Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Liposomes
• • 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
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61K47/24—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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

• the invention relates to the area of pharmaceutics and concerns the production technology of injectable medicinal forms of phospholipid preparation, in particular those sold as "Phosphogliv" for treatment and prevention of acute and chronic liver diseases, lipid exchange disorder and restoration of liver function after intoxication.
• the above- mentioned preparation contains vegetative phospholipids, glycyrrhizic acid or its salts and auxiliary substances.
• liver pathological processes of various diseases are accompanied by the structural and functional damage of membrane hepatocyte systems .
• Damage to membranes is caused by lipid stratum disorder due to the involvement of lipids in the processes of peroxidation and endogenous phospholipase activity. Any change in the physicochemical properties of lipids can result in structural damage to lipid biomembrane matrix and loss of their barrier function that is accompanied by inactivation of membrane enzyme systems .
• Essentiale is one of such preparations which has been applied in practical public health services more than 40 years to restore liver functions.
• a more recent preparation is sold as " Essentiale H” (Natterman Co. Germany) and contains a mixture of phospholipids, unsaturated fatty acids and vitamins .
• a salt of deoxycholic acid is used as a detergent in the production technology of injectable forms of " Essentiale” for dissolution of fatty phospholipid substance.
• This is disadvantageous as it has a degree of cytotoxicity and so may negatively influence cells.
• Phosphogliv which is used for the treatment and prevention of liver disease. It contains vegetative phospholipids with a high phosphatidylcholine content (75- 98 %), as well as glycyrrhizic acid, salts and additional ingredients. Glycyrrhizic acid and its salt, can act as an emulsifier, but also possesses hepatoprotector, antiinflammatory, anti-allergic and anti-viral properties, besides having a mild detergent effect. Injectable formulations of this preparation are known. They take the form of dried liposomal preparations, which are hydrated for use.
• the injectable forms of the compositions are difficult to obtain using conventional methods and may suffer in that the liposomal particles may be non-uniform and rather large in size, with a tendency to aggregate on storage. After storage for 4-6 months for example lyop ⁇ iilized powder preparation produces turbid solutions, because the liposomal/micellar structure is not preserved and the particles become enlarged. Therefore the shelf-life of these preparations is usually limited to 3 months only.
• lysophosphatidylcholine is also frequently observed.
• the contents of lysophosphatidylcholine in ready-to-use preparation should not exceed 3% and where higher levels occur, the product cannot be used in medical practice .
• a method for producing a pharmaceutical composition comprising a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, which composition is hydratable to produce an injectable medicinal form, said method comprising subjecting a mixture of phospholipid and an aqueous solution of glycyrrhizic acid or a pharmaceutically acceptable salt thereof and a carbohydrate to homogenization to form an emulsion comprising nanoparticles and subjecting a product of the homogenization to a sublimation drying step to produce said composition.
• ⁇ nanoparticles means that at least some, and suitably a substantial proportion of the particles within the emulsions are less than lOOnm in size (for example diameter) .
• homogenisers which operate using pressure or ultrasound may be employed.
• the homogenizer used is a device which subjects the mixture to cycling under pressure. Homogenisation pressures in excess of ⁇ OObars may be employed.
• the mixture is subject to homogenization at relatively high pressures , for example at pressures from 800-1200 bar The applicants have found that compositions with improved properties, may be achieved using this method particularly.
• the homogenization is effected at a temperature below 90 0 C and suitably in range of from 20- 50 0 C, for example from room temperature to 46 0 C and conveniently at room temperature.
• the precise number of homogenization cycles can be varied depending upon the nature of the homogenizer etc., but preferably the number of cycles is sufficient to produce, after drying, a preparation comprising liposomal particles of a size of from 20-100 nm, for instance up to ⁇ Onm, more suitably up to 50nm, yet more suitably up to 40nm and preferably up to 30nm in diameter.
• the mixture is subjected to from 5 to 22 homogenization cycles.
• the product of the homogenization is subjected to filtration prior to sublimation drying.
• This may be carried out for example using a membrane under an inert atmosphere, for example of nitrogen.
• the sublimation drying is conducted slowly under relatively mild conditions . The amount of time will depend upon factors such as the batch size etc., but typically will be over a period of days .
• a sterilizing filtration step is effected in a sterile room, for example using pressure filtration, for example under pressure of about 3 atmospheres .
• the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof in the pharmaceutical composition is suitably not greater than 4:1 and is preferably in the range of from 0.5:1 to 4:1.
• the pharmaceutical composition obtained suitably comprises from 2-80%w/w total phospholipid and glycyrrhizic acid or pharmaceutically acceptable salt thereof.
• the phospholipid used is obtained from a vegetative source such as soybean extract, which suitably comprises from 75-98%w/w of phosphatidylcholine .
• the carbohydrate used in the method is suitably selected from maltose, lactose or isomaltose.
• the amount of carbohydrate included will be variable and will depend upon conditions used, but it may comprise the balance of the pharmaceutical composition, and therefore may be present in the range of from for example, 20-98%w/w.
• the pH of the solution used in the method is in the range of from 6.0 to 7.5, preferably from 6.5 to 7.5.
• an aqueous solution of glycyrrhizic acid or pharmaceutically acceptable salt thereof is prepared and phospholid dispersed into it, for example so as to form an emulsion.
• a separately prepared aqueous solution of carbohydrate is then added before the resultant mixture is subjected to homogenization.
• compositions obtainable by a method described above, as well as injectable pharmaceutical composition obtainable by hydration of such compositions form a further aspect of the invention.
• Compositions obtained as described above have been found to be homogenous with a good size range of nanoparticles. Using the method described above, finelydispersed, homogeneous and stable liposomal particles (20-100 nm) are obtained. In some cases, 95 % of the particles are in the 20-35 nm size range , which gives rise to a stable solution, most appropriate for intravenous introduction. Uniformity of particles provides for high transparency and stability of solution. Furthermore, compositions obtained in this way have been found to be particularly stable, and it has been found that the structure can be restored at dissolution in water even after a three-year storage period.
• liver diseases can be used for the treatment and prevention of liver diseases, lipid exchange disorder and/or restoration of liver function after intoxication, and are administered by injection, for example intravenously.
• Solution A 6.9 g of dynatrium salt of GA was dissolved in water for injections and the volume made up to 90ml. NaOH (2.25ml, IN) was added (sufficient to produce a pH in the final 300 ml volume of from 6.7-7.5). Crushed phospholipid (16.5g) with a phosphatidylcholine content of 80% was added. Dispersion was carried out using a highly effective propeller mixer in a current of inert gas (nitrogen) .
• Solution B Maltose (59.4g) was dissolved in water for injection and carefully mixed until the solution became transparent and the final volume was made up to 150 ml. It would be possible to add additional water, provided that the volume of solution A + the volume of solution B ⁇ 300 ml.
• Solutions A and B were then mixed together and the total volume made up to 300 ml by water for injection.
• the solution was passed through a homogenizer (model Mini- Lab 7.30 VH, Rannie, Denmark) for 60 minutes under a pressure of 800 bar. Cooling was carried out through a backflow condenser. Homogeneous liposomes with diameter 40-60nm were obtained at this stage. Transparency of the sample (660 nm) after homogenization was not less than Prefiltration
• the homogenized solution was filtered under nitrogen at a pressure of 2 atmospheres through a membrane ("Vladipor", 3- 4 micron) .
• the transparency of the solution (660 nm) was not less than 60%.
• Sterilizing filtration was carried out in a sterile room in laminar air flow (Laminarbox LB-G, Russia) with the help of a pressure filtering device (PNF-90, Joint-Stock Company "Membranes", Russia) through filter ( " Vladipor”), 0.2 ⁇ m in diameter under pressure of 3 atmospheres.
• the transparency of the solution was approximately 65%.
• the solution was poured into 10ml dark bottles by doser in a laminar stream of sterile air and was frozen at -25°C.
• the frozen samples were exposed to sublimation drying (LSL SECFROID, LYOLAB F, Germany) for a period of 48 hours. A homogeneous liposomal composition of dense consistency was obtained. Bottles were sealed with aluminium capsules.
• the described method results in the production of a stable, highly effective preparation with a good size of nanoparticles which can be used in clinical practice for complex treatment of the various diseases involving liver function disorders.
• the preparation which may be obtained as described above, as a lyophilizate for intravenous introduction solution, had high efficiency for treatment of liver diseases of various etiology.
• the intravenous form of the preparation is tolerated by patients and does not give rise to significant side effects and results in appreciable improvement of clinical tests and the general condition of patients.
• the preparation influences the replicative activity of hepatitis B and C, and also the immune and interferon status indicating that it may be useful for the treatment of chronic viral hepatitis and other diseases associated with liver damage.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dispersion Chemistry (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Gastroenterology & Hepatology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2005
  • 2005-08-12 RU RU2005125634/15A patent/RU2304431C2/ru not_active IP Right Cessation
• 2006
  • 2006-08-11 EP EP06795234A patent/EP1919455A2/de not_active Withdrawn
  • 2006-08-11 CN CNA200680037239XA patent/CN101370482A/zh active Pending
  • 2006-08-11 WO PCT/IB2006/002195 patent/WO2007020505A2/en active Application Filing

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