WO2002066491A1 - Acides boswelliques hydrosolubles, mode d"obtention et utilisation contre des états inflammatoires - Google Patents

Acides boswelliques hydrosolubles, mode d"obtention et utilisation contre des états inflammatoires Download PDF

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Publication number
WO2002066491A1
WO2002066491A1 PCT/US2002/003384 US0203384W WO02066491A1 WO 2002066491 A1 WO2002066491 A1 WO 2002066491A1 US 0203384 W US0203384 W US 0203384W WO 02066491 A1 WO02066491 A1 WO 02066491A1
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WO
WIPO (PCT)
Prior art keywords
mixture
boswellic
boswellic acids
effective amount
composition
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Application number
PCT/US2002/003384
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English (en)
Inventor
Muhammed Majeed
Vladimir Badmaev
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Sabinsa Corporation
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Publication of WO2002066491A1 publication Critical patent/WO2002066491A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention concerns a new composition of boswellic acids, methods of using the composition to treat inflammatory conditions, and methods of producing the new composition.
  • Boswellia serrata is a large, branching, deciduous tree, which grows abundantly in the dry, hilly parts of India.
  • the gum resin exudate of this tree known in the vernacular as "Salai guggal"
  • the major use of Boswellia serrata in modern medicine is as an anti-arthritic and anti-inflammatory pharmacological agent.
  • boswellic acids function as NSAIDs in the treatment of inflammatory conditions. Similar to aspirin, boswellic acids inhibit the pathway leading from arachidonic acid (a derivative of our body's phospholipids) to its metabolic derivatives called leukotrienes and prostaglandins. An excess of leukotrienes and prostaglandins may be responsible, directly or indirectly, for the classic signs of inflammation; redness (due to dilated vessels), swelling (due to the blood vessels leaking out), pain (due to activation of the pain receptors) and increased heat over the affected part of the body.
  • the specific biochemical mechanism of boswellic acids differs from that of aspirin, however both compounds result in the diminishment of the mediators of inflammation, leukotrienes or prostaglandins, and the inflammation is subdued.
  • boswellic acids are safe, specific, non-redox inhibitors of leukotriene synthesis that operate through a well defined mechanism.
  • boswellic acids In in vitro experiments boswellic acids prevented a well- known inflammatory "chain-reaction" involving several protein compounds collectively known as “complement”. This is due to the inhibition of an enzyme that activates one of the components of complement, C3 convertase.
  • C3 convertase an enzyme that activates one of the components of complement
  • the domino effect of the complement in the course of rheumatoid arthritis (or a similar chronic inflammatory process) leads to a subsequent elevation of the enzymes (e.g. cathepsins, glucuronidase and human leukocyte elastase (HLE)) causing excessive catabolism (wasting) of the joint-forming glycoproteins and glycosaminoglycans.
  • the enzymes e.g. cathepsins, glucuronidase and human leukocyte elastase (HLE)
  • BBA b-Boswellic Acid
  • ABBA Acetyl-b-Boswellic Acid
  • KBBA 11-keto-b-Boswellic Acid
  • AKBBA Acetyl-11- keto-b-Boswellic
  • Boswellic acids have been found to be effective in alleviation of numerous inflammatory conditions, including, rheumatoid arthritis and osteoarthritis.
  • a standardized extract of boswellic acids 200 mg tid was evaluated in a four week double blind, cross-over trial in 30 patients suffering from rheumatoid arthritis. The mean arthritic score (sum of symptoms) and the biochemical index of inflammation in the group receiving boswellic acids came down significantly after the treatment. However, when the placebo was substituted (crossover), the subjective and objective indices of arthritis rose again. (See Majeed, M, Badmaev, V, Gopinathan, S, Rajendran, R, Norton, T.
  • Boswellin The Anti-inflammatory Phytonutrient. Nutriscience Publishers, inc. Piscataway, NJ. 1996. pp. 78.
  • a boswellia gum resin extract 200 mg tid
  • Active and placebo treatments were given for a period of three months. After a washout period of two weeks, the regimens were crossed-over. The three month active therapy resulted in a significant decrease in severity of pain, morning stiffness, improved joint mobility score, grip strength score and the overall disability score compared to the placebo group.
  • the biochemical index of inflammation was also significantly improved due to the treatment.
  • Ulcerative colitis is an example of a chronic inflammatory process in the bowel, which may be caused and/or aggravated by excessive leukotriene production. Effects of Boswellia serrata gum resin (350 mg thrice daily for 6 weeks) vs. the NSAID sulfasalazine was studied in patients with ulcerative colitis.
  • the tested parameters including stool properties, istolopathology of rectal biopsies, and blood biochemistry improved after treatment with the gum resin.
  • 82% of patients went into remission, as compared to a 75% remission rate obtained with sulfasalazine.
  • Boswellic acids were also tested in the management of asthma, since a new generation of anti-asthmatic drugs is based on the premise of being leukotriene inhibitors.
  • 40 patients with a several years' history of bronchial asthma were treated with 300 mg tid of boswellia gum resin for a period of six weeks. Seventy percent of the patients responded to the treatment as evidenced by a reduction in dyspnea, ronchi, and number of attacks, improvement in lung tests and blood biochemistry. Only 27% of the patients receiving placebo showed clinical improvement.
  • boswellic acids also have use in the veterinary field. Several veterinarians found success using boswellic acids in the treatment of chronic inflammatory conditions in horses such as stifle problems, sore backs, bowed tendons and bone spurs.
  • Boswellin® standardized for 25% boswellic acids
  • Boswellin Forte standardized for 40% boswellic acids
  • Such non-water soluble mixtures of BBA, ABBA, KBBA, and AKBBA boswellic acids can be used as a pharmaceutical. Since the ancient times, frankincense has been used in the preparation of cosmetics and perfumes, and also as a fixative in perfumes, soaps, creams, lotions and detergents. Frankincense is a common name for Boswellia gum resin, and Boswellia gum resin is a raw source from which boswellic acids are extracted. The stabilizing effect of frankincense in cosmetic preparations is directly related to the biological properties of boswellic acids. The anti-inflammatory properties of boswellic acids can also yield an interesting applications for topical and cosmetic use of the extract of Boswellia serrata.
  • Boswellia cream for the management of inflammatory conditions has been available for several years in the US market. Its therapeutic composition includes, roughly 5 wt. % boswellic acids, 0.025 wt. % capsaicin, an extract of Capsicum annum fruits, and 10 wt. % methyl salicylate.
  • the new water-soluble composition can be formed through a method comprising the steps of:
  • the new composition can be formed by using super critical carbon dioxide.
  • the new composition can be used to alleviate numerous inflammatory conditions, including, but not limited to, rheumatoid arthritis and osteoarthritis, colon cancer, prostate cancer and breast cancer, and a broad range of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. It can also be used in the prevention and treatment of cardiovascular conditions such as stroke, coronary artery disease or thrombophlebitis.
  • the composition can be administered parenterally, orally, or topically.
  • the composition can be formed by (a) dissolving mixtures of boswellic acids in a water and alcohol solution to form a mixture, (b) adding one or more alkali salts to the mixture to form a salt solution, (c) filtering the salt solution to separate un-reacted alkali salt from a filtrate, and (d) recovering the soluble boswellic acid mixture from the filtrate.
  • the method involves (a) dissolving boswellin forte in a water and 5% methanol solution to form a mixture, (b) adding one or more potassium salts to the mixture to form a salt solution and then stirring the salt solution at room temperature, (c) filtering the solution with a nutsche filter to separate un-reacted potassium salts from a filtrate, (d) recovering the soluble boswellic acid mixture from the filtrate, (e) drying the filtrate with a vacuum drier at a temperature of no more than 50° C, and (f) powdering the filtrate.
  • the filtrate can be dried through concentrating the filtrate free of the solvent to obtain a solid, wherein this step also further comprises dissolving the obtained solid in water to obtain a secondary mixture, charcoalizing the secondary mixture, filtering the charcoalized secondary mixture and spray-drying the resulting product.
  • the super critical carbon dioxide method of obtaining the boswellic acid mixture would comprise the steps of (a) dissolving a mixture of boswellic acids, preferably boswellin forte, in a water and alcohol solution to form a mixture, (b) adding one or more alkali salts to the mixture to form a salt solution, (c) treating the salt solution with supercritical carbon dioxide, (d) allowing the supercritical carbon dioxide to evaporate to leave an oleoresin, (e) passing an alcohol solution of the oleoresin through a column packed with an anion exchange resin, and (f) collecting the soluble boswellic acid mixture from the eluent.
  • Suitable resins include Amberjet 4200(d), Amberlite IRA 410, Amberlite IRA 900, Dowex 1x2-100, Dowex 22cl, Dowex Marathon A2, Dowex MSA 1 , Dowex 550 A, all of which are Rohm-Haas or Dow products.
  • the oleoresin is preferably passed through the resin at a rate of 20-50 L per hour.
  • the processes described above produce a water soluble composition, preferably comprising at least 12.5% by weight of the alkali salt of BBA, at least 9.57% by weight of the alkali salt of ABBA, at least 8.15% by weight of the alkali salt of KBBA, and at least 3.72% by weight of the alkali salt of AKBBA, the remainder of the water soluble composition being organic acids or matter, and the alkali salts thereof.
  • This composition of boswellic acids is suitable for the treatment of many inflammatory conditions including rheumatoid arthritis and osteoarthritis, colon cancer, prostate cancer and breast cancer, and a broad range of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. It can also be used in the prevention and treatment of cardiovascular conditions such as stroke, coronary artery disease or thrombophlebitis.
  • the composition may be administered to the subject orally, parenterally, or topically.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, creams, and cachets.
  • a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
  • Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
  • the pharmaceutical compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
  • Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water or other appropriate solvents and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the boswellic acid mixtures.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the specific dosages employed can be varied depending upon the requirements of the patient, and the severity of the condition being treated.
  • the preferred dosage of the alkali boswellic acid salts given is 50-800 mg per day. More preferably, the dosage is 100-600 mg per day. Even more preferred is a dosage of
  • a dosage of about 200 mg per day which is preferably administered by doses of 200 mg of the boswellic acid salt composition 3 times a day.
  • the determination of optimum dosages for a particular situation is within the skill of the art.
  • Figure 1 This diagram reflects the boswellic acid composition of the
  • Figure 2 This diagram reflects the presence of the four boswellic acids in the serum of Individual A at 5, 10, 20, 40, 80, and 160 minutes.
  • Figure 3 This diagram reflects the presence of the four boswellic acids in the serum of Individual B at 5, 10, 20, 40, 80, and 160 minutes
  • Figure 4 This diagram is a graph charting the serum levels of the various four boswellic acids in the serum of Individual A at the 5, 10, 20, 40, 80, and 160 minute intervals.
  • Figure 5 This diagram is a graph charting the serum levels of the various four boswellic acids in the serum of Individual B at the 5, 10, 20, 40, 80, and 160 minute intervals.
  • Potassium Boswellin and Boswellin 40% were then orally administered to two human volunteers who had spent the previous 16 hours fasting. 1 gram of Potassium Boswellin was given to Individual A and 1 gram of Boswellin 40% was given to Individual B. Both the Potassium Boswellin and the Boswellin 40% were suspended in 35 ml of milk and given to the subjects to consume. 5 ml of blood was withdrawn from the volunteers at intervals of 5, 10, 20, 40, 80, and 160 minutes. The blood samples were collected into sterile centrifuge tubes and left for 120 minutes to retract the clot. The samples were then centrifuged to separate the serum. The serum was transferred to sterile 2 ml vials and stored at 0° C - 4° C overnight.
  • the serum samples were then brought to room temperature. 1 ml of the serum was placed into a 10 ml stoppered volumetric flask and 1 ml of 3 N HCI was added to it. This mixture was then sonicated for 20 minutes to free the boswellic acid. The volume of the mixture was then brought to 10 ml with methanol and the resulting solution was sonicated for 10 minutes to extract the boswellic acids and to precipitate the serum proteins. This prepared sample was then transferred into capped centrifuge tubes and centrifuged at 4,000 rpm for 10 minutes. The serum proteins were precipitated as sediment and the clear supernatant was filtered through No. 1 filter paper.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne une nouvelle composition pouvant s"obtenir selon une procédure appropriée. On commence (a) par dissoudre des mélanges d"acides boswelliques dans une solution d"eau et d"alcool de façon à obtenir une mixture. (b) On ajoute à cette mixture au moins un sel alcalin de façon à obtenir une solution saline. (c) Un filtrage de la solution permet de séparer d"un filtrat le sel alcalin resté en dehors de la réaction. Il en reste plus qu"à (d) récupérer du filtrat la mixture d"acide boswellique soluble. En outre, pour obtenir cette nouvelle composition, on peut utiliser du dioxyde de carbone supercritique. Cette nouvelle composition se montre efficace contre divers états inflammatoires, et notamment contre l"arthrite rhumatoïde et l"arthrose, contre les cancers du colon, de la prostate et du sein, et contre une large gamme d"affections neurodégénératives telles que les maladies d"Alzheimer et de Parkinson. Cette composition convient à l"administration par voies parentérales et orales ainsi qu"en application locale.
PCT/US2002/003384 2001-02-15 2002-02-15 Acides boswelliques hydrosolubles, mode d"obtention et utilisation contre des états inflammatoires WO2002066491A1 (fr)

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US60/268,713 2001-02-15

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10331750A1 (de) * 2003-07-14 2005-02-10 Keyneurotek Ag Verwendung der Hydrierungsprodukte von Weihrauch (Olibanum) zur Prophylaxe und/oder Behandlung von zerebraler Ischämie, Schädel/Hirntrauma und/oder Alzheimer-Krankheit
WO2007046113A2 (fr) * 2005-10-18 2007-04-26 Panacea Biotec Ltd. Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede
WO2008058514A1 (fr) * 2006-11-14 2008-05-22 Eberhard Karls Universität Tübingen Préparations contenant des acides boswelliques pour l'inhibition de la synthèse de la prostaglandine e2
ITMI20111975A1 (it) * 2011-10-28 2013-04-29 Labomar S R L Composizioni comprendenti un sale di un acido organico.
CN103193853A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗银屑病的化合物、组合物及其制备方法
CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
ITPD20120343A1 (it) * 2012-11-13 2014-05-14 Matteo Bevilacqua Composto in particolare per la cura della depressione e dell'ansia
WO2022133020A1 (fr) * 2020-12-17 2022-06-23 Majeed, Muhammed Compositions pour la gestion efficace de la polyarthrite rhumatoïde médiée par des synoviocytes de type fibroblastes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4444288A1 (de) * 1994-12-13 1996-06-20 Rainer Dr Med Etzel Verwendung von Weihrauch zur Behandlung der Alzheimer-Krankheit
EP0755940A1 (fr) * 1995-04-13 1997-01-29 Council of Scientific and Industrial Research Compositions de l'acide Boswellique et leur préparation
WO1997007796A1 (fr) * 1995-08-23 1997-03-06 Ammon Hermann P T Utilisation d'acide de boswell et de ses derives pour inhiber l'activite normale ou accrue de l'elastase leucocytaire ou de la plasmine
WO2000066111A1 (fr) * 1999-04-30 2000-11-09 Sabinsa Corporation Compositions a base d'acides boswelliques, derivees de gomme-resine de boswellia serrata et destinees a traiter des etats lymphoproliferatifs et auto-immuns

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4444288A1 (de) * 1994-12-13 1996-06-20 Rainer Dr Med Etzel Verwendung von Weihrauch zur Behandlung der Alzheimer-Krankheit
EP0755940A1 (fr) * 1995-04-13 1997-01-29 Council of Scientific and Industrial Research Compositions de l'acide Boswellique et leur préparation
WO1997007796A1 (fr) * 1995-08-23 1997-03-06 Ammon Hermann P T Utilisation d'acide de boswell et de ses derives pour inhiber l'activite normale ou accrue de l'elastase leucocytaire ou de la plasmine
WO2000066111A1 (fr) * 1999-04-30 2000-11-09 Sabinsa Corporation Compositions a base d'acides boswelliques, derivees de gomme-resine de boswellia serrata et destinees a traiter des etats lymphoproliferatifs et auto-immuns

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10331750A1 (de) * 2003-07-14 2005-02-10 Keyneurotek Ag Verwendung der Hydrierungsprodukte von Weihrauch (Olibanum) zur Prophylaxe und/oder Behandlung von zerebraler Ischämie, Schädel/Hirntrauma und/oder Alzheimer-Krankheit
WO2007046113A2 (fr) * 2005-10-18 2007-04-26 Panacea Biotec Ltd. Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede
WO2007046113A3 (fr) * 2005-10-18 2007-07-26 Panacea Biotec Ltd Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede
WO2008058514A1 (fr) * 2006-11-14 2008-05-22 Eberhard Karls Universität Tübingen Préparations contenant des acides boswelliques pour l'inhibition de la synthèse de la prostaglandine e2
ITMI20111975A1 (it) * 2011-10-28 2013-04-29 Labomar S R L Composizioni comprendenti un sale di un acido organico.
CN103193853A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗银屑病的化合物、组合物及其制备方法
CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
ITPD20120343A1 (it) * 2012-11-13 2014-05-14 Matteo Bevilacqua Composto in particolare per la cura della depressione e dell'ansia
WO2014076643A1 (fr) * 2012-11-13 2014-05-22 ZAGGIA, Guerrino Composé particulièrement utile pour le traitement de la dépression et de l'anxiété
WO2022133020A1 (fr) * 2020-12-17 2022-06-23 Majeed, Muhammed Compositions pour la gestion efficace de la polyarthrite rhumatoïde médiée par des synoviocytes de type fibroblastes

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