AU689603B2 - A pharmaceutical composition for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for the treatment thereof - Google Patents
A pharmaceutical composition for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for the treatment thereof Download PDFInfo
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- AU689603B2 AU689603B2 AU27340/95A AU2734095A AU689603B2 AU 689603 B2 AU689603 B2 AU 689603B2 AU 27340/95 A AU27340/95 A AU 27340/95A AU 2734095 A AU2734095 A AU 2734095A AU 689603 B2 AU689603 B2 AU 689603B2
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- 150000008163 sugars Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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
-
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- 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
-
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- 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
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- 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
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- 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
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- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Description
WO 95135103 PCTIDK9I5/00256 1 Title: A pharmaceutical composition for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for the treatment thereof Field of the Invention 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 p-lupeol as the antivirally 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.
Background Art Until now, it has been impossible to provide an efficient composition for preventing and/or treating viral infections caused by cold virus etc, such as influenza virus, Rhino virus, Corona virus etc. or other viruses in the upper respiratory passages. Practically all humans suffer from infections in the upper respiratory passages from time to time, such as cold and flu. The symptoms of these infections include a sore throat and earache (otitis), a runny nose, itchy eyes, and a pain in the muscles and the joints. The infections are caused by a variety of different viruses which together are referred to as "cold virus". Although vaccines are available for a restricted number of influenza strains, no efficient methods are known for preventing or treating most of the infections in the upper respiratory passages. Such viral infections, eog. caused by Rhino virus, which is responsible for approximately 50% of all viral infections in the upper respiratory passages, are wide-spread and can cause ill health or be directly potentially lethal for susceptible groups, such as children, elderly people, and persons suffering WO 95/35103 PCT/DK95/00256 2 from a deficient immunity, such as AIDS-patients, cancer patients etc. A method of treating these symptoms and the underlying infections would be of immense importance.
GB Patent Application No. 2,198,041 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 P-lupeol, 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. Thus it could not be foreseen that a specific fraction can be extracted from bitter ginseng, viz. P- lupeol, which has the unexpected useful effect described in the present specification.
Brief Description of the Invention.
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 one or more p-lupeol derivatives of the formula WO 95/35103 PCT/DK95/00256 3 H3C CH CHI CH H
H
CH CH3
RO
H3C CH3 where R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 6 -hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a
C
1 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 P- lupeol derivative, as well as conventional pharmaceutically acceptable adjuvants, additives, and carriers.
The aliphatic C 1 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 1 6 -acyl group includes methanoyl, ethanoyl, 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.
It should be understood that a group which is easily decomposed under WO 95/35103 'CTIDK9S5/00256 4 the conditions prevailing in the human or animal body includes any group that can be transformed into the P-lupeol derivative under physiological conditions.
According to a particularly preferred embodiment of the invention, R is hydrogen.
In addition, it has been found that the presence of ammonium ions provides an antiviral effect against a number of laboratory viruses, such as VSV Vesicular Stomatitis Virus) and Semliki virus, as well as against for instance Rhino 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. Such viruses include for instance HIV-virus, hepatitis virus, usual cold viruses (such as Rhino virus, influenza virus etc.) or other infectious ammoniumion-sensitive viruses.
Based on preliminary experiments it appears that 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.
Therefore another aspect of the invention is to provide a pharmaceutical composition comprising a f-lupeol derivative of the above formula I as well as an ammonium ion releasing compound.
The ammonium ions are preferably derived from a salt of a pharmaceutically acceptable inorganic or organic acid. Any pharmaceutically WO 95/35103 PCT/DK95/00256 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.
The ammonium ions may furthermore be derived from a compound of the general formula II
X,
X
4 N- X 2 Y II
X
3 where X 1
-X
4 which may be identical or different, are selected from hydrogen; C1.
6 alkyl, which may be straight-chained or branched, saturated or unsaturated and may optionally contain one or more substituents selected from halogen, hydroxy, C1-4-alkoxy or amino; aryl, which is optionally substituted with C1-4alkyl, halogen, hydroxy, C1-4-alkoxy or amino, and Y is a physiologically acceptable salt-forming anion, preferably selected from F, CIl, Br- and I".
It has been found that the combination of P-lupeol and ammonium ions provides a synergistic antiviral effect against a number of viruses, such as VSV, Rhino virus and 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.
WO 95/35103 PCTIDKc95/00256 6 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. Furthermore, it is thought that cationic protein complexes adjacent to or situated in the neutrophilic granulocytes ptay an important role as they promote the inflammatory reactions causing the known cold symptoms (sore throat, pain in the joints, fever, etc.). Preliminary experiments indicate that the mere presence of a highly anionic substance related to the heparin structure, but without the anti-coagulant effect of heparin, such as the sodium salt of sucrose octasulphate (SOS), or another SOS-like component, can counteract this process because the latter may optionally "neutralize" the charge of the cationic proteins present in the accumulated neutrophilic granulocytes. The latter granulocytes are bound to the virus-infected cells through ICAM-l-markers with the result that the usual inflammatory reactions are considerably reduced or completely suppressed.
It is known to use sulphated sugars including the aluminum complex of sucrose octasulphate, sucralphate, in the treatment of inflammations in the gastrointestinal region or for topical application on the skin for prophylaxis or treatment of inflammation, cf. for instance DK printed accepted application No. 165,357 and DK-PS No. 169,018. Furthermore, EP Patent Application No. 0 230 023 A2 discloses pharmaceutical compositions comprising sulphated oligosaccharides including sucrose octasulphate, for promoting ulcer healing. Thus it is assumed that SOS together with local growth factors form a biologically active complex which initiates and stabilizes, respectively, the growth factors resulting in accelerated ulcer healing processes.
The presence of 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 WO 95/35103 PCT/DK95/00256 7 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.
According to an embodiment of the present invention, the saccharide is a mono or polysulphated mono, di, tri or tetrasaccharide. According to a particular embodiment, the saccharide is a monosaccharide selected from xylose, fructose and glucose or a disaccharide selected from sucrose, lactose, maltose and cellobiose.
In a preferred embodiment the saccharide forms a complex or a salt with ammonium ions or with a metal selected from Al, Na, K, Ca, Mg, Ba, Zn, Cu, Zr, Ti, Bi, Mn, and Os, or with an amino acid.
According to a preferred embodiment of the present invention 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.
Among these sucrose octasulphate or the sodium, potassium or NH 4 salt thereof or the aluminum complex of sucrose octasulphate, sucralphate, are preferred.
Interferons usually present under ordinary virus infections, especially in WO 95/35103 PCT/DK95/00256 8 connection with colds, have been shown to intensify the antiviral effect of lupeol and ammonium ions. Thus it has been found that interferons in relatively low concentrations of 0. 1-2 units/ml intensify the antiviral effect.
Furthermore, it can be advantageous as a further ingredient of the pharmaceutical composition to use human or non-human immunoglobulines directed towards the substances contributing to intensify colds, such as microorganisms (virus) etc.
According to a particular embodiment of the invention the pharmaceutical compositions comprise therefore as a further ingredient human or non-human immunoglobulines.
The pharmaceutical composition is preferably in the form of chewing gums, lozenges, chewinrj tablets, resoriblets, drops, troches, gels, mouth ointments, solutions or in form of mucoadhesive formulations, preferably in the form of depot preparations. By 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: a) 0.01 to 2000, preferably 0.15-1000, particularly preferred 1-800, such as 20-600 pg of a P-lupeol derivative/piece, calculated as flupeol, b) 0 to 100, preferably 1-50, particularly preferred 2 to 40, such as mg of NH 4 +-ions/piece, calculated as ammonium chloride, WO 95/35103 PCT/DK95/00256 9 c) 0 to 1000, preferably 10-500, particularly preferred 25-250 mg of a sulphated saccharide/piece, calculated as SOS, as well as conventional chewing gum ingredients.
The chewing gum is prepared by means of conventional chewing gum ba, s 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. A further illustration of 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 relat-, furthermore to the use of one or more f-lupeol derivatives of the general formula I
CH,
H
I
C6HCHa 6H CH3 CH3
RO
H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 -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 WO 95/35103 PCT/DK95/00256 :onds, or a group which is easily decomposed under the conditions prevailing in the human or animal body to release the P-lupeol derivative for the preparation of a medicament for the prevention and/or treatment of viral infections.
Furthermore, the invention relates to the use of one or more f-lupeol derivatives of the general formula I
CH,
H
S CH CH3
RO
H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 -6-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds,
C
1 6 -acyl group, which may be straight-chained or branched and mJy 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 P-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.
Furthermore the invention relates to the use of one or more p-lupeol derivatives of the formula I WO 95/35103 PCT/DiK'I9500256 11
CH,
H3C
H
CH CH CH3 I II CH C
RO
H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 .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 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.
Finally, the invention relates to the use of one or more P-lupeol derivatives of the formula I in which R represents a hydrogen atom, a straight-chained or branched WO 95/35103 PCi/)K951 00256 12 aliphatic C 1 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 P-lupeol 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.
Thus 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.
In addition, the invention allows the use of one or more of the above mentioned active ingredients for treating HIV, hepatitis virus, cytomegalo viruL, herpes virus and other viral infections as well as for treating atherosclerosis as well as for suppressing tumour c!Al growth.
Antivirally active substances may function in various ways: either as a substance capable of protecting the target cells provided it is present simultaneously with the virus. If the latter is a condition for producing the antiviral activity, it is very likely that the antiviral effects involve a direct binding of the antiviral substance either to the virus or the receptor thereof or a combination lereof. Many plant extracts will show this type of "non-specific", receptor-dependent antiviral activity. Most frequently, it is only possible to produce this type of antiviral activity provided the substance is present at all times, especially from the time the virus is added, WO 95/35103 1P0II95/O0256 13 (ii) or as a substance which is capable of showing an effect without being present during the actual virus infection, such as in connection with a previous contact with the target cell, or by being present after the virus infection, but before a substantial production of viruses has taken place.
It is very likely that through this type of antiviral substances more fundamental changes inside the cells are produced via the synthesis of intracellular proteins/enzymes, which secondarily cause a relatively specific inhibition of the transcription and/or the translation of the virus in such a manner that the new intracellular proteins result in a so-called "antiviral state" of the cell. 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 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.
,P-lupeol is thought to belong to type (ii) in the effect mechanism.
f-lupeol 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. P-lupeol is commercially available and may be obtained e.g. from the company Sigma.
The scope of applicability of the invention will appear from the following with reference to the drawings and the examples. It should, however, be understood that the detailed description and the specific examples are merely included to illustrate preferred embodiments, and that various alterations and modifications within the scope of protection will be obvious to persons skilled in the art on the basis of the detailed description.
WO 95/35103 I'CT/ K95/00256 14 Brief Description of the Drawings The invention is explained in greater detail with reference to the drawings, in which Fig. 1 illustrates the antiviral activity of /-lupeol (also called B1-g) against Rhino virus, Fig. 2 the antiviral activity of interferon-a (HulFN-a) 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-a 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. 7B the same at an SOS dilution of 1:200, Fig. 7C the same at an SOS dilution of 1:400, Fig. 8 the antiviral activity of B1-g, NH 4 CI, SOS and interferon-a against Rhino virus, and WO 95/35103 PCIY/DK95/00256 Fig. 9 the kinetics for the induction of an antiviral state.
Detailed Description of the Invention The method used for determining antiviral activity is described below.
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, Purification and characterisation of murine and human interferons. A review of the literature of the 1970s (thesis). Acta Pathol. Microbiol. Scand., Sec. Suppl. 279.: page 1-136, 1982. The viruses employed are VSV, EMC, Semliki virus, influenza virus and Rhino virus.
Briefly 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 (110 /g MTS 39.2 ml PBS, pH-value 5.6 kept at +4°C in the dark), 2.3 ml medium and 30 pl PMS stock solution (13 mg PMS (Sigma, H5004, Lot 13, P. 9625) 6.5 ml distilled water, kept at 4 0 C in the dark with a layer of paraffin oil on the top) is added, and based on OD(optical density)readings in an OD-scanner the relative protection of the cells against viral attacks can be calculated. A high OD-reading indicates that the cells are protected against virus, and a low OD-value indicates that the cells have been killed by virus. Thus, the virus control cultures will typically have an OD-value of 0.100, while non-infected control cell cultures will have an OD-value 1.000. An antivirally active substance is thus a substance being capable in the presence of medium and challenge virus to provide WO 95/35103 P'C'T/IK95/00256 16 protection against the test virus in a cell culture.
As far as the MTS-methods are concerned, reference is furthermore made to Berg, B. H. Simonsen, M. B. Hansen, and S. Nielsen: A method for analysing a sample for the presence of a biological substance, especially a virus, use of the method for quantitative determination of biological substances and agents for use as novel substances detected by the method. PCT/DK/89/00010. 1 to 32, 1989.
Hansen M. S. E. Nielsen, and K. Berg: Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods. 119: 203 to 210, 1989.
Berg, M. B. Hansen and S. E. Nielsen: A sensitive bioassay for precise quantification of interferon activity as measured via the mitochondrial dehydrogenase function in cells (MTT-method). AMPIS 98: 156 to 162, 1990.
EXAMPLES
Example 1 Antiviral activity of /-lupeol measured by means of the MTS-system 500 to 1000 WISH-cells in 100 pl medium were seeded in wells in a microtray and incubated for 24 hours at 34°C in an atmosphere containing 5% CO 2 The medium was replaced by fresh medium containing dilutions of /-lupeol (25 to 1.6 pg/ml, cf. Fig. 1) and incubated for further 24 hours at 34 0 C in an atmosphere containing 5% CO 2 The following day challenge Rhino virus was added and after 4 to 5 days at 34 0 C in an atmosphere containing 5% CO 2 MTS was added over 2 hours, whereafter the microtray was measured in an OD-scanner. A total protection against WO 95/35103 PCT/I)K95/00256 17 Rhino virus was obtained at 3 pg/ml p-lupeol B1-g). However, at high concentrations of P-lupeol a decreasing cell number appears which must be ascribed to some toxicity of P-lupeol at such concentrations.
Example 2 Antiviral activity of interferon-a (rHulFN-a-2b, "intron against Rhino virus 10,000 WISH cells were seeded in a microtray, and the following morning the medium was replaced by two-fold dilutions of HulFN-a-2b ("intron A") in fresh medium containing 2% serum (cf. Fig. On the following morning the medium was replaced by fresh medium containing Rhino virus. The results in Fig. 2 clearly show that Rhino virus is relatively sensitive to HulFN-a-2b, and that a protection of approximately 90% is achieved at approximately 8 units IFN/ml. Furthermore, the toxicity of intron A appears to be negligible.
Example 3 Antiviral activity of B1-q 10,000 WISH cells were seeded and incubated at 37 0 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 0 C, and the tray was scanned as described above.
WO 95/3.103 ('1i/DK95/00256 18 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-a intensified the antiviral activity considerably. Thus, 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.
Example 4 Anti-Rhino virus activity of B1-a A corresponding experiment as described above was performed with Rhino virus. As illustrated in Fig. 4A, 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%. Corresponding results must be expected with influenza virus. Thus it appears that B1-g has a very strong activity towards Rhino virus compared to the effect towards VSV and EMC. This difference could not be foreseen.
The addition of 0.5 units of interferon-a/ml intensified the antiviral activity to a significant extent, cf. Fig. 4B.
Example Antiviral activity of NH 10,000 WISH cells were seeded in wells in a microtray for 24 hours and incubated for 24 hours at 37 0 C in an atmosphere containing 5% CO 2 Subsequently, the medium was replaced by fresh medium containing WO 95/35103 lP(CT/IK9.5/002$ Tests were carried out as described in Example 5, whereby, however, the temperature was 34°C and the incubation was carried out for 4 to 5 days.
The results appear from Figs. 7A, 7B and 7C.
Neither the use of SOS alone in the dilutions of 1:100, 1:200 or 1:400,
NH
4 CI alone at the dilutions of 1:1000 or 1:2000 nor NH 4 CI in combination with SOS have any significant antiviral effect.
The use of B1-g alone reveals a good effect being intensified by the simultaneous use of NH 4 CI, which alone at 34 0 C only provides a very low protection. Nevertheless, an increasing effect is obtained with an increasing NH 4 concentration. The additional use of SOS in the dilution of 1:100 provides only a moderate increase of the effect.
When comparing Figs. 7A, 7B and 7C it appears that the favourable effect of the combination of B1-g, NH4CI and SOS is most significant at an SOSdilution of 1:400 (Fig. 7C), where a protection of almost 95% is found corresponding to a B1-g concentration of significantly less than 1 pg/ml.
The fact that the most favourable effect is obtained at the lowest concentration of SOS tested is probably due to some toxicity of SOS towards the laboratory cells used. SOS is, however, known to be completely non-toxic to humans in all concentrations relevant in practice.
Example 8 Anti-Rhino virus activity of B1-q, NHCI, SOS and interferon-a Tests were carried out as described in Example 5, whereby all the substances were added simultaneously with the virus. The results appear from Fig. 8. As it appears, interferon-a in an amount of 0.5 units/ml intensifies further the favourable effect obtained by a combination of WO 95/35103 PC'iI)DK95/00256 21
NH
4 CI, B1-g and SOS, whereby an almost total protection is obtained by the use of B1-g, NH 4 ions and interferon-a.
Accordingly, the natural presence of interferon in a human during an infection must be expected to have an intensifying effect on B1-g and
NH
4 Analogous results appear with SOS in the dilutions of 1:200 and 1:400 (not shown). Similar results are obtained with 0.25 and 0.125 units of interferon/ml.
Example 9 Antiviral activity of Bl-q, NH ions, SOS, interferons and combinations thereof The antiviral activity was measured according to the above method. Four different viruses (EMC, VSV, Semliki Forest virus as well as Rhino virus) and three different cell lines (A-549, WISH, VERO) were used for the tests. The results appear from the Table below.
TABLE I Antiviral activity against different viruses on different cell lines.
Target cell WISH cell A-549 cell VERO cell WISH cell Virus VSV Semliki EMC VSV Semliki EMC Influenza A Influenza B Rhino Antiviral component SOS
(NH
4 )250 4
NH
4 Cl SOS+ (NH 4 2 S0 4 ND ND HuIFN-ay ND ND B1-g ND ND Bl-g+HuIFN-a ND ND..
Bl-g+NH 4 cl ND ND ND ND ND ND ND ND B1-g+SOS ND ND ND ND ND ND ND ND Bl-g+NH 4 cl+sos ND ND jND ND ND ND ND B1-g+NH 4 Cl+HuIFN-a ND I ND ND ND IND I ND ND i VSV virus, Semliki Forest virus and influenza virus belong to Rhino virus belong to the non-enveloped viruses.
ND =not determined.
the enveloped viruses; EMC and WO 95/35103 X)C'iI~)Kg /O2 23 As it appears from the above, Rhino virus is inhibited by ammonium ions and by B1-g as well as by interferon-a. 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.
Example Kinetic tests 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.
500 to 1000 WISH cells were seeded on day -1 in wells in microtrays and divided into 3 groups. To one group of cells (group -24h) was added B1-g in various concentrations in the range of 25 to 1.6 /g/ml, whereafter all of the cells were incubated for 24 hours at 37°C in an atmosphere containing C02. On day 0 Rhino-challenge virus was added to all of the wells, and simultaneously B1-g was added to another group of cells (group Oh).
The incubation was continued for 24 hours at 340C and 5% CO 2 Subsequently, 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 results appear from Fig. 9.
As it appears, 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.
Furthermore it is seen that even if the B1-g treatment is not initiated until I M WO 95/35103 PIC'Tlf)K9/I(02S6 24 24 hours after the viral infection, i.e. at the time where the viral infection has manifested itself, a distinct antiviral effect is obtained.
While the invention has been described with reference to specific embodiments thereof, it is obvious that it can be varied in many ways.
Such variations are not to be considered a deviation from the scope of the invention, and all such modifications which are obvious to persons skilled in the art are also to be considered comprised by the scope of the accompanying claims.
Claims (24)
1. A pharmaceutical composition for the prevention and/or treatment of viral infections, c h a r a c t e r i s e d in that it comprises one or more -lupeol derivatives of the formula H CH S'CH CH I CH3 RO H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic Cl.e-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C 1 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, one or more ingredients selected among ammonium ion releasing compounds, mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof, and human and non-human immunoglobulines as well as conventional pharmaceutically acceptable adjuvants, additives, and carriers.
2. A pharmaceutical composition as claimed in claim 1, c h a r a c t e r- is e d by R representing a hydrogen atom. AMENDED SHEET
3. A pharmaceutical composition as claimed in claim 1 or 2, c h a r a c- t e r i s e d in that it comprises one or more 1-lupeol derivatives of the formula H 3 C H I CH CH I CH3 I CH3 H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 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, wich 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 13-lupeol derivative, as well as an ammonium ion releasing compound.
4. A pharmaceutical composition as claimed in claim 3, c h a r a c t e r i s e d in that the ammonium ions are derived from a salt of a pharmaceutically acceptable inorganic or organic acid preferably selected from hydrochloric acid, sulphuric acid, phosphoric acid, carbonic acid, acetic acid, and tartaric acid.
A pharmaceutical composition as claimed in claim 3, c h a r a c t e r- is e d in that the ammonium ions are derived from a compound of the general Formula II AMENDED SHEET X, X 4 N- X 2 Ye II X3 where X 1 -X 4 which may be identical or different, are selected from hydrogen; C 1 .6alkyl, which may be straight-chained or branched, saturated or unsaturated and optionally contain one or more substituents selected from halogen, hydroxy, C 1 4 -alkoxy or amino; aryl, which is optionally substituted with C1, 4 -alkyl, halogen, hydroxy, C 1 4 -alkoxy or amino, and Y is a physiologically acceptable salt-forming anion, preferably selected from CI', Brand I'.
6. A pharmaceutical composition as claimed in claim 1 or 2, c h a r a c t e r i s e d in that it comprises one or more 13-lupeol derivatives of the formula AMENDED SHEET in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 ,.-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 (1-lupeol derivative, as well as one or more mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof.
7. A pharmaceutical composition as claimed in claim 3, c h a r a c t e r i s e d in that it furthermore comprises one or more mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof.
8. A pharmaceutical composition as claimed in claim 6 or 7, c h a r a c t e r i s e d in that the saccharide is a mono or polysulphated mono, di, tri or tetrasaccharide.
9. A pharmaceutical composition as claimed in claim 6 or 7, c h a r a c t e r i s e d in that the saccharide is a monosaccharide selected from xylose, fructose and glucose.
10. A pharmaceutical composition as claimed in claim 6 or 7, c h a r a c t e r i s e d in that the saccharide is a disaccharide selected from sucrose, lactose, maltose and cellobiose.
11. A pharmaceutical composition as claimed in any of the preceding claims, c h a r a c t e r i s e d in that the saccharide forms a complex or a salt with ammonium ions or with a metal selected from Al, Na, K, Ca, Mg, Ba, Zn, Cu, Zr, Ti, Bi, Mn, and Os, or with an amino acid. AMENDED SHEET
12. A pharmaceutical composition as claimed in claim 10, c h a r a c t e r i s e d in that the sulphated disaccharide is sucrose octasulphate, 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.
13. A pharmaceutical composition as claimed in claim 12, c h a r a c t e r i s e d in that the sulphated disaccharide is sucrose octasulphate or a sodium, potassium oF NH 4 salt thereof or the aluminum complex of sucrose octasulphate, sucralphate.
14. A pharmaceutical composition according to claim 1, c h a r a c t e r i s e d in that it comprises one or more I3-lupeol derivatives of the formula CHI H3CH H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic Cl.,-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 human or non-human immunoglobulines.
AMENDED SHEET A pharmaceutical composition as claimed in any of the preceding claims, characterised in that it is in the form of chewing gums, lozenges, chewing tables, resoriblets, drops, troches, gels, mouth ointments, solutions, mucoadhesive formulations and depot preparations.
16. A pharmaceutical composition as claimed in claim 15 in the form of a chewing gum, characterised in that per piece of chewing gum it comprises: a) 0.01 to 2000, preferably 0.15 to 1000, particularly preferred 1 to 800, such as 20 to 600 pg of a /-lupeol derivative/piece, calculated as /-lupeol, b) 0 to 100, prefarably 1 to 50, particularly preferred 2 to 40, such as to 30 mg of NH 4 ions/piece, calculated as ammonium chloride, c) 0 to 1000, preferably 10 to 500, particularly preferred 25 to 250 mg of a sulphated saccharide/piece, calculated as sucrose octasulphate, as well as conventional chewing gum ingredients. AMENDED SHEET
17. A method of preparing a medicament comprising admixing one or more B-lupeol derivatives of the general formula 1 CH2 HaC CH, CH3I ICH3 CH3 RO H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic :oe Cl- 6 -hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C1-6-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 3-lupeol derivative, and one or more ingredients selected among ammonium ion releasing compounds, mono or polysulphated mono, Soligo or polysaccharides or analogues and/or derivatives thereof, and human and non-human immunoglobulines with suitable adjuvants and/or excipients.
18. The method as claimed in claim 17 comprising admixing one or more 3- lupeol derivatives of the general formula 1 CH 2 H3C H CH CH(I) CH 3 RO H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 -6-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a C 1 .e-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 B-lupeol derivative, as well as one or more ammonium ion releasing compounds, with suitable adjuvants and/or excipients.
19. The method as claimed in claim 17 comprising admixing one or more B- lupeol derivatives of the general formula 1 CH 2 CH3 S(I) J H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic S C.-6-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a Ci.--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 B-lupeol derivative, as well as one or more mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof, with suitable adjuvants and/or excipients.
The method as claimed in claim 17 comprising admixing one or more 3- lupeol derivatives of the general formula 1 CH 2 H3C CCH3 I C3 CH3 CH3 RO R3C, CH3 .in which 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 C1.6-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 6-lupeol derivative, one or more ammonium ion releasing compounds, as well as one or more mono or polysulphated mono, oligo or Spolysaccharides or analogues and/or derivatives thereof, with suitable adjuvants and/or excipients. *N IT G s
21. A method of preparing a medicament comprising admixing one or more 3-lupeol derivatives of the general formula 1 H 3 C 'CH 3 CH 3 RO' H 3 C CH 3 o ft o o a o ft in which R represents a hydrogen atom, a straight-chained or branched aliphatic C1-6-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 3-lupeol derivative, with suitable adjuvants and/or excipients.
22. A method for the prevention and/or treatment of viral infections, characterised in that it includes oral administration of a pharmacologically antiviral amount of one or more 1-lupeol derivatives of the formula 1 CH 2 H 3 C 'CH 3 CH 3 RO' H 3 C 'CH 3 ~r4 BPS N 'z_ 0VT in which R represents a hydrogen atom, a straight-chained or branched aliphatic Ci.s-hydrocarbyl group, which may be saturated or may contain one or more unsaturated bonds selected from double and triple bonds, a Ci 1 s-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 B-lupeol derivative, and one or more ingredients selected among ammonium ion releasing compounds, mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof, and human and non-human immunoglobulines in a pharmaceutically acceptable carrier.
23. A method for the prevention and/or treatment of viral infections, characterised in that it includes oral administration of a pharmacologically S* antiviral amount of one or more 1-lupeol derivatives of the formula 1 CH 2 HaC CH :CH3 CH3 3 (I) CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C 1 -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 B-lupeol derivative, as well as one o, more ammonium ion releasing compounds, in a pharmaceutically acceptable carrier. I
24. A method for the prevention and/or treatment of viral infections and associated inflammations, characterised in that it includes oral administration of a pharmacologically antiviral amount of one or more B-lupeol derivatives of the formula 1 CH2 CHC jj( J(I) CH. CH3 CH3 CH3 RO 113 HC CH, in which 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 Cl.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 6-lupeol derivative, as well as one or more mono or polysulphated mono, oligo or polysaccharides or analogues and/or derivatives thereof, in a pharmaceutically acceptable carrier. A method for the prevention and/or treatment of viral infections and associated inflammations, characterised in that it includes oral administration of a pharmacologically antiviral amount of one or more B-lupeol derivatives, of the formula 1 37 CH 2 HaC H CH3 CH3 CH3 1(I) R CH3 RO H3C CH3 in which R represents a hydrogen atom, a straight-chained or branched aliphatic C1-6-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 e* body to release the 1-lupeol derivative, one or more ammonium ion releasing compounds, as well as one or more mono or polysulphated mono, oligo or polysaccharides in a pharmaceutically acceptable carrier. DATED this 9th day of December, 1997. KURT BERG WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA CJH:JZ :(DOC.17) AU2734095.WPC
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK72294 | 1994-06-20 | ||
| DK722/94 | 1994-06-20 | ||
| DK926/94 | 1994-08-09 | ||
| DK92694 | 1994-08-09 | ||
| PCT/DK1995/000256 WO1995035103A1 (en) | 1994-06-20 | 1995-06-20 | A pharmaceutical composition for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for the treatment thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2734095A AU2734095A (en) | 1996-01-15 |
| AU689603B2 true AU689603B2 (en) | 1998-04-02 |
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ID=26064526
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| AU27340/95A Ceased AU689603B2 (en) | 1994-06-20 | 1995-06-20 | A pharmaceutical composition for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for the treatment thereof |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0762876A1 (en) |
| JP (1) | JPH10504279A (en) |
| KR (1) | KR970703759A (en) |
| CN (1) | CN1158566A (en) |
| AU (1) | AU689603B2 (en) |
| CA (1) | CA2193396A1 (en) |
| EE (1) | EE9600190A (en) |
| FI (1) | FI965114A7 (en) |
| NO (1) | NO965468L (en) |
| WO (1) | WO1995035103A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1998017282A1 (en) * | 1996-10-23 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Methods of using sucrose octasulfate to treat or prevent enveloped virus infection |
| EP0988033B1 (en) * | 1997-01-09 | 2001-09-26 | Bifodan A/S | Use of dichlorobenzyl alcohol for preparing a preparation for topical treatment of inflammation |
| WO1998032443A1 (en) * | 1997-01-24 | 1998-07-30 | Marigen S.A. | Ultramicro-emulsions of spontaneously dispersible concentrates containing antitumorally, antivirally and antiparasitically active esters of pentacyclic triterpenes |
| US6124362A (en) * | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
| US6482857B1 (en) | 1998-07-17 | 2002-11-19 | The University Of Texas Southwestern Medical Center | Compositions which contain triterpenes for regulating hair growth |
| DE60214509T2 (en) * | 2001-01-12 | 2007-05-31 | Bsp Pharma A/S | Dihydrotriterpenes in the treatment of viral infections, cardiovascular diseases, inflammation, hypersensitivity or pain |
| FR2822821B1 (en) * | 2001-04-03 | 2004-05-07 | Pharmascience Lab | LUPINE SEED HULL EXTRACT CONTAINING LUPEOL, ESPECIALLY EXTRACT RICH IN LUPEOL AND PROCESS FOR PREPARING THE SAME |
| CN104761460B (en) * | 2015-03-26 | 2017-06-20 | 苏州沪云肿瘤研究中心股份有限公司 | Glaucocalyxin A derivative and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990014764A1 (en) * | 1989-06-08 | 1990-12-13 | Stephen Herman | Method for treating viral infection |
-
1995
- 1995-06-20 AU AU27340/95A patent/AU689603B2/en not_active Ceased
- 1995-06-20 CN CN95194431A patent/CN1158566A/en active Pending
- 1995-06-20 EE EE9600190A patent/EE9600190A/en unknown
- 1995-06-20 WO PCT/DK1995/000256 patent/WO1995035103A1/en not_active Ceased
- 1995-06-20 EP EP95922445A patent/EP0762876A1/en not_active Withdrawn
- 1995-06-20 CA CA002193396A patent/CA2193396A1/en not_active Abandoned
- 1995-06-20 JP JP8501510A patent/JPH10504279A/en active Pending
- 1995-06-20 KR KR1019960707236A patent/KR970703759A/en not_active Withdrawn
-
1996
- 1996-12-19 FI FI965114A patent/FI965114A7/en unknown
- 1996-12-19 NO NO965468A patent/NO965468L/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990014764A1 (en) * | 1989-06-08 | 1990-12-13 | Stephen Herman | Method for treating viral infection |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995035103A1 (en) | 1995-12-28 |
| FI965114A0 (en) | 1996-12-19 |
| CN1158566A (en) | 1997-09-03 |
| NO965468D0 (en) | 1996-12-19 |
| FI965114A7 (en) | 1996-12-19 |
| EP0762876A1 (en) | 1997-03-19 |
| CA2193396A1 (en) | 1995-12-28 |
| KR970703759A (en) | 1997-08-09 |
| EE9600190A (en) | 1997-06-16 |
| AU2734095A (en) | 1996-01-15 |
| NO965468L (en) | 1997-02-19 |
| JPH10504279A (en) | 1998-04-28 |
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