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WO2007046113A2 - Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede - Google Patents

Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede Download PDF

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Publication number
WO2007046113A2
WO2007046113A2 PCT/IN2006/000408 IN2006000408W WO2007046113A2 WO 2007046113 A2 WO2007046113 A2 WO 2007046113A2 IN 2006000408 W IN2006000408 W IN 2006000408W WO 2007046113 A2 WO2007046113 A2 WO 2007046113A2
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optionally
alkaloid
composition according
active agent
tylophorine
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PCT/IN2006/000408
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WO2007046113A3 (fr
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Rajesh Jain
Kour Chand Jindal
Aniruddha Datta
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Panacea Biotec Ltd.
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Publication of WO2007046113A2 publication Critical patent/WO2007046113A2/fr
Publication of WO2007046113A3 publication Critical patent/WO2007046113A3/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
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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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to novel anti-inflammatory, antiallergic and/or antiasthmatic pharmaceutical compositions comprising at least one alkaloid component(s) derived from natural, semi-synthetic or synthetic source as active agent, either alone or in combination with other active agent(s), optionally with other pharmaceutically acceptable excipients.
  • the present invention also describes process for preparation of such compositions and method of using such compositions.
  • the novel composition is preferably in the form of a dry powder inhaler or metered dose inhaler and is preferably intended to be administered by pulmonary, nasal or oral route, most preferably by inhalation, and is useful either prophylactically or therapeutically for the prevention or treatment of particularly inflammatory, allergic, and/or respiratory disorders such as asthma, chronic obstructive pulmonary disease(s), or any other associated disorders.
  • Asthma is a lung disorder in which spasms and inflammation of bronchial passages restrict (low of air in and out of the lungs.
  • the number of people with asthma and the death rate from this condition has been increasing since the late 1980s.
  • An asthma attack usually begins with sudden fits of wheezing, coughing, or shortness of breath. However, it may also begin insidiously with slowly increasing manifestations of respiratory distress. A sensation of tightness in the chest is also common.
  • OTC treatment includes oral expectorant combinations containing ephedrine and inhalers containing epinephrine.
  • Several classes of prescription drugs are commonly used for short-term symptom relief and long-term control such as inhaled beta-adrenergic agonist drugs albuterol, salmeterol, and metaproterenol; oral theophylline and oral corticosteroids, such as prednisone and prednisolone, inhaled corticosteroids such as fluticasone, triamcinolone, budesonide, and flunisolide and oral leukotrie ⁇ e receptor antagonists such as zafiiiukast and montelukast. Cromolyn sodium, a synthetic flavonoid. is also used for long-term care to prevent bronchial asthma.
  • asthma Although anticholinergic drugs such as atropine are less frequently used, a chemically related drug, ipratropium bromide, is currently useful for long-term treatment.
  • Medical management of asthma includes controlling environmental factors that can trigger an attack such as animal dander, dust mites, airborne molds and pollens, and certain foods.
  • Ayurveda is an example of a long standing tradition that offers a unique insight into comprehensive approach to asthma management through proper care of respiratory tract. This includes maintaining the nourishing functions of the lungs, in providing oxygen to the body.
  • respiratory tract functions are interrelated with' those of another organ that introduces nourishment to the body, viz., the stomach.
  • phlegm humor or Kapha which is one of the three basic humors
  • Kapha which is one of the three basic humors
  • Ayurvedic formulations used in the management of asthma therefore judiciously combine herbs for breathing support with antioxidant herbs such as Curcuma longa, herbs to support the digestive, cardiac and nerve functions, expectorant herbs as well as soothing herbs.
  • Ayurveda offers materica medica that has been successfully used in the prevention and the treatment of respiratory tract conditions, some of which have been developed into synthetic compounds for the respiratory tract.
  • Co/ens forskohlii belongs to the Natural Order Labiatae
  • Tylophora asthmalica (syn. Tylophora indica) belonging to family Asclepiadaceae, has been traditionally used as a folk remedy in certain regions of India for the treatment of bronchial asthma, bronchitis, rheumatism and dermatitis. Further, Tylophora asthmalica is shown to exert immunomodulatory and anticancer activities. It is a perennial climbing plant native to the plains " , forests, and hills of southern and eastern India.
  • Powder from the dried leaves, root powder, decoction of the leaves or infusion of the root bark are mainly used.
  • the anti-asthmatic activity of the plant is attributed to the presence of phenanthroindolizidine alkaloids namely tylophorine, tylophorinine and tylophorinidine; tylophorine being the major one having following chemical structure.
  • Tylophora leaf at a dose of 200-400 mg of the dried leaf/day or 1-2 ml of tincture/day can be used to treat asthma [Clinical Applications of Ayurvedic and Chinese Herbs; Australia: Phytotherapy Press, 1996: pp.134-6].
  • the mode of action of the leaf of Tylophora aslhmatica as well as its alkaloids tylophorine and tylophorinine has been studied in experimental animals.
  • a water extract of the plant was administered intraperitoneal Iy to sensitized guinea pigs challenged with egg albumin-induced anaphylaxis.
  • the extract showed anti-anaphylactic effect, leucopenia and inhibition of Schultz-Dale's reaction in experimental animals.
  • the lymphocytes and eosinophils were found to be markedly reduced.
  • the extract also showed brief, nonspecific anti-spasmodic action in isolated tissues of guinea pig ileum, rabbit duodenum, frog rectus and rat stomach wherein contractions had been induced by the administration of spasmolytic agents. Furthermore, the authors of this study postulated that the utility of this plant in the treatment of bronchial asthma could be attributed to its action on cell-mediated immunity. Dhananjayan et al conducted an extensive study on the pharmacological effects of the plant. They observed that the plant extracts produced muscle relaxant effect, antagonism of smooth muscle stimulants and immunosuppressive effects in different species of laboratory animals.
  • Adhaloda vaiica contains two major alkaloids namely vasicine and vasicinone, and has been used for the treatment of bronchitis and asthma for many centuries. It relieves cough and breath lessness. It is also prescribed commonly for bleeding due to idiopathic thrombocytopenic purpura, local bleeding due to peptic ulcer, piles, menorrhagia etc. Its local use gives relief in pyorrhoea and in bleeding gums.
  • the active alkaloid vasicine and its autooxidation product vasicinone have shown bronchodilator and antihistaminic effects. ' Uterine stimulant activity and moderate hypotensive activity of the alkaloids were reported.
  • vasicine hydrochloride Thrombopoeitic activity of vasicine has been observed. Intraamniotic injection of vasicine hydrochloride was effective in inducing mid-trimester abortions at a dose of 60 mg.
  • Saussurea lappa commonly known as Costus Root
  • the root has a pungent taste and a peculiar fragrance. It is a tonic, aphrodisiac, antiseptic and a stimulant It strengthens functioning of the stomach and promotes its action. It is helpful in arresting secretion or bleeding.
  • the essential oil has antiseptic and disinfectant properties. It relaxes the involuntary muscle tissues and serves as a cardiac stimulant.
  • Saussurea is beneficial in the treatment of respiratory disorders like bronchitis, asthma and cough, especially controlling attacks of bronchial asthma.
  • the combined action of the essential oil and the alkaloid in the root restrict the paroxysms.
  • the alkaloid saussurine has a depressant action on the vagus centre in the medulla, which supplies motor nerve fibre, as well as on the involuntary muscle fibres of the bronchioles and gastrointestinal tract. It produces a slight but persistent rise in blood pressure and increases the force of contraction and amplitude of the ventricles.
  • Costunolide is an active sesquiterpene lactone with anti-inflammatory and potential anti-cancer, activity. Nevertheless, the pharmacological pathways of costunolide have not yet been fully elucidated. Boswellic acids obtained from the gum resin of Boswellia serrata offer the most promising phytonutritional approach as antileukotrienes. This facet of the pharmacological activity of boswellic acids was first observed in an in vitro search for new plant constituents with potential antiphlogistic and antiallergic activity. Boswellic acids were proven to be the most potent inhibitors of the classical component pathway of the inflammatory response, producing 100% inhibition at a concentration of 0.1 mM.
  • Boswellic acids appear to be specific inhibitors of leukotriene formation, functioning by inhibiting the activity of the enzymes that involve in formation. Boswellic acids are therefore effective in the prevention and/or control of inflammatory processes, which are typically characterized by increased leukotriene formation.
  • Indian and German researchers conducted the first study of boswellia's effect on the symptoms of asthma. The double blind, randomized pilot study involved 80 patients with a history of asthma. 70% of patients treated with 900 mg of powdered boswellia gum resin per day showed a significant decrease in symptoms after six weeks compared to twenty-seven percent of control group patients (treated with lactose). In recent studies, it has been established that acetyl keto- ⁇ -boswellic acid is the most active among Boswellic acids.
  • compositions- comprising specifically alkaloid(s) either alone or in combination with other components which can be preferably administered by the pulmonary, nasal or oral route, most preferably by inhalation route, but associated with minimal toxic or side effects.
  • the present invention provides such novel compositions comprising at least one alkaloid, process of preparation of such compositions and methods of using them.
  • It is an objective of the present invention to provide novel anti-inflammatory, antiallergic and/or antiasthmatic pharmaceutical compositions comprising at least one alkaloid component derived from natural, semi-synthetic or synthetic source as active agent, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more other pharmaceutically acceptable excipient(s).
  • compositions comprising phenanthroindolizidine alkaloid(s) or its salts, esters, derivatives, isomers, hydrates or solvates as the major alkaloid component derived from natural, semi-synthetic or synthetic source as active agent, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more other pharmaceutically acceptable excipient(s).
  • compositions comprising tylophorine or its salts, esters, derivatives, isomers, hydrates or solvates as the major phenanthroindolizidine alkaloid component derived from natural, semi-synthetic or synthetic source as active agent, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more other pharmaceutically acceptable excipient(s).
  • compositions comprising an extract of the plant Tylophora sp. as active agent which comprises tylophorine or its salts, esters, derivatives, isomers, hydrates or solvates as the major alkaloid component, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more another pharmaceutically acceptable excipien ' t(s).
  • compositions comprising at least one alkaloid component additionally with at least another component derived from natural, semi-synthetic or synthetic source as the active agent; their salts, esters, derivatives, isomers, hydrates or solvates optionally with a vehicle and optionally other pharmaceutically acceptable excipients, wherein the alkaloid component is selected from a group comprising tylophorine, saussurine, vasicine, and the like or mixtures thereof, and the other additional component is selected from the group comprising costimolide, forskolin, curcumin, boswellic acid, and the like or mixtures thereof. It is also an objective of the present invention to provide process for preparation of an extract from one or more part(s) of the plant Tylophora sp. which is used in the formulation of novel anti-inflammatory, antiallergic and/or • antiasthmatic pharmaceutical compositions.
  • It is a further objective of the present invention to provide process for the preparation of such novel composition which comprises of the following steps: i) mixing the active agent(s) optionally with a vehicle, ii) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulating the mixture into a suitable dosage form.
  • It is a further objective of the present invention to provide process for the preparation of such novel composition which comprises of the following steps: i) micronizing the active agent(s) and vehicle(s), ii) mixing the micronized active agent(s) with micronized vehicle(s), iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iv) formulating the mixture into a suitable dosage form.
  • novel compositions of.the present invention can be used either prophylactically or therapeutically for the prevention or treatment of inflammation, allergy and/or asthma or. any other associated disorders.
  • novel compositions of the present invention are intended preferably for nasal, pulmonary, oral or topical administration. More preferably, the novel composition is in the form of a dry powder inhaler or metered does inhaler and is intended to be administered by pulmonary, nasal or oral route, and is useful preferably in the treatment of inflammatory, allergic, and/or respiratory disorders such as asthma, or any other associated. disorders.
  • compositions of the present invention are highly stable and effective, and are substantially devoid of any toxic or side effects.
  • the present, invention provides novel anti-inflammatory, antiallergic and/or antiasthmatic pharmaceutical compositions comprising at least one alkaloid component derived from natural, semi-synthetic or synthetic source as active agent, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more other pharmaceutically acceptable excipient(s).
  • the major alkaloid component is preferably phenanthroindolizidine alkaloid(s) or its salts, esters, derivatives, isomers, hydrates or solvates derived from natural, semi-synthetic or synthetic source.
  • the phenanthroindolizidine alkaloid(s) is selected from but not limited to a group comprising tylophorine, tylophorinine and tylophorinidine or mixtures thereof, more preferably tylophorine.
  • the present invention provides novel anti-inflammatory, antiallergic and/or antiasthmatic pharmaceutical compositions comprising an extract of the plant Tylophora sp. as active agent which comprises tylophorine or its salts, esters, derivatives, isomers, hydrates or solvates as the major alkaloid component, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more another pharmaceutically acceptable excipient(s).
  • active agent which comprises tylophorine or its salts, esters, derivatives, isomers, hydrates or solvates as the major alkaloid component, either alone or in combination with other active agent(s), optionally with a vehicle and optionally with one or more another pharmaceutically acceptable excipient(s).
  • the present invention provides novel pharmaceutical compositions comprising at least one alkaloid component additionally with at least another component derived from natural, semi- synthetic or synthetic source as the active agent; their salts, esters, derivatives, isomers, hydrates or solvates optionally with a vehicle and optionally other pharmaceutically acceptable excipients, wherein the alkaloid component is selected from a group comprising tylophorine, saussurine, vasicine, and the like or mixtures thereof, and the other additional component is selected from the group comprising costunolide, forskolin, curcumin, boswellic acid, and the like or mixtures thereof.
  • Step 1 Collecting, drying and powdering the plant part(s),
  • Step 2 (Optional) Treatment of powdered dried plant part(s) with a mild aqueous alkali solution wherein the alkali is selected from but not limited to calcium hydroxide, ammonium hydroxide, sodium carbonate, ammonium carbonate, potassium carbonate and the like used either alone or in combination thereof.
  • a mild aqueous alkali solution wherein the alkali is selected from but not limited to calcium hydroxide, ammonium hydroxide, sodium carbonate, ammonium carbonate, potassium carbonate and the like used either alone or in combination thereof.
  • Step 3 Repeated extraction of the powdered dried plant part(s) (with or without alkali) with a polar to medium polar solvent selected from but not limited to acetone, methanol, ethanol, isopropanol, ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and like used either alone or in combination.
  • a polar to medium polar solvent selected from but not limited to acetone, methanol, ethanol, isopropanol, ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and like used either alone or in combination.
  • Step 4 Concentration of the combined polar solvent extracts to a syrupy mass.
  • Step 5 Extraction of the concentrated solvent extract with an aqueous acid solution wherein the acid is selected from but not limited to acetic acid, citric acid, tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like used either alone or in combination thereof and wherein the acidic extraction is repeated till the residue tests negative for alkaloids.
  • the acid is selected from but not limited to acetic acid, citric acid, tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like used either alone or in combination thereof and wherein the acidic extraction is repeated till the residue tests negative for alkaloids.
  • Step 6 Filtration of the combined acidic extracts and repeated washing of it with a medium to low polar solvent selected from but not limited to ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof.
  • a medium to low polar solvent selected from but not limited to ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof.
  • Step 7 Adjustment of the pH of the washed acidic extract to greater than 7.2 with an alkali wherein the alkali is selected from but not limited to sodium hydroxide, ammonium hydroxide, sodium carbonate, ammonium carbonate, potassium carbonate and the like used either alone or in combination thereof.
  • the alkali is selected from but not limited to sodium hydroxide, ammonium hydroxide, sodium carbonate, ammonium carbonate, potassium carbonate and the like used either alone or in combination thereof.
  • Step 8 Separation of the resultant precipitates (alkaloids) by a method selected from but not limited to decantation, filtration, centrifugation and the like used either alone or in combination thereof.
  • Step 9 (Optional) Repeated extraction of the alkaline extract after step 7, or the supernatant liquid after separation of the precipitate of step 8 with a medium to low polar solvent selected from but not limited to ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof; the medium to low polar solvent extract is further concentrated. dried to a powder form and optionally mixed with the separated precipitate of step 8.
  • a medium to low polar solvent selected from but not limited to ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof; the medium to low polar solvent extract is further concentrated. dried to a powder form and optionally mixed with the separated precipitate of step 8.
  • Step 10 (Optional) Dissolution of the alkaloids obtained from steps 8 and 9 in dilute aqueous acid solution, where the acid is selected from but not limited to acetic acid, citric acid, tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like used either alone or in combination thereof; thereafter steps 6 to 9 are repeated.
  • the acid is selected from but not limited to acetic acid, citric acid, tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like used either alone or in combination thereof; thereafter steps 6 to 9 are repeated.
  • Step 11 (Optional) Crystallization of the alkaloids obtained from steps 8, 9 or 10 from a solvent selected from but not limited to acetone, methanol, ethanol, isopropanol, ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof.
  • a solvent selected from but not limited to acetone, methanol, ethanol, isopropanol, ethyl acetate, ethyl methyl ketone, dichloromethane, chloroform, dichloroethane, butanol and the like used either alone or in combination thereof.
  • the extraction of the plant part(s) is carried out with aqueous acid solution, where the acid is selected from but not limited to acetic acid, citric acid, tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like used either alone or in combination thereof.
  • steps 6 to 1 1 are followed as stated herein above.
  • the extract in the present invention is either all parts of the plant i.e. the whole plant or one or more parts of the plant selected from but not limited to leaf, root, stem, and the like.
  • the process of preparation of salts of alkaloids such 0 as tylophorine (from Tvhphora aslhmatica). vasicine (from Adathoda va.sica). saussurine
  • Step 1 Collecting, drying and powdering the plant part(s),
  • Step 2 Preparation of an alkaloid rich extract as described herein above,
  • Step 3 Dispersion by rigorous shaking of alkaloid rich extract in aqueous acid solution 5 wherein the acid is selected from but not limited to sulphuric acid, hydrochloric acid, nitric acid, acetic acid, citric acid, tartaric acid, aspartic acid and the like.
  • Step 4 (Optional) Precipitation of alkaloid salt by addition of salts selected from but not limited to sodium chloride, potassium chloride, sodium sulphate, potassium nitrate and the like used either alone or in combination thereof.
  • Step 5 (Optional) Separation of the resultant alkaloid salt obtained from step 4 and 5 by a method selected from- but not limited to decantation, filtration, centrifugation and the like used either alone or in combination thereof.
  • Step 6 Repeated washing of alkaloid salt with a solvent selected from but not limited to absolute alcohol, methanol, chloroform, ethyl acetate, dichloromethane and the like used 35 either alone or in combination thereof.
  • Step 7 (Optional) Crystallization of alkaloid salt with polar solvents selected from but not limited to water, ethanol, methanol and the like used either alone or in combination.
  • alkaloids primarily comprising tylophorine was extracted from the plant Tylophora aslhmaiica using polar organic solvents such as methanol, ethanol, dichloroethane, or the like optionally followed by treatment with an acidic substance using conventional methods known to the art.
  • the extract obtained contained from about 40% to about 99% of alkaloids primarily as tylophorine.
  • the term 'tylophorine' as used herein unless otherwise specified refers to either pure tylophorine alone obtained by synthetic route or a tylophorine enriched extract obtained from the Tylophora plant. The pure compound i.e.
  • tylophorine was isolated by adsorbing it on a Column comprising aluminum oxide (neutral) or silica gel using hexane or hexane-chloroform mixture as the mobile phase. The fractions collected were monitored by TLC and those containing the pure compounds were pooled, dried and crystallized with solvents like methanol, acetone or hexane-ethyl acetate mixture to yield pure tylophorine.
  • the alkaloid tylophorine was isolated by preparative thin layer chromatography using silica gel TLC plate and solvent system toluene-ethyl acetate-diethylamine.
  • the tylophorine obtained by such extraction process melts between 280-284 0 C with decomposition. Also, the spectral data like Proton NMR, Carbon-13 NMR, Mass spectrum, UV and IR spectra were comparable to those reported for the pure compound in literature.
  • the tylophorine was synthesized by using 2,3- dimethoxyphenathrene-9-carboxylic acid as starting raw material, which on reduction with sodium borohydride was converted into 9-Hydroxymethyl-2,3- dimethoxyphenanthrene followed by Marchini and Belleau reaction (Can. J. Chem. 1958, 36, 581 ) to give 9-chloromethyl-2,3-dimethoxyphenanthrene.
  • Pharmacological study was carried out to ascertain the anti-asthmatic effect of tylophorine on Guinea Pigs weighing between 300-35Og of either sex.
  • the animals used in the study were fasted for 18 hours and anaesthetized with Urethane.
  • D-tubocurarine (3 mg/kg i.v.) was administered to prevent spontaneous respiratory movements.
  • the guinea pigs were artificially ventilated by a UGO Basile Rodent ventilator through a tracheal cannula at a rate of 60 strokes/minute and a stroke volume of 1 ml/100g.
  • Insufflation pressure was measured by attaching a pressure transducer (UGO Basile) to a Gemini two channel recorder ( 1 JGO Basile). A polyethylene catheter was inserted into the left jugular vein for i.v. administration of the drug. The animals were stabilized for 15 minutes. Guinea pigs were sensitized by i.m. injections of 0.35 ml of ovalbumin (5% w/v in saline solution) into each thigh (total 0.7 ml) on days 1 and 7. The guinea pigs were ready for use after day 25. Animals were challenged with 0.25 mg/kg and 0.50 mg/kg of ovalbumin and increase in insufflation pressure was noted. The guinea pigs were placed in chamber and exposed with nebulized dose of
  • 'N' denotes the number of guinea pigs
  • S. E. M. is the abbreviation for 'Standard Error of Mean'
  • 'Mixture' denotes a physical mixture of Tylophorine, Costunolide and Vasicine in equal proportions
  • composition of the present invention is in the form of a tablet, capsule, solution, suspension, patch, topical preparation or inhalable composition.
  • novel inhalable compositions of the present invention is administered preferably in the form of a dry powder
  • inhaler or metered dose inhaler is preferably intended to be administered by pulmonary, nasal or oral route, most preferably by inhalation, and is useful preferably in the treatment of respiratory disorders such as asthma.
  • the composition may preferably be in the form of solution, suspension or aerosol and may be formulated as dry powder inhaler (DPI), metered dose inhaler (MDI), nebulizer, spray or drops such as nasal spray or nasal drops.
  • DPI dry powder inhaler
  • MDI metered dose inhaler
  • nebulizer nebulizer
  • spray or drops such as nasal spray or nasal drops.
  • asthmatic patients are often treated by the administration of appropriate topically active medicines to the nose either by means of pressurized aerosol, liquid (usually aqueous) or dry powder formulations of the active ingredients).
  • the dry powder formulations are often the same as, or slight modifications of, inhalation formulations of the same active ingredient(s) for use in the treatment of the lung.
  • Such inhalation formulations contain the active ingredient(s) in
  • the formulation comprising alkaloid(s) according to the present invention may be administered using any known dry powder inhaler, for example the inhaler may be a single or a multidose inhaler, and may be a breath actuated dry powder inhaler.
  • the pharmaceutical composition comprises alkaloid(s) optionally with a vehicle and optionally with other
  • a method of using the composition wnicn comprises administering to a subject in need thereof an effective amount of the composition.
  • the compositions of the present invention can be used prophylactically for the prevention of inflammation, allergy and/or asthma or any other associated disorders or therapeutically for the treatment of inflammation, allergy and/or asthma or any other associated disorders such as arthritis, asthma or inflammatory bowel disease, chronic obstructive pulmonary disease(s), common cold or rhinitis.
  • the compositions are particularly useful for the prevention and/or treatment of inflammation, allergy and/or asthma or any other associated disorders, more particularly respiratory disorders such as asthma and/or chronic obstructive pulmonary disease(s).
  • the active agent(s) is diluted with a pharmaceutically acceptable vehicle in order to obtain a dosable unit amount meeting the demands on dosage accuracy.
  • a pharmaceutically acceptable vehicle for this purpose, the preferably microfine, inhalable active agent(s) particles are mixed with pharmacologically acceptable vehicle.
  • the dilution is chosen such that the amount applied from the powder inhaler exactly contains the desired dose.
  • the vehicle used in the present invention also serves for the adjustment of a flowability of the powder mixture and maintain homogeneity of the mixture.
  • the proportion of vehicle to the total formulation of the present invention is approximately 40 to 99.99% by weight, where, however, higher or lower proportions can also be advantageous depending on the active agent(s).
  • the vehicle used in the present invention is selected from but not limited to a group comprising monosaccharides such as glucose, arabinose; disaccharides such as trehalose, sucrose, lactose; polysaccharides such as starch, raffinose, melezitose; sugar alcohols such as lactitol. maltitol, man ⁇ itol, xylitol; polylactic acid, cyclodextrin, and dextran.
  • the vehicle used is lactose particularly in the form of its monohydrate preferably in micronized form.
  • surfactants including ionic and non-ionic surfactants, sorbitan esters such as sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate,
  • Polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, poloxamer, fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylaf.es, natural lecithin, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether, lauryl polyoxyethylene ether, block copolymers of oxycthylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrah yd rofti rfury 1 oleate. ethyl oleate, glyceryl monooleate, polyethylene glycol 400 and glyceryl monolaurate and the like or mixtures thereof are used in the composition.
  • lubricants such as calcium, magnesium and zinc salts of palinitic acid and stearic acid, sodium benzoate, colloidal silica, hydrogenated oil or fatty substances are used in the present invention preferably for the preparation of inhalation powders to improve flow and self-lubricating properties.
  • metal stearates such as magnesium stearate, zinc stearate or the like are used to provide the formulation with an improved resistance to moisture.
  • the dry powder inhalation compositions of the present invention can be in the form of unit dose powder inhalers which release the medicament from pre-dosed units, e.g. capsules or blister packs or multi-dose powder inhalers which contains a powder reservoir from which the individual doses are withdrawn by means of a dosage mechanism.
  • the ingredients of the formulation are in a finely divided form or micronized form having a particle size of 0.4-150 microns, preferably 1 - 60 microns.
  • the microparticles preferably are prepared by adding the lubricant to an aqueous solution of a part of the vehicle, granulating the remaining vehicle together with this mixture and sieving the granules obtained.
  • an inhalable medicinal aerosol formulation comprises an effective amount of alkaloid(s) and a pressure-liquefied homogeneous propellant mixture, comprising carbon dioxide and hydrofluoroalkane selected from the group consisting of 1,1 , 1 ,2-tetrafluoroethane; 1 ,1,1,2,3,3,3-heptafluoropropane; and 1 , 1,1 ,2-tetrafluoroethane in the presence of- 1 ,1 , 1 ,2,3, 3,3-heptafluoropropane, wherein the inhalable medicinal aerosol formulation is contained in a metered dose inhaler.
  • a pressure-liquefied homogeneous propellant mixture comprising carbon dioxide and hydrofluoroalkane selected from the group consisting of 1,1 , 1 ,2-tetrafluoroethane; 1 ,1,1,2,3,3,3-heptafluoropropane; and 1 , 1,1 ,2-tetrafluoroethane in the
  • the formulation comprises a co-solvent selected from but not limited to a group comprising water, ethanol, propanol, ethylene glycol, propylene glycol, propane, butane, isobutane, pentane, dimethyl ether and diethyl ether. Still further, the composition comprises surface-active agents.
  • a co-solvent selected from but not limited to a group comprising water, ethanol, propanol, ethylene glycol, propylene glycol, propane, butane, isobutane, pentane, dimethyl ether and diethyl ether.
  • the composition comprises surface-active agents.
  • Other conventional propellants such as dinitrogen monoxide, hydrocarbons and fluorocarbons or liquid carriers, such as ethanol, perchloroethylene, trichloroethylene, bis (difluoromethyl) ether, acetone, amyl acetate, water and the like can be added to the propellant system.
  • compositions comprising alkaloid particularly tylophorine additionally comprise other active agents .either alone or in combination obtained from natural sources including but not limited to vasicine (from Adathoda vasica), costunolide and saussurine (from Saiissurea lappa), curcumin (from Curcuma domestica), forskolin (from Coleiis forskohlii) and boswellic acid (from Boswellia serrat ⁇ ) or mixtures thereof.
  • vasicine from Adathoda vasica
  • costunolide and saussurine from Saiissurea lappa
  • curcumin from Curcuma domestica
  • forskolin from Coleiis forskohlii
  • boswellic acid from Boswellia serrat ⁇
  • the pharmaceutical compositions comprise at least one alkaloid component additionally with at least another component derived from natural, semisynthetic or synthetic source as the active agent; their salts, esters, derivatives, isomers, hydrates or solvates optionally with a vehicle and optionally other pharmaceutically acceptable excipients, wherein the alkaloid component is selected from a group comprising tylophorine, saussurine, vasicine, or mixtures thereof and the other additional component is selected from the group comprising costunolide, forskolin, curcumin, boswellic acid or mixtures thereof.
  • compositions comprises one or more other active ingredients used either alone or in combination thereof selected from but not limited to a group comprising antiarrhythmic drug, tranquilizer, cardiac glycoside, hormone, antihypertensive drug, antidiabetic or anticancer drug, sedative or analgesic drug, antibiotic, antirheumatic drug, immunotherapy, antifungal or antihypotensive drug, vaccine, antiviral drug, protein (e.g.
  • insulin insulin
  • peptide a cell surface receptor blocker
  • beta-mimetics beta-mimetics,- corticosteroids, anticholinergics, cyclooxygenase inhibitors, mast cell inhibitors, lipoxygenase and proteolytic enzyme inhibitors
  • arachidonic acid leukotriene, thromboxane, sodium/potassium channel blockers, neurokinin, tachykinin, bradykinin, muscarine, histamine, phosphodiesterase and selectin antagonists
  • potassium channel blockers anti- infective agents, cytostatics, fungi-statics, free-radical scavengers, vitamins, hormones, immunostimulants, immunosuppressants, mucolytics, heparin, analgesics and the like or their solvates, hydrates, derivatives, esters, isomers, enantiomers, racemates or pharmaceutically acceptable salts.
  • the additional active agent is selected from anticholinergics and spasmolytics such as atropine, scopolamine, N-butylscopolamine, trospium chloride, ipratropium bromide, oxitropium bromide, ihiotropium bromide, drofenine, oxybutynin, moxaverin, glycopyrrolate; mast cell inhibitors such as cromoglycic acid, nedocromil; and lipoxygenase inhibitors such as zileuton, leukotriene antagonists such as iralukast, zafirlukast and pranlukast;.
  • anticholinergics and spasmolytics such as atropine, scopolamine, N-butylscopolamine, trospium chloride, ipratropium bromide, oxitropium bromide, ihiotropium bromide, drofenine, oxybutynin, moxa
  • sodium channel antagonists such as amiloride; potassium channel antagonists such as bimakalim; arachidonic acid antagonists such as 2- benzoxazolamine; histamine receptor antagonists such as epinastine, cetirizine, mizolasline and mequitamium; antimigraine agents such as ergot alkaloids, methysergide, ergotamine, serotonin, sumatriptan, zolmitriptan, cyclandelate; analgesics such as fentanyl, morphine, buprenorphine, opium, heroin, nalbuphine, pentazocine, oxycodone, tramadol, pethidine, tilidine, methadone, nefopam, dextropropoxyphene, piritramide; mucolytics such as RNase, acetylcysteine, ambroxol, apafant, bromhexine; or antiemetics such as bromo
  • the other active agent(s) is a steroid such as beclomethasone, betamethasone, ciciomethasone, dexamethasone, flunisolide, triamcinolone acetonide, fluticasone propionate, ciclesonide, budesonide.
  • rofleponide mometasone, tipredane, RPR 106541. terbutaline, salbutamol.
  • a metered dose inhaler composition is prepared by mixing the active agent(s) comprising at least one alkaloid with a suitable vehicle and optionally other pharmaceutically acceptable excipient(s) such as a lubricant to obtain a homogeneous mixture followed by micronization of the mixture to produce the bulk material, which is then filled into a suitable metered dose inhaler.
  • a multidose MDI or DPI is prepared in the form of capsule comprising a mixture of active agent(s).
  • Aerosol for inhalation is prepared comprising the active agent(s) preferably in the micronized form alongwith a suitable vehicle or a propellant system preferably dispensed into aluminium containers sealed with metering valves by means of the pressure-filling technique.
  • Nebulizable dispersions or solutions for atomization are prepared by dispersing the active agent(s) homogeneously in a hydro-alcoholic solvent system such as ethanol-purified water mixture.
  • Inhalation suspension compositions are prepared by wetting the active agent(s) with a wetting agent such as surfactant followed by addition of optionally other pharmaceutically acceptable excipient(s), sterilization of the bulk filling into sterile containers, for example unit dose containers such as vials or ampoules which are suitably molded from thermoplastics.
  • compositions for delivery of the active agent(s) by the nasal route prepared as nasal spray or drops is prepared by mixing the active agent(s) with vehicle and optionally other excipient(s) such as solubilizing agents and preservatives, dissolving the mixture in sterile hydro-alcoholic mixture such as a mixture comprising purified water and ethanol.
  • injectable compositions are prepared by dispersing the active agent(s) in a hydroalcoholic solvent system such as a mixture comprising water and ethanol by rapid and continuous stirring to obtain a homogeneous dispersion, which is then filtered, sterilized and filled into suitable containers.
  • compositions of the present invention can be formulated as oral dosage forms such as tablets, capsules, solutions, suspensions, patches, topical preparations, parenteral preparations and the like.
  • excipients can be used for such compositions such as diluents, disintegrants, binders, fillers, bulking agents, anti-adherants, antioxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like known to the art used either alone or in combination thereof.
  • the diluents is selected from but not limited to a group comprising lactose, cellulose, microcrystalline cellulose, mannitol, dicalcium phosphate, pregelatinized starch, and the like, used either alone or in combination thereof; polymers such as cellulosic derivatives, polyalkylene oxides, acrylic acid and methacrylic acid polymers, crosslinked polyacrylic acids, polysaccharide gums such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginic acid, alginates, benitonite, arabin ⁇ glactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, and the like or mixtures thereof; used alone or in combination; lubricant such as magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium
  • beeswax camauba wax
  • cetyl alcohol glyceryl stearate
  • glyceryl palmitate glyceryl behenate
  • hydrogenated vegetable oils and stearyl alcohol and the like used either alone or in combination thereof.
  • a process for the preparation of such novel composition which comprises of the following steps: i) mixing the active agent(s) optionally with a vehicle, ii) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulating the mixture into a suitable dosage form.
  • a process for the preparation of such novel composition which comprises of the following steps: i) micronizing the active agent(s) and vehicle(s), ii) mixing the micronized active agent(s) with micronized vehicle(s), iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iv) formulating the mixture into a suitable dosage form.
  • a process for the preparation of such novel composition which comprises the following steps: i) mixing the active agent(s) and vehicle(s), ii) micronizing the mixture of active agent(s) and vehicle(s), iii) optionally adding one or more other pharmaceutically acceptable excipients, and iv) formulation of the mixture into a suitable dosage form.
  • the invention further provides use of alkaloid(s) in the manufacture of a medicament for use in therapy.
  • the composition according to the invention is useful in the treatment of respiratory disorders, more particularly asthma and/or chronic obstructive pulmonary disease(s).
  • the present invention also provides a method of treating a subject or patient suffering from a respiratory disorder, which comprises administering to the patient a therapeutically effective amount of a composition according to the invention.
  • the examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention.
  • Example-l Extraction of tylophorine rich extract from Tyhphora asthmalica leaves Powdered Tyhphora aslhmalica leaves (5 kg) were refluxed with 25 L ethanol (90% v/v) four times for I h each time. Pooled ethanol extracts were dried under vacuum to get a semisolid mass. This mass was extracted thrice with 2% v/v aqueous sulphuric acid ( 1.5 L) by stirring. Pooled acidic aqueous extract was filtered. The filtrate was washed thrice with 1 L ethyl acetate in a separating funnel. Ethyl acetate layer was discarded.
  • Aqueous layer was taken and basified to pH ⁇ 9 by addition of saturated solution of sodium hydroxide. This process resulted in formation of precipitates, which were separated by centrifugation at 4000 rpm for 15 minutes. The precipitates were washed thrice with 1 L distilled water and dissolved in 2% v/v aqueous sulphuric acid (1 L). Aqueous layer was again basified to pH ⁇ 9 by addition of saturated solution of sodium hydroxide. The precipitates formed were separated by centrifugation at 4000 rpm for 15 minutes and dried under vacuum in desiccator to get dry powder ( ⁇ 9 g, tylophorine content 32.14% w/w).
  • the dried powder was further purified by extracting twice with 80% ethanol (500 ml) for I h each time on magnetic stirrer. Residue obtained after filtration of above extract was crystallized in a mixture of chloroform and ethanol (1 :4). Finally, crystallized material was separated, dried, and powdered (3.1 g, tylophorine content 85%).
  • Example-3 Extraction of vasicine rich extract from Adhatoda vasica leaves Powdered Adhatoda vasica leaves (5 kg) were moistened with distilled water and mixed with lime (1.5 kg). This was refluxed with 25 L chloroform four times for I h each time. Pooled chloroform extracts were concentrated to 2 L under vacuum. Chloroform extract was fractionated thrice with 2% v/v aqueous sulphuric acid in a separating funnel. Pooled aqueous layer was washed thrice with 1 L ethyl acetate in a separating funnel. Aqueous layer was basified to pH ⁇ 9 by addition of saturated solution of sodium hydroxide.
  • Aqueous layer was fractionated thrice with I L chloroform. Pooled chloroform layer was washed thrice with 1 L distilled water, dehydrated by treating with anhydrous sodium sulphate and dried under vacuum ( ⁇ -70 g, vasicine content 65% w/w).
  • Tylophorine base ( 1O g, purity 86.96%) was dissolved in 2% v/v aqueous sulphuric acid (5 L).
  • Tylophorine sulphate was precipitated from the solution by adding sodium chloride (10 g), and precipitates were separated by centrifugation at 4000 rpm for 15 minutes. The precipitates were washed with absolute alcohol till washings test negative for acid on pH paper. Further, repeated washings were given to the precipitates (tylophorine sulphate) with chloroform in order to remove presence of unchanged tylophorine base.
  • Tylophorine sulphate was crystallized in 70% v/v aqueous ethanol. Finally 5 g of tylophorine sulphate (purity 79.0%) was obtained.
  • Tylophorine base (1O g, purity 86.96%) was dissolved in 5% w/v aqueous citric acid (5 L).
  • Tylophorine citrate was precipitated from the solution by adding sodium chloride (10 g), and precipitates were separated by centrifugation at 4000 rpm for 15 minutes. The precipitates were washed with absolute alcohol till washings test negative for acid on pH paper. Further, repeated washings were given to the precipitates (tylophorine citrate) with chloroform in order to remove presence of unchanged tylophorine base. Finally 4 g of tylophorine citrate (purity 63.82%) was obtained.
  • Vasicine base (10 g, purity 65%) was shaken rigorously by stirring on magnetic stirrer for
  • Tylophorine base ( 1 O g, purity 86.96%) was shaken rigorously by stirring on magnetic stirrer for 12 hours with 20% aqueous hydrochloric acid (5 L). This treatment resulted in formation of precipitates of tylophorine chloride. These precipitates were separated by centrifugation at 4000 rpm for 15 minutes. The precipitates were washed with absolute alcohol till washings test negative for acid on pH paper. Further, repeated washings were given to the precipitates (tylophorine chloride) with chloroform in order to remove presence of unchanged tylophorine base. Finally 6 g of tylophorine chloride (purity 75.15%) was obtained.
  • 92.262% w/w of lactose and 7.45% w/w of micronized lactose are mixed in a tumbling mixer. 0.288% w/w of micronized tylophorine and said mixture are mixed to obtain an evenly distributed mixture.
  • the powder is then agglomerated by feeding the powder into a twin screw feeder, sieving in an oscillating sieve, spheronising in a rotating pan and then sieving again using the same sieve to obtain the bulk material which is then filled into a hard gelatin capsule and can be made into a suitable Dry Powder inhaler product.
  • tylophorine and 3 parts of lactose monohydrate are mixed in a tumbling mixer to obtain an evenly distributed mixture, whereafter the mixture is micronized in a spiral jet mill.
  • the powder is then agglomerated by feeding the powder into a twin screw feeder, sieving in an oscillating sieve, spheronising in a rotating pan and then sieving again using the same sieve to obtain the bulk material which is then filled into a suitable inhaler.
  • tylophorine 0.12 parts of vasicine, 4 parts of mannitol and 0.12 parts of zinc stearate are mixed in tumbling mixer to an evenly distributed mixture followed by micron ization of the mixture in a spiral jet mill.
  • the bulk material is then filled into a dry powdered inhaler.
  • micronized tylophorine 600 mg of micronized tylophorine, 400 mg of micronized ciclesonide and 10 mg of micronized sorbitan trioleate are dispersed in 100 ml of elhanol.
  • the micronized suspension of particles and a 1 : 1 mixture of propella ⁇ ts comprising trichlorofluoromethane and dichlorotetrafluoromethane are filled into a metered dose inhaler.
  • Example-12 Multidose metered inhaler
  • a capsule is prepared with a mixture of micronized tylophorine 0.12 mg and micronized Lactose 20 mg and incorporated into a suitable multidose metered inhaler.
  • Example-13 Aerosol for inhalation
  • micronized tylophorine 2.2 mg are weighed into a pressure addition vessel. After sealing and evacuation thereof, suitable quantity of 1 , 1 , 1 ,2-tetrafluoroethane is added. After homogenization of this mixture, the suspension obtained is dispensed into aluminium containers sealed with metering valves by means of the pressure-filling technique.
  • Example-14 Pressurized aerosol for oral and nasal inhalation
  • Tylophorine micronized 0.1% w/w and Salbutamol micronized 0.1% w/w are mixed together and to the said mixture Dichlorotetrafluoroethane 49.2% w/w and Dichlorodifluoromethane 50% w/w are added followed by dispensing into metered aluminium containers.
  • Example-15 Nebulizable dispersion Saussurine 0.06 mg, Formoterol fumarate 0.012 mg and Propylene glycol 5.0 g are dispersed homogeneously in Purified water 10.0 g. The said dispersion is filled into a suitable container for atomization such as a nebulizer.
  • Example-16 Solution for Atomization Tylophorine 0.06 mg and Costunolide 0.05 mg are dispersed homogeneously in Ethanol- Purified water mixture (2.0 g & 6.0 g respectively); the said dispersion is filled into a suitable container.
  • Example-17 Inhalation suspension
  • the active agents namely 0.06 mg/ml of Tylophorine and 0.525 mg/ml Fluticasone propionate micronised are wetted with a surfactant solution consisting of 0.1 O- mg/ml Polyoxyethylene sorbitan monolaurate and 0.01 mg/ml Sorbitan monolaurate.
  • 8.6 mg/ml Monopotassium phosphate, 1.4 mg/ml Dibasic potassium phosphate and 3.8 mg/ml Potassium chloride are dissolved in water with stirring to obtain a homogeneous bulk.
  • the active agents wetted with surfactants are then added to the bulk with constant mixing to obtain a homogeneous suspension.
  • the bulk suspension is sterilized, preferably by thermal sterilization using . steam. Aliquots of the suspension are filled into stail ⁇ containers, for example unit dose containers such as vials or ampoules which are suitably molded from thermoplastics.
  • a composition in the form of a nasal drop is prepared containing Tylophorine hydrochloride 0.1%, Beta-cyclodextrin 1.0% and Mannitol 5.0%.
  • the said composition is dissolved in sterile hydro-alcoholic mixture consisting of Purified water 8 ml and ethanol 2 ml to give a nasal drop (total amount 10 ml).
  • Conventional additives such as preservatives can be added as necessary.
  • Tylophorine, Zafirlukast, Mannitol and Croscarmellose sodium are sifted through 425 micron sieve.
  • step (1) Material of step (1) is granulated in a Rapid Mixer Granulator (RMG) using a solution of Polyvinylpyrrolidone in Purified water. 3. The granules are dried in Fluidized Bed Dryer (FBD) followed by sifting the dried granules through 600 micron sieve.
  • RMG Rapid Mixer Granulator
  • BBD Fluidized Bed Dryer
  • Magnesium stearate is sifted through 250 micron sieve and mixed with material of step (3).
  • step (4) The material of step (4) is compressed into tablets.
  • step (1 ) The material of step (1 ) is granulated in a Rapid Mixer Granulator (RMG) using a solution of Polyvinylpyrrolidone in Purified water.
  • RMG Rapid Mixer Granulator
  • the granules are dried in Fluidized Bed Dryer (FBD) followed by sifting the dried granules through 600 micron sieve.
  • BBD Fluidized Bed Dryer
  • Magnesium stearate is sifted through 250 micron sieve and mixed with the material of step (3).
  • step (4) The material of step (4) is compressed into tablets.
  • Vasicine, Nimesulide, Cetirizine, Microcrystalline cellulose, Corn starch and Hydroxypropyl methylcellulose are sifted through 425 micron sieve.
  • step (1) Material of step (1) is mixed in polygonal blender to obtain a uniform mixture.
  • Sodium stearyl fumarate and Colloidal silicon dioxide are sifted through 250 micron sieve and mixed with the material of step (2) in a blender.
  • step (3) The material of step (3) is compacted and filled into a hard gelatin capsule.
  • step (3) The material of step (3) is cooled to room temperature to obtain the desired product.
  • Soft paraffin, Liquid paraffin and Sorbitan monooleate are mixed at about 45°C by continuous stirring to obtain a homogeneous dispersion.
  • step (3) to step (2) is added with continuous stirring at about 45°C followed by the addition of the remaining part of Purified water and stirring.
  • step (4) The material of step (4) is cooled to room temperature to obtain the desired product.

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Abstract

Compositions pharmaceutiques antiinflammatoires, antiallergiques et/ou antiasthmatiques comprenant au moins un ou plusieurs composants alcaloïdes dérivés d'une source naturelle, semi-synthétique ou synthétique, comme principe actif, soit isolément soit en combinaison avec un ou plusieurs autres principes actifs, éventuellement avec d'autres excipients pharmaceutiquement acceptables. On décrit aussi des procédés d'élaboration et d'utilisation correspondants. De préférence, ce type de composition se présente sous la forme d'inhalateur à poudre sèche ou d'aérosol-doseur, de préférence aux fins d'administration par voie pulmonaire, nasale ou orale, et de préférence encore par inhalation, utile pour la prévention ou le traitement, notamment de troubles inflammatoires, allergiques et/ou respiratoires du type asthme et/ou maladie(s) pulmonaire(s) obstructive(s) chronique(s), ou tout autre trouble associé.
PCT/IN2006/000408 2005-10-18 2006-10-17 Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede WO2007046113A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2012146194A1 (fr) * 2011-04-29 2012-11-01 Industrial Technology Research Institute Extraits de cynanchum sp. et principes actifs contenus dedans, utilisés dans le traitement de l'arthrite
CN103408557A (zh) * 2013-08-19 2013-11-27 南京大学 一类吲哚里西啶生物碱及其制备方法和应用
WO2016178101A1 (fr) * 2015-05-06 2016-11-10 Eid Parry (India) Limited Composition bio-stimulante pour favoriser la croissance de plantes et procédé de préparation correspondant
WO2024252238A1 (fr) * 2023-06-06 2024-12-12 HASSEN, Mohammed, Ameen Traitement du psoriasis

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012146194A1 (fr) * 2011-04-29 2012-11-01 Industrial Technology Research Institute Extraits de cynanchum sp. et principes actifs contenus dedans, utilisés dans le traitement de l'arthrite
GB2498677A (en) * 2011-04-29 2013-07-24 Ind Tech Res Inst Extracts of cynanchum SP.and active ingredients contained therein in use of arthritis treatment
US9549958B2 (en) 2011-04-29 2017-01-24 Industrial Technology Research Institute Extracts of Cynanchum sp. and active ingredients contained therein in use of arthritis treatment
CN103408557A (zh) * 2013-08-19 2013-11-27 南京大学 一类吲哚里西啶生物碱及其制备方法和应用
CN103408557B (zh) * 2013-08-19 2015-04-29 南京大学 一类吲哚里西啶生物碱及其制备方法和应用
WO2016178101A1 (fr) * 2015-05-06 2016-11-10 Eid Parry (India) Limited Composition bio-stimulante pour favoriser la croissance de plantes et procédé de préparation correspondant
KR20170139488A (ko) * 2015-05-06 2017-12-19 이아이디 패리 (인디아) 리미티드 개선된 식물 성장을 위한 생물자극제 조성물 및 이의 제조방법
US10624352B2 (en) 2015-05-06 2020-04-21 Coromandel International Limited Bio-stimulant composition for improved plant growth and the process of preparing the same
US11122809B2 (en) 2015-05-06 2021-09-21 Coromandel International Limited Bio-stimulant composition for improved plant growth and the process of preparing the same
KR102565972B1 (ko) 2015-05-06 2023-08-10 이아이디 패리 (인디아) 리미티드 개선된 식물 성장을 위한 생물자극제 조성물 및 이의 제조방법
WO2024252238A1 (fr) * 2023-06-06 2024-12-12 HASSEN, Mohammed, Ameen Traitement du psoriasis

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