenated Lecithin 12 Vitamin E 10 Glycerin 25 EDTA 5 Injection-grade water make up to 1000 ml
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• Drugs and Excipients Amount (g) Biphenol 10.0 Injection-grade Soybean oil 100 Synthetic phospholipids 12 Vitamin E 10 Glycerin 25 EDTA 5 Injection-grade water make up to 1000 ml
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the preliminary emulsion was homogenized with a high-pressure homogenizer for 5 ⁇ 8 times at 800 ⁇ 900 bar and filtered with a microporous membrane filter before being flushed with nitrogen, sealed, autoclaved at 115° C. to obtain the final product.
• the osmolarity of the final emulsion was determined to be 300 ⁇ 400 mOsm/L by an osmometer (freezing point depression method) which fulfilled the requirement for a lipid microsphere preparation to be used for intravenous injection.
• the biphenol lipid microspheres prepared were kept at 4° C. for 6 months before subjected to 45° C. for 6 months and, after which, were placed at room temperature for 12 months.
• the stability of the products was evaluated in terms of their appearance, pH and encapsulation efficiency. Results are shown in Table 1.
• Example 0 mth Homogenous Homogenous Homogenous 7.85 7.86 7.84 98.45 98.35 98.46 1 1 mth Homogenous Homogenous Homogenous 7.74 7.71 7.68 98.45 98.38 98.45 2 mth Homogenous Homogenous Homogenous 7.66 7.64 7.55 98.40 98.36 98.44 3 mth Homogenous Homogenous Homogenous 7.54 7.66 7.46 98.41 98.37 98.45 6 mth Homogenous Homogenous Homogenous 7.32 7.52 7.29 98.38 98.25 98.36 9 mth — Homogenous — — 7.48 — — 98.26 — 12 mth — Homogenous — — 7.31 — — 98.23 — Example 0 mth Homogenous Homogenous Homogenous 7.94 7.84 7.91 98.54
• the lipid microspheres of this invention have good stability. No significant change to their appearance and encapsulation efficiency was noticed after being placed at 4° C. for 6 months followed by 45° C. for 6 months and, subsequently, placed at room temperature for 12 months. Although there were some degrees of decrease in pH, this did not affect the stability of the preparations.
• lipid microsphere preparations prepared according to this invention possessed good stability which met the requirements on the stability of preparations stipulated in China's National Guidelines on Novel Drug Research.
• the biphenol content in this invention was determined by high performance liquid chromatography.
• a C18 column (4.6 mm ⁇ 200 mm, 5 ⁇ m) was used with methanol-acetonitrile-water (60:22:18) as the mobile phase at a flow rate of 1.0 ml/min and UV detection at 275 nm.
• Lipid microsphere preparations were centrifuged at 10000 r/min for 30 minutes by ultracentrifugation. 0.5 ml of the supernatant was obtained and dissolved with isopropyl alcohol and the biphenol content was characterized with high performance liquid chromatography to determine the encapsulated biphenol content, M1. The total biphenol content in lipid microsphere preparation is M0. The following formula was used for calculating the encapsulation efficiency which is the weight ratio of biphenol lipid microspheres to biphenol.
• Three groups of 8 guinea pigs were randomly separated based on their weight. Each of the guinea pigs from group 1 and group 2 was given 3 successive peritoneal injections of the biphenol lipid microsphere preparations at a dose of 0.5 ml/guinea pig every other day to induce sensitization. On day 14 and day 21 after the first peritoneal injection, guinea pigs from groups 1 and 2 were given intravenous injections of the biphenol lipid microsphere preparations at the toe at a dose of 1.0 ml/guinea pig so as to cause stimulation.
• the guinea pigs were given 3 successive peritoneal injections of 20% egg white at a dose of 0.5 ml/guinea pig every other day to induce sensitization and, after 14 days, were given intravenous injection of egg white at the toe at a dose of 1.0 ml/guinea pig so as to cause stimulation. All three groups were observed for 15 minutes after injection to notice for allergic reactions.
• results The two groups of guinea pigs injected with biphenol lipid microspheres which received the stimulation dose of same drug on day 14 and day 21 respectively did not show any allergic response.
• the guinea pigs in the positive control group had breathing difficulty and spasm within 2 minutes after injection before they died. The death of the guinea pigs were within 1 ⁇ 3 minutes after injection.
• Biphenol lipid microsphere preparations were intravenously injected at the left ear of 2 New Zealand white rabbits at a dose of 5 ml/kg while 10% sucrose injections were intravenously injected at the right ear at a dose of 5 ml/kg.
• the injections were given daily for a total of five days. The injection site was observed for any swelling or rashes since day 1. Within 24 hours after the last injection, the ears were removed and fixed in 10% formalin before being prepared for histopathological examination.
• the allergy test, hemolytic test and irritation test on the lipid microsphere preparations of this invention showed that the lipid microsphere preparations of this invention are highly stable and do not cause any allergic, hemolytic or irritation effects. It therefore complies with the relevant requirements for clinically used drugs.

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• 2012
  • 2012-02-06 CN CN2012100256112A patent/CN102525921B/zh active Active
  • 2012-03-07 JP JP2014555918A patent/JP5748926B2/ja active Active
  • 2012-03-07 CA CA2865777A patent/CA2865777C/en active Active
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