WO2020058785A1 - Formulation de complexe amphiphile comprenant de multiples principes actifs et formes pharmaceutiques associées - Google Patents

Formulation de complexe amphiphile comprenant de multiples principes actifs et formes pharmaceutiques associées Download PDF

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WO2020058785A1
WO2020058785A1 PCT/IB2019/056963 IB2019056963W WO2020058785A1 WO 2020058785 A1 WO2020058785 A1 WO 2020058785A1 IB 2019056963 W IB2019056963 W IB 2019056963W WO 2020058785 A1 WO2020058785 A1 WO 2020058785A1
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complex formulation
active ingredients
amphiphilic complex
phospholipid
blend
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PCT/IB2019/056963
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English (en)
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Tejaswini Ashish KALKUNDRI
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Kalkundri Tejaswini Ashish
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/235—Foeniculum (fennel)
    • 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)
    • A61K36/58—Meliaceae (Chinaberry or Mahogany family), e.g. Azadirachta (neem)
    • 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)
    • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present disclosure pertains to technical field of amphiphilic complex formulations comprising active ingredients.
  • the present disclosure pertains to amphiphilic complex formulation comprising multiple active ingredients, compositions comprising the same, and dosage form thereof for the management of oral sub-mucosal fibrosis.
  • Oral submucous fibrosis is a chronic debilitating disease of the oral cavity. It is a precancerous condition and is resistant disease manifested by inflammation and progressive fibrosis of the submucosal tissues. Oral submucous fibrosis leads to lack of blood supply, marked rigidity and an eventual inability to open the mouth.
  • Oral submucous fibrosis occurs mainly in India and the major etiology is chronic chewing of tobacco or areca nut or both. Other factors such as nutritional deficiencies, genetics and immunology are believed to play a role in the etiopathogenesis of oral submucous fibrosis. Associated with this condition is also oropharyngeal cancer, also with a high frequency in India and associated in 70% of cases with chewing tobacco. Smokeless tobacco and areca nut usage is also common in Pakistan, Bangladesh and Java and in these and Indian immigrants to the United States and United Kingdom.
  • aspects of the present disclosure relate to a simple, effective, and patient friendly regimen for the management of oral submucous fibrosis.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients for management of oral sub-mucosal fibrosis.
  • the present disclosure provides an amphiphilic complex formulation comprising a multiple active ingredients complexed with phospholipid in a specific ratio.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein the multiple active ingredients are entrapped in a phospholipid. In one aspect, the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein multiple active ingredients are incorporated in a phospholipid bilayer.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein the multiple active ingredients comprise the extracts of neem, fennel, clove, and curcuminoids in a specific ratio.
  • the multiple active ingredients comprise the extract of neem: extract of fennel: extract of clove: curcuminoids in a specific ratio, wherein the extract of neem, the extract of fennel, and the extract of clove individually vary from 1 to 12 and the curcuminoids vary from 0.5 to 4.
  • the present disclosure provides an amphiphilic complex formulation comprising the extracts of neem, fennel, clove, and curcuminoides entrapped within the phospholipid, wherein the blend of extracts of neem, fennel, clove, and curcuminoids are present in relation to the phospholipid in a specific ratio, wherein the phospholipid ranges from about 1.1 to 2 and the blend of active ingredients ranges from 1 to 2.
  • the present disclosure provides a composition comprising the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phospholipid ranging from about 15% to about 85%; and pharmaceutically acceptable excipients.
  • the present disclosure provides a dosage form for providing targeted delivery of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phospholipid for management of oral sub-mucosal fibrosis
  • the present disclosure provides a dosage form for example mouth dissolving tablets for providing targeted delivery of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phospholipid; and suitable excipient(s).
  • the present disclosure provides a dosage form for example mucoadhesive buccal film comprising for providing targeted delivery of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phospholipid; and suitable excipient(s).
  • FIGURE 1 It is FTIR spectra of the blend of active ingredients consisting of extracts of neem, fennel, and clove, and curcuminoides as per one exemplary embodiment of the present invention.
  • FIGURE 2 It is FTIR spectra of the phosphatidylcholine.
  • FIGURE 3 It is FTIR spectra of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phosphatidylcholine in different ratios.
  • FIGURE 4 Is a plot showing the absorbance obtained through UV spectroscopy of the various concentrations of blend of active ingredients, elucidating entrapment of 95% the active ingredients in the phosphatidylcholine as per one of the exemplary embodiment of the present invention.
  • FIGURE 5 It is a phase transition plot obtained by DSC, showing the phase transition temperature of the blend of active ingredients at 126 °C as per one of the exemplary embodiment of the present invention.
  • FIGURE 6 It is a phase transition plot obtained by DSC, showing the phase transition temperature of phosphatidylcholine at 189 °C.
  • FIGURE 7 It is a phase transition plot obtained by DSC, showing an increase in the phase transition temperature of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phosphatidylcholine as per one of the exemplary embodiment of the present invention to be 246.7°C.
  • FIGURE 8 It is a photomicrograph showing more or less spherical shaped amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phosphatidylcholine as per one of the exemplary embodiment of the present invention.
  • FIGURE 9 Is a graph showing the polydispersity index of 0.513 and a zeta potential of -33.9mV of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phosphatidylcholine as per one of the exemplary embodiment of the present invention.
  • FIGURE 10 Is a 1H NMR spectra of the phosphatidylcholine.
  • FIGURE 11 Is a 1H NMR spectra of the amphiphilic complex formulation comprising the extracts of neem, fennel, and clove, and curcuminoides entrapped within the phosphatidylcholine as per one of the exemplary embodiment of the present invention.
  • FIGURE 12 Is a 31 P NMR spectra of the phosphatidylcholine.
  • FIGURE 13 Is a 31 P NMR spectra of the amphiphilic complex formulation comprising multiple active ingredients as per one of the exemplary embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term“about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
  • inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
  • the present disclosure relates to an amphiphilic complex formulation comprising multiple active ingredients for management of oral sub-mucosal fibrosis.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein a blend of multiple active ingredients is incorporated in a phospholipid bilayer.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein a blend of multiple active ingredients is incorporated within phospholipid, wherein the mean particle size of the amphiphilic complex formulation ranges from about 185 nm to 3 m. In one embodiment the mean particle size of the amphiphilic complex formulation ranges from about 0.5 m to about 3 m. In one embodiment the mean particle size of the amphiphilic complex formulation ranges from about 185 nm to about 500 nm. In one embodiment the mean particle size of the amphiphilic complex formulation ranges from about 200 nm to about 300 nm.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein a blend of multiple active ingredients is incorporated in a phospholipid bilayer in the form of nanophytosomes having mean particle size ranging from about 185 nm to about 500 nm.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein a blend of multiple active ingredients is incorporated in a phospholipid bilayer in the form of nanophytosomes having mean particle size ranging from about 200 nm to about 300 nm.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein a blend of multiple active ingredients is incorporated in a phospholipid bilayer in the form of phytosomes having mean particle size ranging from about 0.5 m to about 3 m.
  • the present disclosure provides an amphiphilic complex formulation comprising multiple active ingredients, wherein the extracts of: neem, fennel, and clove, and curcuminoids are complexed and incorporated in a phospholipid bilayer.
  • the extract of neem is an extract of leaves of Azadirachta indica.
  • the extract of fennel is an extract of fruits of Foeniculum vulgare.
  • the extract of clove is an extract of Syzygium aromaticum.
  • These extracts can be aqueous extracts, or solvent extracts or water and solvent mixture extracted extracts commercially available in unrecognizable and physically inseparable form in a liquid, a paste, or a powder, a granule, or any other form.
  • the curcuminodies used is the family of compounds namely curcumin and derivative thereof.
  • the curcuminoids can be an organic solvent extracted fraction of rhizomes of Curcuma longa, for example the curcuminoids can be commercially available ethyl acetate extracted fraction of rhizomes of Curcuma longa, in unrecognizable and physically inseparable form in liquid, a paste, or a powder, a granule, or any other form.
  • the neem extract, the fennel extract, the clove extract and curcuminoids can be present in any suitable ratio to impart the desired activity. In an embodiment the neem extract, the fennel extract the clove extract, and curcuminoids can be present in the mixture in a defined ratio with respect to each other.
  • the blend of multiple active ingredients comprises the mixture of neem extract, fennel extract, clove extract and curcuminoids in defined ratio, wherein the neem extract, fennel extract, clove extract ranges from about 0.5 to 12 and the curcuminoids is present in the range of 0.5 to 4.
  • the neem extract, fennel extract, clove extract and curcuminoids are in the ratio ranging from about 1:1:1:05 to about 12:12:12:4.
  • the neem extract, fennel extract, clove extract and curcuminoids are in the ratio of about 6:6:6:2.
  • the phospholipid to be used in the amphiphilic complex formulation can be any phospholipid suitable to entrap the blend of active ingredients.
  • the phospholipid can be a phospholipid having structure which can incorporate or entrap the active ingredients in a phospholipid, for example in a bilayer.
  • the phospholipid is phosphatidylcholine.
  • the amphiphilic complex formulation comprises a blend of multiple active ingredients and a phospholipid in a defined ratio.
  • the ratio of the phospholipid for example phosphatidylcholine to the blend of active ingredients can be ranging from about 1.1:1 to about 2:1.
  • the ratio of the phospholipid for example phosphatidylcholine to the blend of multiple active ingredients can be about 1.1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or 2:1.
  • amphiphilic complex formulation comprising multiple active ingredients can have a polydispersity index of about 0.35 to about 0.75.
  • amphiphilic complex formulation comprising multiple active ingredients exhibit a zeta potential of about -25mV to about -45mV.
  • amphiphilic complex formulation comprising multiple active ingredients can be prepared by employing any suitable method capable of sufficiently complexing with or entrapping the active ingredients in phospholipid.
  • the amphiphilic complex formulation comprising multiple active ingredients entrapped in the phospholipid is prepared using suitable solvent by reflux method for example an anti-solvent method.
  • the present disclosure provides a method for preparing the an amphiphilic complex formulation comprising multiple active ingredients entrapped in phospholipid, in which said method comprises: providing a solution of the multiple active ingredients and phospholipid in a defined ratio in a suitable solvent; refluxing the solution comprising the blend of active ingredients and phospholipid at an appropriate temperature and sufficient time for entrapment or incorporation of the active ingredients in a phospholipid; separating the solvent and drying the complex of active ingredients and phospholipid by a suitable technique; and using the suitable solvent precipitating the amphiphilic complex formulation comprising multiple active ingredients.
  • the solution of the blend of multiple active ingredients and phospholipid in a defined ratio in a suitable solvent can be obtained by dissolving the blend of active ingredients and phospholipid in a defined ratio separately and mixing the solutions comprising the dissolved active ingredients and phospholipid for example phosphatidylcholine.
  • the solvent that can be used in the method in accordance with the present disclosure can be any solvent capable of dissolving the active ingredients and phospholipid for example phosphatidylcholine.
  • the solvent to prepare the solution of the active ingredient and phospholipid can be a solvent selected from but not limiting to methanol, ethanol, propanol, water, hydroalcohol containing mixture of water and alcohol containing 1-3 carbon, ethylacetate, or the like or the mixture thereof.
  • the solution comprising the blend of active ingredients and phospholipid can be refluxed at a temperature from about 50°C to about 70°C, or an appropriate temperature depending upon the solvent used.
  • the time for which the solution comprising the blend of active ingredients and phospholipid can be refluxed from about 2 hours to about 4 hours.
  • separating the solvent can be carried out by evaporation and condensation of separated solvent for example by using rotary evaporator to obtain the complex of active ingredients and phospholipid in dried form.
  • the amphiphilic complex formulation comprising multiple active ingredients can be obtained in dried form by precipitating the amphiphilic complex formulation comprising the multiple ingredients entrapped in phospholipid using a suitable solvent selected; and drying the precipitate.
  • the solvent used for precipitating the amphiphilic complex formulation is selected from but not limiting to hexane, tetrahydrofuran, or the like, or the mixture thereof.
  • amphiphilic complex formulation comprising the multiple active ingredients including the neem extract, fennel extract, clove extract, and curcuminoids entrapped in the phospholipid for example phosphatidylcholine exhibited potent anti-proliferation activity on human sublingual cancer cell line at around 9.6 ul, which is the least concentration compared to the individual active ingredients, or the blend of active ingredients with mixture of extracts of neem, fennel, clove extract, and curcuminoids in ratio of 6:6:6:2.
  • amphiphilic complex formulation comprising the multiple active ingredients incorporated in a phospholipid bilayer in accordance with the present disclosure unexpectedly provides significantly less toxic and potent anti-proliferation therapeutic regimen for management of oral sub-mucosal fibrosis.
  • the present disclosure provides a composition comprising the amphiphilic complex formulation comprising the multiple active ingredients including the extracts of neem, fennel, clove, and curcuminoids incorporated in the phospholipid in an amount ranging from about 15% to about 85% by weight of the composition; and one or more pharmaceutically acceptable excipient.
  • the present disclosure provides a dosage form for providing targeted delivery of the amphiphilic complex formulation comprising a blend of multiple active ingredients comprising extracts of: neem, fennel, clove, and curcuminoids; and a phospholipid, in an amount ranging from 15% to 85% by weight of the dosage form; and pharmaceutically acceptable excipients for management of oral sub-mucosal fibrosis.
  • the present disclosure provides a dosage form for providing targeted delivery of the amphiphilic complex formulation comprising the multiple active ingredients comprising the extracts of neem, fennel, clove, and curcuminoids entrapped in phospholipid in a daily dose of about 300 mg to about 550 mg for management of oral sub-mucosal fibrosis.
  • the present disclosure provides a dosage form for providing targeted delivery of the amphiphilic complex formulation comprising the multiple active ingredients comprising the extracts of neem, fennel, clove, and curcuminoids entrapped in phospholipid in a daily dose of about 350 mg to about 450 mg for management of oral sub-mucosal fibrosis.
  • the dosage forms comprising the amphiphilic complex formulation comprising the multiple active ingredients entrapped in phospholipid in accordance with the present disclosure can be oral or topical dosage forms.
  • the dosage form is selected from but not limiting to tablets, capsules, soluble granules, gel, suspensions, films, wafers, patches, or the like.
  • the tablet dosage form can be fast dissolving tablets or dispersible tablets.
  • the dosage form is fast dissolving tablet, especially mouth dissolving tablet.
  • the present disclosure provides a dosage form in the form of mouth dissolving tablets comprising the amphiphilic complex formulation of the multiple active ingredients incorporated in phospholipid in accordance with the present disclosure, ranging from about 15% to about 85% by weight of the tablet; and pharmaceutically acceptable excipient(s).
  • the pharmaceutically acceptable excipients that may be used in mouth dissolving tablets dosage form can be selected from but not limiting to a bulking agent, a binder, a disintegrating agent, a lubricant, a surfactant, a dry binder, a coloring agent, a flavoring agent a sweetening agent, a souring agent, a stabilizing agent, and an antioxidant.
  • the bulking agent employed may be one or more selected from the group consisting of but not limiting to polysaccharide, saccharide, starch, sugar alcohol, cellulose derivative, or a mixture thereof.
  • the binder is selected from but not limiting to the group consisting of mannitol, fructose, lactose, maltose, maltitol, sorbitol, erythritol, xylitol, isomalt, sucrose, dextrin, maltodextrin, dextrose, starch, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate or the like.
  • the bulking agent and binding agent may be the same in some embodiments.
  • the bulking agent may be present in an amount ranging from about 50% to about 98% by weight of the tablet.
  • the disintegrating agent especially the one of the type superdisintegrant may be used in the mouth dissolving tablets.
  • the superdisinegrant may be selected from the group consisting of but not limiting to crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, or the like.
  • the superdisintegrant may be present in an amount ranging from about 1% to about 10% by weight of the tablet.
  • the lubricanting agent may be one or more selected from the group consisting of but not limiting to stearic acid, magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, silicon dioxide, talc, sugar ester, sodium stearyl fumarate, magnesium silicate, poly(ethylene glycol), polyoxypropylene -polyoxyethylene block copolymer, colloidal silicon dioxide, sucrose esters of fatty acids or the like.
  • the lubricanting agent may be present in an amount ranging from about 0% to about 5% by weight of the tablet.
  • the mouth dissolving tablet may include the pharmaceutical acceptable excipients more than 50% by weight of the tablet.
  • the mouth dissolving agent may be prepared by dry granulation and compression method as known to a person having skill in the art.
  • the mouth dissolving tablets in accordance with the present disclosure have desirable characteristics like hardness and dissolution.
  • the mouth dissolving tablets in accordance with the present disclosure have hardness of about 2 (kg/mm ) or more, preferably hardness of about 3 to about 5 (kg/mm ).
  • the mouth dissolving tablets in accordance with the present disclosure exhibit dissolution of less than 30 seconds, preferably dissolution of less than 20 seconds, more preferably dissolution of about 5 seconds to about 20 seconds.
  • the present disclosure provides a dosage form for example mucoadhesive buccal film comprising the amphiphilic complex formulation of the multiple active ingredients incorporated in phospholipid in accordance with the present disclosure ranging from about 15% to about 85% by weight of the film; and suitable excipient(s).
  • the mucoadhesive film is the film made of materials that do not harm the buccal cavity or teeth, and adhere to a mucosal tissue surface upon hydration. Such adhesion will adherently localize the dosage form onto the mucus membrane for localized delivery of the active ingredients.
  • the term“film” includes thin films, sheets and wafers, in any shape, including rectangular, square, or other desired shape.
  • the films may be any desired thickness and size such that it may be placed into the oral cavity of the user. For example, the films may have a thickness of from about 100 microns to about 200 microns.
  • the mucoadhesive film in accordance with the present disclosure is a fast dissolving film, dissolving in about 20 second to about 90 seconds in the mouth.
  • the mucoadhesive film dosage includes a polymeric carrier matrix, which also act as adhering agent formed of a polymer, which may be one or more of water-soluble, water-swellable, or water-insoluble polymers.
  • the polymer may include cellulose or a cellulose derivative.
  • the water-soluble polymers is selected from but not limited to, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene oxide, pullulan, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof.
  • the polymer is low molecular weight polymer selected from but not limited to ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof.
  • the low molecular weight hydrophilic polymers are polymers having a molecular weight between about 1,000 to 9,000, or polymers having a molecular weight below 200,000.
  • the mucoadhesive film dosage form includes polymeric adhering agent including combination of various grades of hydroxypropylmethyl cellulose, for example HPMC grade E5, and/or HPMC grade El 5, which can be added in concentration ranging from about 20% to about 70% by weight of the film composition.
  • the mucoadhesive film further includes plasticizer which can be a suitable polymer for example selected from but not limiting to polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, added in concentrations ranging from about 0.5% to about 30% by weight of the film composition.
  • plasticizer which can be a suitable polymer for example selected from but not limiting to polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol,
  • the mucoadhesive film can include optional components, which include, without limitation: solvents; elastomers; surfactants; emulsifiers; anti-foaming agents, such as silicone-containing compounds, which promote a smoother film surface by releasing oxygen from the film; thermo -setting gels such as pectin, carageenan, and gelatin, which help in maintaining the dispersion of components; inclusion compounds, such as cyclodextrins and caged molecules; antioxidants; sweetening agents; acidulants; coloring agent; flavoring agent; preservatives; buffering agents; stabilizers; blowing agents; diluents; glidants; binders; absorbents; fillers; bulking agents; lubricants; granulating agents; release modifiers; flow accelerators; mold release agents; permeation enhancers; anti-adherents; adhesives; adjuvants; polyols; softeners; resins; demulcents; or the like
  • the mucoadhesive film includes anti-foaming and/or de-foaming agent.
  • agent aid in the removal of air, such as entrapped air, from the film, as entrapped air may lead to non-uniform films.
  • a suitable solvent may be used as a de-foaming agent, which can lower water density as well as lower the water's surface tension, so, any air bubbles trapped inside this mixture solution will also be easily dissipated.
  • the mucoadhesive films may be produced by a combination of at least one polymer and a solvent, optionally including other excipients known in the art.
  • the solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof.
  • the solvent may be a non-polar organic solvent, such as methylene chloride.
  • the film may be prepared by utilizing a selected casting or deposition method and a controlled drying process.
  • the mucoadhesive film may be prepared through controlled drying processes, which include application of heat and/or radiation energy to the wet film matrix to form a visco-elastic structure, thereby controlling the uniformity of content of the film.
  • a process of preparing a mucoadhesive film dosage form including the steps of: casting a film-forming composition comprising a therapeutically effective amount of the amphiphilic complex formulation of the multiple active ingredients incorporated in phospholipid; polymers including adhering agent, and plasticizer; a solvent; and subjecting the wet film formed to a drying process by subjecting it to a higher temperature.
  • the dosage forms in accordance with the present disclosure for example mouth dissolving tablets and mucoadhesive films are formulated for providing targeted delivery of the amphiphilic complex formulation of the multiple active ingredients incorporated in phospholipid for management of oral sub-mucosal fibrosis.
  • amphiphilic complex formulation of the multiple active ingredients incorporated in phospholipid, compositions and dosage forms thereof in accordance with the present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the existing art.
  • Example 1 Preparation of the amphiphilic complex formulation comprising extracts of neem, fennel, clove, and curcuminoids incorporated in phosphatidylcholine
  • amphiphilic complex formulation comprising multiple active ingredients and phosphatidylcholine in different ratios were prepared as follows:
  • Table 1 Blends of extracts of neem, fennel, clove and curcuminoids
  • Example 2 Evaluation of the amphiphilic complex formulation comprising extracts of neem, fennel, clove, and curcuminoids incorporated in phosphatidylcholine
  • amphiphilic complex formulation with phosphatidylcholine prepared as per Example 1 and blend of active ingredients in the ratio of 1.2:1 (lOmg) was centrifuged in methanol (50ml) at 10,000 rpm for 15 min at 4°C and the supernatant (IOOmI) was diluted to obtain a concentration of 0.2pl/ml.
  • This parameter is used to determine the peak of the temperature at which a phase transition takes place. It is expected that the amphiphilic complex formulation has a higher phase transition temperature compared to the blend of active ingredients and phosphatidylcholine.
  • Phase transition by DSC of the blend of active ingredients comprising of the extracts of neem, clove, fennel, and curcuminoids in 6:6:6:2 ratio; phosphatidylcholine; and the amphiphilic complex formulation prepared as per Example 1 was determined to compare the temperature of the phase transition as an increase in the phase transition temperature of the amphiphilic complex formulation being 246.7°C (Fig. 7) in comparison to the blend of active ingredients at l26°C (Fig. 5) and phosphatidylcholine at l89°C (Fig. 6), which serves as an evidence for the complex formation between the lipid layer and the active ingredient extracts.
  • the average particle size of the amphiphilic complex formulation prepared as per Example 1 was determined to be 226.3 nm with a polydispersity index of 0.513 and a zeta potential of -33.9mV (Fig.9). These results indicate that the size of the amphiphilic complex formulation are well under limit and will ensure better absorption of the amphiphilic complex formulation into the buccal cavity.
  • amphiphilic complex formulation was subjected to 1H NMR and 31 P NMR experimentations against the phosphatidylcholine.
  • the amphiphilic complex formulation as per Example 1 comprises the blend of multiple active ingredients consisting of the extracts of neem, fennel, clove and extract, which comprise large number of compounds, posing difficulty in the determination of the specific grouping or interaction, hence in such case the shift in the aliphatic protons provides preliminary confirmation.
  • 1H NMR shows significant reduction in the number of aliphatic protons between 3-5 ppm in the spectrum of the amphiphilic complex formulation (Fig. 11) compared to that of phosphatidylcholine (Fig. 10) thus proving that the lipid layer has involved itself in the formation of the amphiphilic complex formulation by forming a complex with the group of compounds present in the active ingredient extracts.
  • 31P NMR showed the merging of the signal 0.169 of phosphatidylcholine with a significant shift in the signal from 1.161 and 1.187 of phosphatidylcholine (Fig. 12) to 1.102 and 1.255 in the amphiphilic complex formulation (Fig. 13) respectively further indicates the formation of the amphiphilic complex formulation comprising blend of multiple active ingredients.
  • SRB Sulforhodamine B
  • HSC-2 Human squamous carcinoma cell line
  • 100 pL of cell suspension of Human squamous carcinoma cell line (HSC-2) was introduced into each well of 96-well tissue culture plate.
  • Cells were treated with 100 pL of various concentrations (25, 50, 100 and 200 pg/mL) of the test solutions and incubated for 48hrs.
  • cells were fixed by treating with ice cold TCA for 1 hour at 40° C. Plates were washed and allowed for drying.
  • Cells were subjected for staining at room temperature for 30min by adding 50 pL of SRB solution. 1% v/v acetic acid was added to remove unbound SRB and allowed to dry.
  • the IC50 values were determined by plotting O.D. values against the tested concentrations of the active ingredients. Experiment was done in triplicates; results were expressed as Mean ⁇ SEM values (proportional to cell survival).
  • amphiphilic complex formulation showed potent activity at a least concentration as compared to the individual active ingredients, as well as the blend of active ingredients consisting of the mixture of extracts of neem, fennel, clove, and curcuminoids at 6:6:6:2 ratio.
  • Example 4 Mouth dissolving tablets comprising the amphiphilic complex formulation
  • the mouth dissolving tablets dosage form comprising the amphiphilic complex formulation prepared as per Example 1 was formulated for buccal administration as per the composition in Table 4: Table 4 : Compositions for Mouth dissolving tablets
  • mouth dissolving tablets of batch Fl was found to have desired formula for a mouth dissolving tablet to achieve better permeation and to attain patient compliance.
  • Example 5 Mucoadhesive fast dissolving buccal wafers comprising the amphiphilic complex formulation
  • the buccal films were prepared by a solvent casting method using the compositions as per Table 7 comprising PEG 400 as plasticizer and HPMC (E5/E15) as adhering agents.
  • PEG 400 plasticizer
  • HPMC HPMC
  • Table 7 Composition for Mucoadhesive fast dissolving buccal wafers
  • Example 6 Ex Vivo permeation studies of mouth dissolving tablets and mucoadhesive fast dissolving buccal wafers
  • the formulated dosage forms have the tendency to disintegrate within 30 secs, it was necessary to determine the amount of active ingredients being taken up by the cells of the buccal mucosa.
  • two sets of experiments were set up using a Franz diffusion cell apparatus for assessing the permeation of active ingredients from the mouth dissolving tablets as per Example 3 and mucoadhesive fast dissolving buccal wafers as per Example 4.
  • the lower cell in both the sets contained the phosphate buffer solution having pH 6.2, which is the pH of the buccal cavity. The mucosa was clamped between the two cells.
  • the samples were withdrawn through an outlet attached to the lower cell and an equal amount of buffer solution was injected through an inlet at the same time as the sample was withdrawn, to maintain sink condition.
  • the sample was withdrawn at an interval of 0, 1, 5, 15, 30, 60, 90 and 120 min, and subjected to UV spectroscopy at 430 nm to determine the percentage of active ingredients permeated from the mouth dissolving tablets prepared as per Example 4 and the fast dissolving buccal films prepared as per Example 5, through the porcine mucosa within a minimal time span of 15-30 min.

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Abstract

La présente invention concerne une formulation de complexe amphiphile comprenant un mélange de multiples principes actifs comprenant des extraits de : margousier, fenouil, clou de girofle et curcuminoïdes ; et un phospholipide dans un rapport allant d'environ 1,1 : 1 à environ 2 : 1, la taille moyenne des particules de la formulation de complexe amphiphile étant comprise entre 185 nm et 3 µ. La présente invention concerne en outre une composition comprenant la formulation de complexe amphiphile selon la présente invention à hauteur d'environ 15 % à environ 85 % en poids de la composition ; et un ou plusieurs excipients pharmaceutiquement acceptables. La présente invention concerne en outre des formes pharmaceutiques pour permettre une administration ciblée de la formulation de complexe amphiphile comprenant un mélange de multiples principes actifs comprenant des extraits de : margousier, fenouil, clou de girofle et curcuminoïdes incorporés dans un phospholipide pour la gestion de la fibrose sous-muqueuse buccale.
PCT/IB2019/056963 2018-09-17 2019-08-19 Formulation de complexe amphiphile comprenant de multiples principes actifs et formes pharmaceutiques associées WO2020058785A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160050914A1 (en) * 2006-02-15 2016-02-25 Botanocap Ltd. Applications Of Microencapsulated Essential Oils
US20180042989A1 (en) * 2010-11-25 2018-02-15 Sigmoid Pharma Limited Immunomodulatory compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160050914A1 (en) * 2006-02-15 2016-02-25 Botanocap Ltd. Applications Of Microencapsulated Essential Oils
US20180042989A1 (en) * 2010-11-25 2018-02-15 Sigmoid Pharma Limited Immunomodulatory compositions

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SHWETA DANARADDI ET AL.: "Natural ways to prevent and treat oral cancer", JOURNAL OF ORAL RESEARCH AND REVIEW, vol. 6, no. 1, 5 September 2014 (2014-09-05), pages 34 - 39, XP055694437 *

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