US20100222291A1 - Medicinal forms of phospholipid preparations and methods for their preparation - Google Patents

Medicinal forms of phospholipid preparations and methods for their preparation Download PDF

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US20100222291A1
US20100222291A1 US12/063,585 US6358506A US2010222291A1 US 20100222291 A1 US20100222291 A1 US 20100222291A1 US 6358506 A US6358506 A US 6358506A US 2010222291 A1 US2010222291 A1 US 2010222291A1
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pharmaceutically acceptable
phospholipid
glycyrrhizic acid
acceptable salt
additive
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US12/063,585
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Mariya Kirillovna Guseva
Vasiliy Fedorovich Uchaikin
Elena Georgievna Tikhonova
Olga Mikhailovna Ipatova
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Assigned to ARCHAKOV, ALEXANDR IVANOVICH reassignment ARCHAKOV, ALEXANDR IVANOVICH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUSEVA, MARIYA KIRILLOVNA, IPATOVA, OLGA MIKHAILOVNA, TIKHONOVA, ELENA GEORGIEVNA, UCHAIKIN, VASILIY FEDOROVICH
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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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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 encapsulated medicinal form of a phospholipid preparation, in particular that available as “Phosphogliv” for treatment and preventive measures of acute and chronic liver diseases, lipid exchange disorder and/or 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 and unsaturated fatty acids.
  • a key component of the phospholipids used in the preparations is phosphatidylcholine and so this should be present at high concentrations. At present, only a viscous syrupy form is available for use in the production of encapsulated forms of phospholipid preparations with high contents of phosphatidylcholine.
  • 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, anti-inflammatory, antiallergic and anti-viral properties, besides having a mild detergent effect.
  • lactose and aerosil have previously been included in the formulations in order to produce successfully granulated forms.
  • the obtained tablet mass including phospholipid and salt of glycyrrhizic acid is inappropriate for formation of tablets. Tablets turn out non-uniform and chipped.
  • the storage time for aerosil is limited (no more than 6 months). It has a high toxicity and may constitute a health hazard during the manufacturing process.
  • a method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable carrier substances or additives, granulating the resultant mixture, and encapsulating the resultant product.
  • the method is used to produce compositions in which the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof is not greater than 4:1, suitably in the range of from 0.5:1 to 4:1, for example at about 2:1.
  • the encapsulated material 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 organic solvent (or spirit) used in the method is suitably an organic solvent in which the phospholipid is soluble.
  • the organic solvent is a pharmaceutically acceptable organic solvent such as ethanol.
  • Suitable pharmaceutically acceptable salts of glycyrrhizic acid are alkaline or alkaline earth metal salts such as sodium, potassium, calcium and magnesium salts.
  • a particularly suitable salt of glycyrrhizic acid is the trisodium (trinatrium) salt.
  • the granulation step is suitably effected using an initial damp granulation procedure, followed by a dry granulation procedure, as would be understood in the art.
  • the product of the granulation step is powdered with a pharmaceutically acceptable carrier substance or additive, before encapsulation.
  • the expression “pharmaceutically acceptable carrier substance or additive” includes materials in particular solid materials which are well known in the formulation art, for example, as carriers, diluents, preservatives, dispersants, colouring, sweetening, flavouring agents etc, or mixtures thereof. They include for example calcium carbonate, calcium stearate, talc, sodium carbonate, calcium phosphate, microcrystalline cellulose or mixtures of one or more of these.
  • glycyrrhizic acid or a pharmaceutically acceptable salt thereof, where particularly suitable pharmaceutically acceptable carrier substances or additives include microcrystalline cellulose, calcium stearate and calcium carbonate or mixtures of one or more of these.
  • the product of the granulation step may be ground or powdered together with a suitable pharmaceutically acceptable carrier substance or additive.
  • a suitable pharmaceutically acceptable carrier substance or additive may be calcium carbonate, calcium stearate, talc or a mixture thereof.
  • Encapsulation of the resultant product is carried out in a conventional manner, for example using gelatinous or other capsule materials.
  • Preparations prepared by the method described above form a further aspect of the invention. They may be used in particular for the preparation for the treatment and prevention of liver diseases, lipid exchange disorder, as well as the restoration of liver function after intoxication.
  • the obtained capsulated preparation preserves physicochemical properties, does not become compressed and does not conglutinate for a long period of time (storage over 4 years has been demonstrated).
  • Phospholipid (PL) (0.52 Kg) from soya with a content of phosphatidylcholine (PC) of 80% was dissolved in ethanol (0.52 kg; 0.65 litre) over a period of 3-4 hours.
  • the organic solution of phospholipid was added to the resultant mixture obtained giving a ratio of PL:GA of 2:1.
  • the contents of the mixer were mixed for three minutes and thereafter subjected to a damp granulation procedure in which the diameter of apertures was 3.0 mm.
  • the damp granulated material was dried for 3-4 hours and then subjected to a dry granulation procedure in which it was passed through apertures with diameter of 1.2 mm.
  • the obtained granulated material (2.80-2.85 kg) was ground (powdered) together with calcium carbonate (0.71 kg), talc (0.078 kg) and calcium stearate (0.024 kg) for no more than 10 minutes (total contents of PL and GA about 22%).
  • This mass was encapsulated in gelatinous (or other) capsules.
  • the preparation was found to be stable after four years.
  • the described method therefore provides a stable, highly effective preparation which can be used in clinical practice for complex treatment of various diseases associated with liver function disorders.

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Abstract

A method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier substance or additive, granulating the resultant mixture, and encapsulating the resultant product, for example after grinding with a pharmaceutically acceptable carrier substance or additive. Products obtained by this method form a further aspect of the invention, and are useful in the treatment or prevention of diseases associated with liver disorders.

Description

  • The invention relates to the area of pharmaceutics and concerns the production technology of encapsulated medicinal form of a phospholipid preparation, in particular that available as “Phosphogliv” for treatment and preventive measures of acute and chronic liver diseases, lipid exchange disorder and/or restoration of liver function after intoxication. The above-mentioned preparation contains vegetative phospholipids, glycyrrhizic acid or its salts and auxiliary substances.
  • It is known that 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.
  • It has been shown in numerous research studies (including some conducted by the Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences) that the most effective phospholipids for use in the restoration of the damaged hepatocyte membranes are phospholipids derived from vegetative material. Such vegetative phospholipids incorporate essential fatty acids (linoleic and linolenic acid), which make them more liquid than usual membrane phosphatidylcholine. This seems to allow them to play the role of “membrane glue”, capable to repair defects of the damaged cellular membranes more effectively. The mechanism of action of vegetative phospholipids appears to be due to the inclusion of polyunsaturated phosphatidylcholine into membranes and it is capable of restoring the structure and function of the damaged cells.
  • Therefore the development of effective medicinal forms which incorporate phospholipids remains important.
  • There are a number of preparations which include phospholipids, which are produced in capsules, dragee or pills, and also injectable forms.
  • “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 and unsaturated fatty acids.
  • A key component of the phospholipids used in the preparations is phosphatidylcholine and so this should be present at high concentrations. At present, only a viscous syrupy form is available for use in the production of encapsulated forms of phospholipid preparations with high contents of phosphatidylcholine.
  • The above-mentioned known oral forms of preparations “Essentiale” and “Essentiale H” represent the capsules containing the syrupy substance. This mass contains moisture. considerably reducing the shelf life or storage ability of the preparations and increasing their toxicity due to formation of lysophosphatidylcholine, which is a product of phosphatidylcholine oxidation. There is also another known phospholipid preparation,
  • “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, anti-inflammatory, antiallergic and anti-viral properties, besides having a mild detergent effect.
  • There are however, problems associated with the production of suitable medicinal forms of these phospholipid preparations.
  • In particular, lactose and aerosil have previously been included in the formulations in order to produce successfully granulated forms. However, the obtained tablet mass including phospholipid and salt of glycyrrhizic acid is inappropriate for formation of tablets. Tablets turn out non-uniform and chipped.
  • In addition, the storage time for aerosil is limited (no more than 6 months). It has a high toxicity and may constitute a health hazard during the manufacturing process.
  • On the other hand, the usage of lactose hinders the preparation of capsules and the resultant granules are not compatible with automatic capsule filling machines. As a result, the filling is non-uniform, the mass is cloddy and the machine finally becomes clogged.
  • The applicants have found a way by which certain problems in the production of encapsulated medicinal forms of the phospholipid compositions and in particular those sold as “Phosphogliv”, can be reduced or eliminated.
  • According to the present invention, there is provided a method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable carrier substances or additives, granulating the resultant mixture, and encapsulating the resultant product.
  • In particular, the method is used to produce compositions in which the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof is not greater than 4:1, suitably in the range of from 0.5:1 to 4:1, for example at about 2:1. Suitably the encapsulated material comprises from 2-80% w/w total phospholipid and glycyrrhizic acid or pharmaceutically acceptable salt thereof.
  • In a particular embodiment the phospholipid used is obtained from a vegetative source such as soybean extract, which suitably comprises from 75-98% w/w of phosphatidylcholine.
  • The organic solvent (or spirit) used in the method is suitably an organic solvent in which the phospholipid is soluble. Preferably the organic solvent is a pharmaceutically acceptable organic solvent such as ethanol.
  • Suitable pharmaceutically acceptable salts of glycyrrhizic acid are alkaline or alkaline earth metal salts such as sodium, potassium, calcium and magnesium salts. A particularly suitable salt of glycyrrhizic acid is the trisodium (trinatrium) salt.
  • The granulation step is suitably effected using an initial damp granulation procedure, followed by a dry granulation procedure, as would be understood in the art. In particular, in the method, the product of the granulation step is powdered with a pharmaceutically acceptable carrier substance or additive, before encapsulation.
  • As used herein, the expression “pharmaceutically acceptable carrier substance or additive” includes materials in particular solid materials which are well known in the formulation art, for example, as carriers, diluents, preservatives, dispersants, colouring, sweetening, flavouring agents etc, or mixtures thereof. They include for example calcium carbonate, calcium stearate, talc, sodium carbonate, calcium phosphate, microcrystalline cellulose or mixtures of one or more of these.
  • Suitably they do not include either lactose or aerosil.
  • They may be added together with the glycyrrhizic acid or a pharmaceutically acceptable salt thereof, where particularly suitable pharmaceutically acceptable carrier substances or additives include microcrystalline cellulose, calcium stearate and calcium carbonate or mixtures of one or more of these.
  • Alternatively, as mentioned above, the product of the granulation step may be ground or powdered together with a suitable pharmaceutically acceptable carrier substance or additive. In an embodiment the pharmaceutically acceptable carrier substance or additive may be calcium carbonate, calcium stearate, talc or a mixture thereof.
  • Encapsulation of the resultant product is carried out in a conventional manner, for example using gelatinous or other capsule materials. Preparations prepared by the method described above form a further aspect of the invention. They may be used in particular for the preparation for the treatment and prevention of liver diseases, lipid exchange disorder, as well as the restoration of liver function after intoxication. The obtained capsulated preparation preserves physicochemical properties, does not become compressed and does not conglutinate for a long period of time (storage over 4 years has been demonstrated).
  • The invention will now be particularly described by way of example.
    • EXAMPLE 1.
  • Phospholipid (PL) (0.52 Kg) from soya with a content of phosphatidylcholine (PC) of 80% was dissolved in ethanol (0.52 kg; 0.65 litre) over a period of 3-4 hours. Microcrystalline cellulose (1.28 Kg), the trinatrium salt of glycyrrhizic acid (GA) (0.28 Kg) and calcium carbonate (0.71 Kg) were loaded into the mixer. The organic solution of phospholipid was added to the resultant mixture obtained giving a ratio of PL:GA of 2:1. The contents of the mixer were mixed for three minutes and thereafter subjected to a damp granulation procedure in which the diameter of apertures was 3.0 mm. The damp granulated material was dried for 3-4 hours and then subjected to a dry granulation procedure in which it was passed through apertures with diameter of 1.2 mm. The obtained granulated material (2.80-2.85 kg) was ground (powdered) together with calcium carbonate (0.71 kg), talc (0.078 kg) and calcium stearate (0.024 kg) for no more than 10 minutes (total contents of PL and GA about 22%). This mass was encapsulated in gelatinous (or other) capsules.
  • The preparation was found to be stable after four years. The described method therefore provides a stable, highly effective preparation which can be used in clinical practice for complex treatment of various diseases associated with liver function disorders.

Claims (10)

1. A method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier substance or additive, granulating the resultant mixture, and encapsulating the resultant product.
2. A method according to claim 1 wherein the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof is not greater than 4:1.
3. A method according to claim 1 wherein the total content of phospholipid and glycyrrhizic acid or pharmaceutically acceptable salt in the encapsulated material is from 2-80% w/w of the encapsulated material.
4. A method according to claim 1 wherein the phospholipid used is in the form of a vegetative extract.
5. A method according to claim 4 wherein the vegetative extract comprises from 75-98% of phosphatidylcholine.
6. A method according to claim 1 wherein the granulation is effected using an initial damp granulation procedure, followed by a dry granulation procedure.
7. A method according to claim 1 wherein the product of the granulation step is powdered with a pharmaceutically acceptable carrier substance or additive before encapsulation.
8. A method according to claim 7 wherein the pharmaceutically acceptable carrier substance or additive is calcium carbonate, calcium stearate, talc or a mixture thereof.
9. A method according to claim 1 wherein a pharmaceutically acceptable carrier substance or additive which comprises microcrystalline cellulose, calcium stearate and/or calcium carbonate is added with the glycyrrhizic acid or a pharmaceutically acceptable salt thereof.
10. An encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof obtainable by a method according to claim 1.
US12/063,585 2005-08-12 2006-08-11 Medicinal forms of phospholipid preparations and methods for their preparation Abandoned US20100222291A1 (en)

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RU2005125633/15A RU2304430C2 (en) 2005-08-12 2005-08-12 Method for preparing injection medicinal formulation of phospholipid preparation "fosfogliv" for treatment and prophylaxis of acute and chronic hepatic diseases
RU2005125633 2005-08-12
PCT/IB2006/002198 WO2007020507A2 (en) 2005-08-12 2006-08-11 Medicinal forms of phospholipid preparations and methods for their preparation

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RU2463057C2 (en) * 2010-11-03 2012-10-10 Общество с ограниченной ответственностью "ЭкоБиоФарм" Phospholipid nanoform for oral application (sachet) and method for preparing it (versions)
RU2448715C1 (en) * 2010-12-30 2012-04-27 Общество с ограниченной ответственностью "ЭкоБиоФарм" Phospholipid therapeutic composition with nano-sized particles for lipid storage disease and comatose states and method for preparing it
CN103110607B (en) * 2013-03-01 2014-02-19 浙江华立南湖制药有限公司 Cefixime capsule and preparation method thereof
RU2725622C1 (en) * 2019-10-30 2020-07-03 Открытое акционерное общество "Фармстандарт-Лексредства" (ОАО "Фармстандарт-Лексредства") Pharmaceutical composition for treating and/or preventing liver diseases

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DE4002166A1 (en) 1990-01-25 1991-08-01 Nii Fiz Khim Mediciny Suspensions for reconstructing cell membranes - are prepd. from phosphatidyl-choline and glycyrrhizate salt
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RU2133122C1 (en) * 1998-10-14 1999-07-20 Научно-исследовательский институт биомедицинской химии РАМН Composition exhibiting property for biological membrane repairing
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EP1919461A2 (en) 2008-05-14
US20100179100A1 (en) 2010-07-15
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RU2005125633A (en) 2007-02-20
US8680061B2 (en) 2014-03-25

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