Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7016—Disaccharides, e.g. lactose, lactulose
• • 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
• • 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
  • A61K31/075—Ethers or acetals
• • 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
  • A61K31/13—Amines
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof
• • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
  • A61K9/0058—Chewing gums
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a pharmaceutical composition for the prevention and treatment of viral infections and optionally inflammations accompanying viral infections.
• the invention relates more specifically to pharmaceutical compositions comprising /Mupeol as the antivir ally active substance.
• the invention relates furthermore to a method of preventing and treating viral infections and optionally inflammations by oral administration of the pharmaceutical composition to a person with a need thereof.
• GB Patent Application No. 2, 1 98,041 A discloses compositions which i.a. contain lupeol.
• the compositions are stated to have an effect on alcohol addiction, but it does not appear that this effect can be ascribed to lupeol.
• EP-A-0 287 000 discloses a process for the preparation of plant extracts, which i.a. may contain lupeol. These extracts are stated to be applicable by the treatment of prostatic hypertrophy, but it does not appear whether the effect can be ascribed to lupeol.
• WO 90/14764 discloses a number of terpenozonides having an antiviral effect. These compounds differ, however, essentially from Mupeol, as they contain three oxygen atoms to form a trioxycyclopentane ring. The antiviral effect is ascribed to this trioxycyclopentane ring system.
• Aqueous, unpurified extracts of bitter ginseng orally administered have been used for many years in China against chronic hepatitis.
• the chemical compound or compounds active by the above treatment are, however, not known.
• a specific fraction can be extracted from bitter ginseng, viz. ⁇ - lupeol, which has the unexpected useful effect described in the present specification.
• the invention relates according to a first aspect to a pharmaceutical composition for the prevention and/or treatment of viral infections, said composition being characterised by comprising
• R represents a hydrogen atom, a straight-chained or branched aliphatic C.,_ 6 -hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C.,. 6 -acyl group, which may be straight-chained or branched and may contain one or more unsaturated bonds selected from double and triple bonds, or a group, which is easily decomposed under the conditions prevailing in the human or animal body to release the ⁇ - lupeol derivative, as well as conventional pharmaceutically acceptable adjuvants, additives, and carriers.
• the aliphatic C.,_ 6 -hydrocarbyl group includes methyl, ethyl, branched and unbranched propyl, butyl, pentyl and hexyl, ethenyl, branched and unbranched propenyl, butenyl, pentenyl and hexenyl, ethynyl, branched and unbranched propynyl, butynyl and hexynyl and corresponding compounds containing two or more double or triple bonds.
• the C- j . ⁇ -acyl group includes methanoyl, ethanoyi, branched and unbranched propanoyl, butanoyl, pentanoyl and hexanoyl, ethenoyl, branched and unbranched propenoyl, butenoyl, pentenoyl and hexenoyl, butynoyl, branched and unbranched propynoyl, butynoyl, pentynoyl and hexynoyl and corresponding compounds containing two or more double or triple bonds.
• a group which is easily decomposed under the conditions prevailing in the human or animal body includes any group that can be transformed into the . -lupeol derivative under physiological conditions.
• R is hydrogen
• VSV Vesicular Stomatitis Virus
• Semliki virus Semliki virus
• the most probable mechanism of the antiviral effect mediated through ammonium ions is considered to be related to the fact that ammonium ions interfere with the binding of ammonium-sensitive viruses to virus receptors on the target cell and therefore improve the capacity of the host or the environment of eliminating the virus via non-specific cell processes, or via neutralization by means of suitable antibodies.
• viruses include for instance HIV-virus, hepatitis virus, usual cold viruses (such as Rhino virus, influenza virus etc.) or other infectious ammoniumion-sensitive viruses.
• ammonium ions have an effect exclusively on the receptor level through membrane-like interactions, as said ammonium ions must be constantly present at the time when the virus is introduced in the cell cultures in order to provide an optimum antiviral effect.
• Another aspect of the invention is to provide a pharmaceutical composition
• a pharmaceutical composition comprising a Mupeol derivative of the above formula I as well as an ammonium ion releasing compound.
• ammonium ions are preferably derived from a salt of a pharma ⁇ ceutically acceptable inorganic or organic acid.
• Any pharmaceutically acceptable acid can be used, and examples thereof are hydrochloric acid, sulphuric acid, phosphoric acid, carbonic acid, acetic acid, and tartaric acid.
• Ammonium chloride, ammonium sulphate, ammonium hydrogen carbonate or monoammonium dihydrogen phosphate are preferably used.
• ammonium ions may furthermore be derived from a compound of the general formula II
• X ⁇ X ⁇ which may be identical or different, are selected from hydrogen; C-,_ 6 alkyl, which may be straight-chained or branched, saturated or unsaturated and may optionally contain one or more substituents selected from halogen, hydroxy, C.,_ 4 -alkoxy or amino; aryl, which is optionally substituted with C 1 _ 4 alkyl, halogen, hydroxy, C.,_ 4 -alkoxy or amino, and
• Y is a physiologically acceptable salt-forming anion, preferably selected from F “ , Cl “ , Br “ and I “ .
• VSV Rhino virus
• probably also influenza virus probably also influenza virus.
• a third aspect of the invention relates to a pharmaceutical composition as defined above and further comprising one or more mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof, including compounds with heparin or heparan structure, which do not possess essential anti-coagulant properties.
• Viral infections are known to produce inflammations which are probably mediated via neutrophilic granulocytes accumulated in the affected area and causing further inflammation through the release of various substances, such as cytokines and other mediators.
• cationic protein complexes adjacent to or situated in the neutrophilic granulocytes play an important role as they promote the inflammatory reactions causing the known cold symptoms (sore throat, pain in the joints, fever, etc.).
• sulphated saccharides in or around the upper respiratory passages is thought to be advantageous in that these substances can accelerate the ulcer healing/curing in the throat or the oral cavity during minor microbial infections, especially during virus infections causing inflammations, e.g. by the presence of cationic substances.
• the sulphated saccharides will be retained in the inflammatory areas and thereby reduce the inflammatory processes in the affected area.
• a particular aspect of the present invention is therefore sulphated saccharides for use as an anti-inflammatory substance in the oral cavity and the lymphatic ring, respectively, around the lower respiratory passages (below the nasopharynx), as well as a method of treating inflammations in this area.
• the saccharide is a mono or polysulphated mono, di, tri or tetrasaccharide.
• the saccharide is a monosaccharide selected from xylose, fructose and glucose or a disaccharide selected from sucrose, lactose, maltose and cellobiose.
• the saccharide forms a complex or a salt with ammonium ions or with a metal selected from Al, Na, K, Ca, Mg, Ba, 2n, Cu, Zr, Ti, Bi, Mn, and Os, or with an amino acid.
• the sulphated disaccharide is sucrose octasulphate or a complex or a salt of sucrose octasulphate with ammonium ions or with a metal selected from Al, Na, K, Ca, Mg, Ba, Zn, Cu, Zr, Ti, Bi, Mn and Os, or a salt of sucrose octasulphate with an amino acid.
• sucrose octasulphate or the sodium, potassium or NH 4 + salt thereof or the aluminum complex of sucrose octasulphate, sucralphate are preferred.
• compositions comprise therefore as a further ingredient human or non-human immunoglobulines.
• the pharmaceutical composition is preferably in the form of chewing gums, lozenges, chewing tablets, resoriblets, drops, troches, gels, mouth ointments, solutions or in form of mucoadhesive formulations, preferably in the form of depot preparations.
• depot preparations is in this connection to be understood preparations and formulations with a controlled, sustained release of active ingredients.
• the pharmaceutical composition is preferably in the form of a chewing gum, which per piece of chewing gum having a weight of 500 to 3000 mg, preferably of approximately 1000 mg, comprises:
• the chewing gum is prepared by means of conventional chewing gum bases and conventional chewing gum additives, such as sweeteners, flavours, colorants, softeners, and texturizing substances. It may furthermore be necessary to use solubilizers or other release-controlling measures in order to release the pharmacologically active substances disclosed herein from the chewing gum.
• solubilizers can for instance be found in EP-0 486 563 B1 , in which a general mention of the preparation of chewing gum is found together with examples of applicable chewing gum ingredients.
• the invention relates furthermore to the use of one or more /.-lupeol derivatives of the general formula I
• R represents a hydrogen atom, a straight-chained or branched aliphatic C j .g-hydrocarbyl group, which may be saturated or may contain
• C ⁇ g-acyl group which may be straight-chained or branched and may contain one or more unsaturated bonds selected from double and triple bonds, or a group which is easily decomposed under the conditions prevailing in the human or animal body to release the /.-lupeol derivative for the preparation of a medicament for the prevention and/or treatment of viral infections.
• the invention relates to the use of one or more /. -lupeol derivatives of the general formula I
• R represents a hydrogen atom, a straight-chained or branched aliphatic C.,_ 6 -hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C 1 -6 -acyl group, which may be straight-chained or branched and may contain one or more unsaturated bonds selected from double and triple bonds, or a group which is easily decomposed under the conditions prevailing in the human or animal body to release the ⁇ -lupeol derivative, as well as one or more ammonium ion releasing compounds for the preparation of a medicament for the prevention and/or treatment of viral infections.
• R represents a hydrogen atom, a straight-chained or branched aliphatic C ⁇ g-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C ⁇ g-acyl group, which may be straight-chained or branched and may contain one or more unsaturated bonds selected from double and triple bonds, or a group which is easily decomposed under the conditions prevailing in the human or animal body to release the /.-lupeol derivative, as well as one or more mono or polysulphated mono, oligo, or polysaccharides or analogues or derivatives thereof, for the preparation of a medicament for the prevention and/or treatment of viral infections and associated inflammations.
• R represents a hydrogen atom, a straight-chained or branched aliphatic C ⁇ g-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C ⁇ g-acyl group, which may be straight-chained or branched and may contain one or more unsaturated bonds selected from double and triple bonds, or a group which is easily decomposed under the conditions prevailing in the human or animal body to release the Mupeol derivative, one or more ammonium ion releasing compounds, as well as one or more mono or polysulphated mono, oligo, or polysaccharides for the preparation of a medicament for the prevention and/or treatment of viral infections and associated inflammations.
• the invention is particularly useful in treating infections in the upper respiratory passages, especially cold viruses, such as Rhino virus, influenza virus, enterovirus, Coxsackie virus and other cold viruses.
• cold viruses such as Rhino virus, influenza virus, enterovirus, Coxsackie virus and other cold viruses.
• the invention allows the use of one or more of the above mentioned active ingredients for treating HIV, hepatitis virus, cytomegalo virus, herpes virus and other viral infections as well as for treating atherosclerosis as well as for suppressing tumour cell growth.
• Antivirally active substances may function in various ways:
• antiviral state When the antiviral state has been produced in the cell, the substance need no longer be present in principle as the cells are protected for a certain period of time, although the protection must be expected to decrease gradually over time.
• Ammonium ions are thought to belong to type (i) in the effect mechanism, although a certain, but weaker antiviral activity can be measured in cell cultures by the addition of NH 4 + 2 to 4 hours after the infection.
• Mupeol is present in many plants, such as in the shell of lupin seeds, in chiccle rubber, in latex from figs and rubber plants, and in various medicinal plants, such as in extracts from bitter ginseng, .-lupeol is commercially available and may be obtained e.g. from the company Sigma.
• Fig. 1 illustrates the antiviral activity of /. -lupeol (also called B1 -g) against Rhino virus,
• Fig. 2 the antiviral activity of interferon- ⁇ (HulFN- ⁇ ) against Rhino virus
• Fig. 3 the antiviral activity of B1 -g against EMC virus
• Fig. 4A the antiviral activity of B1 -g against Rhino virus at various dilutions
• Fig. 4B the antiviral activity of B1 -g + interferon- ⁇ against Rhino virus
• Fig. 5 the antiviral activity of NH 4 + ions against VSV, Semliki virus and EMCIII virus
• Fig. 6 the antiviral activity of NH 4 CI against Rhino virus
• Fig. 7A the antiviral activity of B1 -g, B1 -g + NH 4 CI as well as B1 -g, NH 4 CI + SOS against Rhino virus at an SOS dilution of 1 : 100 relative to a 20% SOS stock solution in water,
• Fig. 8 the antiviral activity of B1 -g, NH 4 CI, SOS and interferon- ⁇ against Rhino virus
• Fig. 9 the kinetics for the induction of an antiviral state.
• the cell cultures employed are VERO cells, WISH cells, MDBK cells and HEP cells which are common laboratory cell cultures and which are described in greater detail in Berg, K.: Purification and characterisation of murine and human interferons. A review of the literature of the 1 970s (thesis). Acta Pathol. Microbiol. Scand., Sec. C, Suppl. 279.: page 1 -1 36, 1 982.
• the viruses employed are VSV, EMC, Semliki virus, influenza virus and Rhino virus.
• a single-layer cell culture is established in microtrays.A certain amount of the antivirally active substance in a suitable dilution is added to the cell culture together with or followed by a suitable amount of virus ("challenge virus"). A control culture receives nothing but challenge virus. The virus infected cultures are incubated until the production of virus is distinct in the virus control culture (4 to 5 days as far as Rhino virus is concerned).
• An MTS/PMS solution comprising 1 .0 ml MTS stock solution (1 10 /g MTS + 39.2 ml PBS, pH-value 5.6 kept at + 4°C in the dark), 2.3 ml medium and 30 ⁇ PMS stock solution (1 3 mg PMS (Sigma, H5004, Lot 13, P.
• virus control cultures will typically have an OD-value of ⁇ 0.100, while non-infected control cell cultures will have an
• An antivirally active substance is thus a substance being capable in the presence of medium and challenge virus to provide protection against the test virus in a cell culture.
• Antiviral activity of .-lupeol measured bv means of the MTS-svstem
• Example 3 10,000 WISH cells were seeded and incubated at 37°C for 24 hours as described in Example 2, and dilutions of B1 -g were added to the cultures in dilutions corresponding to the concentration range indicated in Example 1 . After 24 hours the medium was replaced by challenge virus in fresh medium while simultaneously growing challenge virus control cultures and non-infected control cultures. 24 hours later, the cultures were incubated with MTS for 2 hours at 37°C, and the tray was scanned as described above. The results (Fig. 3) show that B1 -g has a moderate antiviral activity against EMC virus. Similar results were obtained against VSV and Semliki virus. The addition of small amounts of interferon- ⁇ intensified the antiviral activity considerably.
• interferon As little as 0.5 units of interferon resulted in almost 80% protection compared to 30% protection without interferon. It should be noted, that very often interferon is present in these amounts (0.2 to 0.6 units/ml) in patients suffering from moderate viral infections, such as ordinary cold and the like.
• Rhino virus appears to be much more sensitive to B1-g at a dilution of 1 :100 - 1 :200 than for instance VSV and EMC (from a 1 mg/ml stock solution of B1 -g), as it is able to suppress the viral infection by more than 80 to 90%.
• VSV and EMC from a 1 mg/ml stock solution of B1 -g
• Corresponding results must be expected with influenza virus.
• B1 -g has a very strong activity towards Rhino virus compared to the effect towards VSV and EMC. This difference could not be foreseen.
• NH 4 + ions are capable of inhibiting VSV, and to a minor extent Semliki virus, whereas no protection appears against EMC.
• Example 5 the antiviral activity of NH 4 + towards Rhino virus was tested, and after incubation for 24 hours at 37°C in an atmosphere containing 5% CO 2 , MTS was added over 2 hours at 37°C and 5% CO 2 , whereafter the microtray was measured in an OD-scanner.
• NH 4 + possesses a varying antiviral strength towards different viruses, and furthermore the NH 4 + concentration varies which in each particular case provides the optimum antiviral effect.
• the antiviral activity was measured according to the above method.
• Four different viruses EMC, VSV, Semliki Forest virus as well as Rhino virus
• three different cell lines A-549, WISH, VERO
• Rhino virus is inhibited by ammonium ions and by B1 -g as well as by interferon- ⁇ . Influenza virus is also assumed to be inhibited by ammonium ions. SOS appears to have some antiviral effect towards EMC, but no detectable antiviral activity towards Rhino virus. It appears clearly that Rhino virus (which exemplifies a cold virus) is inhibited by the combination of B1 -g, NH 4 + , interferon ⁇ SOS.
• a test was performed to examine possible differences in the antiviral effect as a function of the time for the initiation of the antiviral treatment relative to the establishment of the viral infection.
• the third group of cells received B1 -g (group + 24h), and all of the cells were further incubated for 4 to 5 days at 34°C and 5% CO 2 followed by an MTS treatment and measuring in an OD-scanner as described above.
• the antiviral effect is almost the same regardless whether the B1 -g addition is carried out 24 hours before the viral infection or simultaneously with said viral infection.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Inorganic Chemistry (AREA)
• Molecular Biology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Communicable Diseases (AREA)
• Zoology (AREA)
• Pain & Pain Management (AREA)
• Pulmonology (AREA)
• Oncology (AREA)
• Virology (AREA)
• Emergency Medicine (AREA)
• Rheumatology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)

Priority Applications (7)

Applications Claiming Priority (4)

Publications (1)

Family

ID=26064526

Family Applications (1)

Country Status (10)

Cited By (7)

Families Citing this family (1)

Citations (1)

• 1995
  • 1995-06-20 WO PCT/DK1995/000256 patent/WO1995035103A1/en not_active Application Discontinuation
  • 1995-06-20 KR KR1019960707236A patent/KR970703759A/ko not_active Application Discontinuation
  • 1995-06-20 JP JP8501510A patent/JPH10504279A/ja active Pending
  • 1995-06-20 CA CA002193396A patent/CA2193396A1/en not_active Abandoned
  • 1995-06-20 EE EE9600190A patent/EE9600190A/xx unknown
  • 1995-06-20 AU AU27340/95A patent/AU689603B2/en not_active Ceased
  • 1995-06-20 EP EP95922445A patent/EP0762876A1/en not_active Withdrawn
  • 1995-06-20 CN CN95194431A patent/CN1158566A/zh active Pending
• 1996
  • 1996-12-19 FI FI965114A patent/FI965114A0/fi unknown
  • 1996-12-19 NO NO965468A patent/NO965468L/no not_active Application Discontinuation

Patent Citations (1)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events