WO2012067491A2 - Compositions comprising extracts obtained from oil palm based materials for providing anti -inflammatory effects and method of producing thereof - Google Patents

Compositions comprising extracts obtained from oil palm based materials for providing anti -inflammatory effects and method of producing thereof Download PDF

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WO2012067491A2
WO2012067491A2 PCT/MY2011/000234 MY2011000234W WO2012067491A2 WO 2012067491 A2 WO2012067491 A2 WO 2012067491A2 MY 2011000234 W MY2011000234 W MY 2011000234W WO 2012067491 A2 WO2012067491 A2 WO 2012067491A2
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WIPO (PCT)
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composition
oil palm
extracts
oil
opp
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PCT/MY2011/000234
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French (fr)
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WO2012067491A3 (en
Inventor
Hyun Kang
Chokyun Rha
Ravigadevi Sambanthamurthi
Anthony J Sinskey
Yew Ai Tan
Kalyana Sundram Manickam
Mohd Basri Wahid
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Malaysian Palm Oil Board
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Publication of WO2012067491A2 publication Critical patent/WO2012067491A2/en
Publication of WO2012067491A3 publication Critical patent/WO2012067491A3/en

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    • 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)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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]

Definitions

  • the invention generally relates to compositions and method to obtain and produce compositions comprising phenolics obtained from plants and plant based materials, and more particularly to a composition comprising phenolics obtained from oil palm and oil palm based materials, and method of producing thereof for use in providing anti-inflammatory effects.
  • Microglia are tissue macrophages known to populate a mammalian central nervous system within the brain. These brain microglial cells play an essential role particularly with respect to immune surveillance, host defense and tissue repair in the central nervous system. For instance, as a major part of the immune system, brain microglial cells react to signals received based on constant communication with the brain and produces signaling molecules including nitric oxide (NO), which is one of the key signaling molecules in neurons and the immune system. The production of nitric oxide (NO) can be influenced or mediated by glial cells whereby in recent findings suggest that microglial-produced NO and reactive nitrogen oxides may act as neurotoxic agent in neurodegenerative diseases.
  • NO nitric oxide
  • Nitric Oxide is soluble in both aqueous and lipid media. NO plays several roles, subject to the cell or tissue in which it is produced, or the particular component of any inflammatory process it might interact with. For instance, in many cell types in vitro, inflammatory cytokines (protein secreted by cells within the immune system and glial cells) either suppress or enhance iNOS expression and NO production. It is further known that NO has effects on neuronal transmission in the central nervous system. Therefore, albeit the fact that nitric oxide (NO) is required for normal maintenance and function of the cell, excessive production may lead to several behavioral deficits and promote toxicity.
  • NO nitric oxide
  • miroglial activation of the immune system may aid to either accelerate or repair neurodegenerative diseases, or provide neuroprotective functions subject to the production of neurotoxins.
  • the extraction of palm oil which is the primary product of palm fruit, involves a combination of various processes, wherein the main steps include the reception of fresh fruit bunches from plantations, sterilizing and threshing of the bunches, mashing the fruit and pressing the crude palm oil prior to storage and exportation.
  • the extraction of palm oil leads to the production of oil palm vegetation liquor which is discarded in the waste stream as Palm Oil Mill Effluent (POME).
  • PME Palm Oil Mill Effluent
  • EFB Empty Fruit Bunches
  • other waste materials are discarded in the milling process
  • Palm oil mill effluent for instance, if untreated, is a pollutant due to the high chemical oxygen demand (COD) and biological oxygen demand (BOD).
  • COD chemical oxygen demand
  • BOD biological oxygen demand
  • the major components of POME include oil and grease and solids, while elements found in POME include phosphorus, potassium, boron, iron, manganese, copper, magnesium and zinc. So far POME has been used in the preparation of fertilizers or as a substrate for bacterial production of biodegradable plastics.
  • It is another object of the present invention to provide a composition and a method for producing a composition comprising extracts obtained from oil palm based materials, and more particularly from palm vegetation liquor used for providing anti-inflammatory effects in a human subject, a mammal or a subject of any animal species in need thereof.
  • OPP oil palm phenolics
  • FIG 1 shows the OPP attenuation on the LPS-mediated expression of CD l ib in BV-2 microglial cells based on an embodiment of the present invention
  • FIG 2 plots OPP dose-dependantly inhibits the LPS-stimulated NO production in BV-2 microglia in accordance with an embodiment of the present invention
  • FIG 3 plots the effect of normal growth medium (media control) and media supplemented with OPP on the viability of the murine microglia cells in another embodiment of the present invention
  • FIG 4 provides the effects of LPS on inducible nitric oxide synthase (iNOS) in accordance with another preferred embodiment of the present invention
  • FIG 5 shows the effects of OPP extracts on the protein expression of iNOS and COX-2 in accordance with an embodiment of the present invention
  • FIG 6 shows the dose-dependent inhibition of LPS-dependant NF-kB by OPP in accordance with an embodiment of the present invention
  • FIG 7 shows the synergistic effect on nitrite concentration between OPP and caffeoylshikimic acid in accordance with another embodiment of the present invention.
  • the present invention provides a composition used to provide anti-inflammatory effects and activities in mammals or a subject of any animal species, said composition comprising extracts obtained from oil palm based materials.
  • the composition is used to down regulate the production of Nitric Oxide (NO) produced by LPS-stimulated murine microglia cells.
  • NO Nitric Oxide
  • the composition is used to inhibit LPS- induced increase in iNOS protein levels in LPS stimulated BV-2 cells.
  • the composition is used to inhibit the LPS- induced increase in NF- ⁇ protein levels in LPS- stimulated BV-2 cells.
  • the present invention further discloses a method for use in producing an anti-inflammatory composition comprising the step of obtaining extracts from from oil palm based materials and administering said composition to a mammal.
  • the disclosed description and examples relates to a composition comprising extracts from oil palm based materials which is used for providing anti-inflammatory effects in a manner to be described herein, and method of producing the said composition based on oil palm based materials.
  • the exemplifications are provided to better elucidate the embodiments of the present invention and therefore should not be construed as limiting the scope of protection.
  • the extraction of palm oil generates a waste stream of vegetation liquor, which is thereby considered as an aqueous phase of the milling process prior to being discarded as palm oil mill effluent (POME) and solid wastes.
  • POME palm oil mill effluent
  • composition used for providing anti-inflammatory effects whereby said composition comprises oil palm phenolics (OPP) and other components in the extracts obtained from oil palm based materials.
  • OPP oil palm phenolics
  • the composition as covered in the appended claims significantly suppresses LPS-induced NO formation, thus providing direct anti-inflammatory effect on microglia, glial cells which are responsible in the production of Nitric Oxide (NO) for the immune surveillance function of the central nervous system.
  • the composition used for providing anti-inflammatory effects in accordance with the present invention comprises oil palm phenolics (OPP) extracts preferably derived from palm oil mill effluent (POME), whereby said extracts comprises shikimic acid, which may be of any one from the following: protocatechuic acid, parahydyroxy benzoic acid, caffeic acid, 3-O-caffeoylshikimic acid, 4-0- caffeoylshikimic acid, and 5-0- caffeoylshikimic acid.
  • OPP oil palm phenolics
  • POME palm oil mill effluent
  • a method for producing an anti-flammatory composition comprises the steps of obtaining extracts from oil palm based materials is disclosed.
  • oil palm based materials including vegetation liquors, any oil palm by products, palm oil milling wastes materials, oil palm based waste materials (liquid and solid), materials from oil palm based industries, any ancillary oil palm vegetative matters, any part of the oil palm tree for instance but not limiting to the stem, pulp, seed, trunk, fruitlet, fruitbunch, frond, any part of the oil palm fruit and other oil palm based materials and sources not name explicitly herein.
  • the method further includes the step of obtaining extracts from oil palm based materials preferably without using solvents.
  • the method may include the step of obtaining water soluble, and enriched with phenolic compounds, extracts from oil palm based materials.
  • the step of obtaining extracts from oil palm based materials may be performed based on conventional separation principles. It should be noted that however the method involved for extraction is solvent-free.
  • the method may further include the step of obtaining water soluble, antioxidant rich extracts known as oil palm phenolics (OPP) from oil palm based materials including vegetation liquors, any oil palm by products, palm oil milling wastes materials, materials from oil palm based industries, any ancillary oil palm vegetative matters, any part of the oil palm tree for instance but not limiting to the stem, pulp, seed, trunk, fruitlet, fruitbunch, frond, any part of the oil palm fruit and other oil palm based materials and sources not name explicitly herein.
  • OPP oil palm phenolics
  • the extracts may be obtained from materials used or generated from oil palm based industries.
  • the extraction of the oil palm phenolics (OPP) as briefly described above in accordance with a preferred embodiment of the present invention may involve the steps of providing three-phase decantor system, and preferably a plurality of separation stages using different types of membranes suitably adapted to separate residual oil, ionic contaminants and components of high molecular weight, thereby obtaining oil palm phenolics (OPP).
  • an immunofluorescence analysis can be carried out with a suitable surface marker.
  • CDbl 1 was upregulated by LPS and the expression was reduced by 800 ⁇ g/ml OPP.
  • the OPP extracts of the present invention inhibits the nitric oxide production as seen in EXAMPLE 2 below.
  • OPP oil palm phenolics
  • a culture medium of BV-2 microglial cells was used, with a stable metabolite of nitric oxide (NO) to provide the concentration of nitrite.
  • NO nitric oxide
  • cells were co-treated with LPS at 0.1, 1 , 2 and 5 ⁇ and concentrations of OPP ranging from 100-800 ⁇ g/ml for a period of 24 hours.
  • the nitrite levels were determined using Griess reagent. As seen in FIG 2, it is observed that the LPS at concentrations up to 5 ⁇ g/ml increased the NO production in the culture medium.
  • the concentration of OPP inhibiting NO production by 50% was approximately 100-400 ⁇ g/ml. It can be concluded that the inhibitory effect may level off at higher OPP concentrations.
  • the OPP extracts do not affect the viability of the microglial cells as shown in the results for EXAMPLE 3 below.
  • the viability of the microglial cells may be determined based on standard procedures available.
  • the CellTiter-GloTM Assay was used to examine the in vitro cytotoxicity.
  • BV-2 cells 2 x 105/well in 1 ml of F 12/DMEM plus 10% FBS were plated in clear bottom 24 well plates. Cells were allowed to attach and grow for 18 hours. The medium was then replaced by F12/MEM with or without varying concentrations of OPP and subsequently incubated for 24 hours.
  • viability was assayed using the CellTiter-Glo Assay, and luminescence was measured with a Thermo plate reader.
  • OPP did not increase the viability of microglial cells.
  • Cell viability was suitably determined after 24 hours of growth in normal condition medium and medium supplemented with OPP.
  • the OPP extracts showed significant activity in suppressing the protein expression of iNOS and COX-2. From the obtained results, it can be concluded that OPP extracts of the present invention can significantly reduce the protein levels of iNOS in LPS-activated cells.
  • the OPP extracts showed significant activity in suppressing the protein expression of iNOS and COX-2. From the obtained results, it can be concluded that OPP extracts of the present invention can significantly reduce the protein levels of iNOS in LPS-activated cells.
  • OPP extracts of the present invention aids in suppressing COX-2 more effectively than that of Prostaglandin-2 than iNOS protein, as suitably shown in FIG 5.
  • the OPP extracts show significant activity in inhibiting the increase of LPS-induced NF-kB protein levels in a dose responsive manner.
  • BV-2 microglia cells were co-treated with LPS (1 ⁇ g ml) and corresponding concentration of CS A (caffeoylshikimic acid) and OPP extracts, 1.2 ⁇ for a period of 24 hours. Nitrite levels in medium were determined.
  • composition comprising extracts from oil palm based materials may be prepared in various suitable forms for direct or oral administration for providing anti- inflammatory effects.
  • compositions of the invention include those suitable for oral, rectal, optical, buccal (for example, sublingual), parenteral (for example, subcutaneous, intramuscular, intradermal and intravenous) and transdermal administration.
  • buccal for example, sublingual
  • parenteral for example, subcutaneous, intramuscular, intradermal and intravenous
  • transdermal administration The most suitable route in any given case will depend on the nature and severity of the condition being treated and the state of the patient in need thereof.
  • compositions suitable for oral administration may be presented in discrete units, such as capsules, sachets, lozenges, or tablets, each containing a pre-determined amount of the extract: as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid.
  • Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the extract of the present invention and one or more suitable carriers (which may contain one or more accessory ingredients as noted below).
  • the compositions of the invention are prepared by uniformly and intimately admixing the extract with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or moulding a powder or granules containing the extract, optionally with one or more accessory ingredients.
  • Compressed tablets may be, optionally mixed with a binder, lubricant, inert diluents, and/or surface active/dispersing agent(s).
  • Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Suitable carriers may be fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using for example, corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinylpyrrolidone, agar or algin acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes using for example, corn
  • compositions may be prepared in a manner, and in a form/amount as is conveniently practiced. See, for example, Goodman & Gillman, The Pharmacological Basis of Therapeutics (7 th Edition, 1985) and Remington's Pharmaceutical Science (Mack Publishing Company, 10 th Edition), both of which are incorporated herein by reference.
  • Compositions may contain, for example, from 0.1 mg to 2g OPP such as 0.1 mg to 200mg, more particularly 15mg to 50mg OPP.
  • compositions of the invention may also be administered to a human in a dietary supplement form.
  • Dietary supplements incorporating the active composition can be prepared by adding the composition to a food in the process of preparing the food.
  • An effective amount of the compositions of the present invention is administered to a human subject, a mammal or any animal species. The actual dosage levels will depend upon the number of factors, such as specific mode of administration, the condition being treated, the condition of the patient and the judgement of the health care giver.
  • composition comprising extracts from oil palm based materials of the present invention may be prepared for use in a pharmaceutically effective or nutraceutically effective amount, solely on its own or in combination with other agents or compounds deemed appropriate by a person skilled in the art.
  • the term 'pharmaceutically effective' and 'nutraceutically effective' amount includes a quantification that is acceptable for providing anti-inflammatory effects in a patient in need thereof.
  • the composition may be administered in form of doses, within a predetermined period of time, whereby it may be administered for example but not limiting to daily, weekly or monthly.
  • composition may be provided in conventional treatment forms, pharmaceutical formulations or as nutritional supplement.
  • composition of the present invention may be provided in a nutraceutical form.
  • the compositions according to the present invention may include one or more pharmaceutically acceptable or nutraceutically acceptable carriers. Carriers are selected so as to be acceptable in the sense of being ingredients in the composition and must not be deleterious to the patient.
  • the carriers may be solid or a liquid, or both, and may be formulated with extracts from oil palm based materials at the desired ratios.
  • compositions may be prepared by any of the well known techniques of pharmacy, for example admixing the extract, optionally including excipients, diluents (for example water) and auxiliaries as are well known in the pharmaceutical field.
  • the compositions may include one or more agents, such as vitamins (for example, Vitamin A, Vitamin B group, Vitamin C, Vitamin D, Vitamin E and Vitamin K), and minerals (for example magnesium, iron, zinc, calcium and manganese in the form of pharmaceutically or nutraceutically acceptable salts).
  • composition of the present invention have anti-inflammatory properties.

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Abstract

The present invention provides compositions and method for production of a composition used to provide anti-inflammatory effects on microglial cells in the brain. The composition comprises extracts obtained from oil palm based materials.

Description

COMPOSITIONS COMPRISING EXTRACTS OBTAINED FROM OIL PALM BASED MATERIALS FOR PROVIDING ANTI -INFLAMMATORY EFFECTS AND
METHOD OF PRODUCING THEREOF
FIELD OF INVENTION
The invention generally relates to compositions and method to obtain and produce compositions comprising phenolics obtained from plants and plant based materials, and more particularly to a composition comprising phenolics obtained from oil palm and oil palm based materials, and method of producing thereof for use in providing anti-inflammatory effects.
BACKGROUND OF THE INVENTION
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that this prior art forms part of the common general knowledge in Malaysia or any other country.
Microglia are tissue macrophages known to populate a mammalian central nervous system within the brain. These brain microglial cells play an essential role particularly with respect to immune surveillance, host defense and tissue repair in the central nervous system. For instance, as a major part of the immune system, brain microglial cells react to signals received based on constant communication with the brain and produces signaling molecules including nitric oxide (NO), which is one of the key signaling molecules in neurons and the immune system. The production of nitric oxide (NO) can be influenced or mediated by glial cells whereby in recent findings suggest that microglial-produced NO and reactive nitrogen oxides may act as neurotoxic agent in neurodegenerative diseases.
Nitric Oxide (NO) is soluble in both aqueous and lipid media. NO plays several roles, subject to the cell or tissue in which it is produced, or the particular component of any inflammatory process it might interact with. For instance, in many cell types in vitro, inflammatory cytokines (protein secreted by cells within the immune system and glial cells) either suppress or enhance iNOS expression and NO production. It is further known that NO has effects on neuronal transmission in the central nervous system. Therefore, albeit the fact that nitric oxide (NO) is required for normal maintenance and function of the cell, excessive production may lead to several behavioral deficits and promote toxicity. In many scientific findings and as mentioned briefly in the preceding paragraphs, excessive production or hyperactivation of microglia accelerates the progression of neurodegenerative diseases or neurological disorders due to aberrant proinflammatory factors. Accordingly, it can be concluded that miroglial activation of the immune system may aid to either accelerate or repair neurodegenerative diseases, or provide neuroprotective functions subject to the production of neurotoxins.
Following this there is a great need to provide a renewable and inexpensive source or viable alternative as an anti-inflammatory agent or provide direct anti-inflammatory effects on microglia.
The commercial value of oil palm ( Elaies guineensis) is in the oil, which offers various health advantages and benefits, owing to its high content of phytonutrients demonstrate antioxidant properties. Nevertheless, at present, the oil palm based extracts, in particular its vegetation liquour and palm oil mill effluent (POME), has been discovered by way of various studies to have beneficial implications on skin ageing, cancer and heart diseases. Malaysia is currently one of the world's largest producers of palm oil. Being the major foreign exchange earner industry and to fulfill the rapid progression of the world's demand for palm oil based on the world population growth, Malaysia has at least 265 palm oil mills all over the country.
Typically, the extraction of palm oil which is the primary product of palm fruit, involves a combination of various processes, wherein the main steps include the reception of fresh fruit bunches from plantations, sterilizing and threshing of the bunches, mashing the fruit and pressing the crude palm oil prior to storage and exportation. However, the extraction of palm oil leads to the production of oil palm vegetation liquor which is discarded in the waste stream as Palm Oil Mill Effluent (POME). In addition Empty Fruit Bunches (EFB) and other waste materials are discarded in the milling process
Palm oil mill effluent (POME) for instance, if untreated, is a pollutant due to the high chemical oxygen demand (COD) and biological oxygen demand (BOD). The major components of POME include oil and grease and solids, while elements found in POME include phosphorus, potassium, boron, iron, manganese, copper, magnesium and zinc. So far POME has been used in the preparation of fertilizers or as a substrate for bacterial production of biodegradable plastics.
It is being reported that more than 500 kg (around 0.5 m3) of liquid wastes, primarily in the form of palm oil mill effluent (POME), are discharged during the processing of 1.0 metric tons of fresh fruit bunches {Ma et al. 1996) in a typical oil palm mill. Accordingly, it is expected that more than 50 m3 of POME from a mill after processing 100 metric tons of fresh fruit bunches. Proceeding from the above and based on recent studies on phytochemicals extracted from oil palm, the palm oil industry creates an abundance of prospect in beneficial phytochemicals and other compounds recovery due to the amount of oil palm based materials including waste materials generated from the industry, if treated effectively.
It is a primary object of the present invention to provide a composition based on oil palm based materials used as an anti-inflammatory agent and method of production thereof.
It is yet another object of the present invention to provide a composition based on oil palm based materials used as anti-inflammatory agent whereby said composition comprises oil palm based materials and method for production thereof.
It is another object of the present invention to provide a composition and a method for producing a composition comprising extracts obtained from oil palm based materials, and more particularly from palm vegetation liquor used for providing anti-inflammatory effects in a human subject, a mammal or a subject of any animal species in need thereof.
It is yet another object of the present invention to provide a composition comprising extracts obtained from palm oil mill effluent (POME).
It is yet another object of the present invention to provide a composition comprising extracts from oil palm-based materials and method for producing said composition, wherein said extracts comprises oil palm phenolics (OPP). It is yet another object of the present invention to provide a composition further comprising shikimic acid used for providing anti-inflammatory effects and method for producing said composition. It is yet a further object of the present invention to provide a composition comprising extracts obtained from oil palm liquid waste based materials.
Further objects and advantages of the present invention may become apparent upon referring to the preferred embodiments of the present invention as shown in the accompanying drawings and as described in the following description.
BRIEF DESCRIPTION OF DRAWINGS
FIG 1 shows the OPP attenuation on the LPS-mediated expression of CD l ib in BV-2 microglial cells based on an embodiment of the present invention;
FIG 2 plots OPP dose-dependantly inhibits the LPS-stimulated NO production in BV-2 microglia in accordance with an embodiment of the present invention; FIG 3 plots the effect of normal growth medium (media control) and media supplemented with OPP on the viability of the murine microglia cells in another embodiment of the present invention;
FIG 4 provides the effects of LPS on inducible nitric oxide synthase (iNOS) in accordance with another preferred embodiment of the present invention; FIG 5 shows the effects of OPP extracts on the protein expression of iNOS and COX-2 in accordance with an embodiment of the present invention;
FIG 6 shows the dose-dependent inhibition of LPS-dependant NF-kB by OPP in accordance with an embodiment of the present invention;
FIG 7 shows the synergistic effect on nitrite concentration between OPP and caffeoylshikimic acid in accordance with another embodiment of the present invention. SUMMARY OF INVENTION
The present invention provides a composition used to provide anti-inflammatory effects and activities in mammals or a subject of any animal species, said composition comprising extracts obtained from oil palm based materials.
In one embodiment of the present invention, the composition is used to down regulate the production of Nitric Oxide (NO) produced by LPS-stimulated murine microglia cells.
In another embodiment of the present invention, the composition is used to inhibit LPS- induced increase in iNOS protein levels in LPS stimulated BV-2 cells.
In one embodiment of the present invention, the composition is used to inhibit the LPS- induced increase in NF-κΒ protein levels in LPS- stimulated BV-2 cells. The present invention further discloses a method for use in producing an anti-inflammatory composition comprising the step of obtaining extracts from from oil palm based materials and administering said composition to a mammal. DETAILED DESCRIPTION OF THE INVENTION
In line with the above summary, the disclosed description and examples relates to a composition comprising extracts from oil palm based materials which is used for providing anti-inflammatory effects in a manner to be described herein, and method of producing the said composition based on oil palm based materials. It shall be apparent however to one skilled in the art that the exemplifications are provided to better elucidate the embodiments of the present invention and therefore should not be construed as limiting the scope of protection. As briefly described earlier, during oil palm fruit processing, the extraction of palm oil generates a waste stream of vegetation liquor, which is thereby considered as an aqueous phase of the milling process prior to being discarded as palm oil mill effluent (POME) and solid wastes. In one embodiment of the present invention, there is provided a composition used for providing anti-inflammatory effects, whereby said composition comprises oil palm phenolics (OPP) and other components in the extracts obtained from oil palm based materials. The composition as covered in the appended claims significantly suppresses LPS-induced NO formation, thus providing direct anti-inflammatory effect on microglia, glial cells which are responsible in the production of Nitric Oxide (NO) for the immune surveillance function of the central nervous system.
In one embodiment, the composition used for providing anti-inflammatory effects in accordance with the present invention comprises oil palm phenolics (OPP) extracts preferably derived from palm oil mill effluent (POME), whereby said extracts comprises shikimic acid, which may be of any one from the following: protocatechuic acid, parahydyroxy benzoic acid, caffeic acid, 3-O-caffeoylshikimic acid, 4-0- caffeoylshikimic acid, and 5-0- caffeoylshikimic acid.
In another embodiment of the present invention, there is disclosed a method for producing an anti-flammatory composition comprises the steps of obtaining extracts from oil palm based materials is disclosed. Suitably, it should be noted that oil palm based materials including vegetation liquors, any oil palm by products, palm oil milling wastes materials, oil palm based waste materials (liquid and solid), materials from oil palm based industries, any ancillary oil palm vegetative matters, any part of the oil palm tree for instance but not limiting to the stem, pulp, seed, trunk, fruitlet, fruitbunch, frond, any part of the oil palm fruit and other oil palm based materials and sources not name explicitly herein. The method further includes the step of obtaining extracts from oil palm based materials preferably without using solvents.
In one embodiment of the present invention, the method may include the step of obtaining water soluble, and enriched with phenolic compounds, extracts from oil palm based materials. In accordance with the present invention, the step of obtaining extracts from oil palm based materials may be performed based on conventional separation principles. It should be noted that however the method involved for extraction is solvent-free. According to the present invention, the method may further include the step of obtaining water soluble, antioxidant rich extracts known as oil palm phenolics (OPP) from oil palm based materials including vegetation liquors, any oil palm by products, palm oil milling wastes materials, materials from oil palm based industries, any ancillary oil palm vegetative matters, any part of the oil palm tree for instance but not limiting to the stem, pulp, seed, trunk, fruitlet, fruitbunch, frond, any part of the oil palm fruit and other oil palm based materials and sources not name explicitly herein.
Based on another embodiment of the present invention, the extracts may be obtained from materials used or generated from oil palm based industries.
In another embodiment of the present invention, the extraction of the oil palm phenolics (OPP) as briefly described above in accordance with a preferred embodiment of the present invention may involve the steps of providing three-phase decantor system, and preferably a plurality of separation stages using different types of membranes suitably adapted to separate residual oil, ionic contaminants and components of high molecular weight, thereby obtaining oil palm phenolics (OPP).
The following experiments were carried out to ascertain and thus confirm the effects of oil palm phenolics (OPP) on murine BV-2 microglia. EXAMPLE 1
Immunofluorescence Analysis
In order to determine or sort out the cells for the purpose of the present invention, an immunofluorescence analysis can be carried out with a suitable surface marker.
Immunofluorescence analysis was performed with LPS (5 μ^ηιΐ) at 37°C, whereby CDl lb was selected was a marker for microglial cells. It is observed that OPP attenuated the lipopolysaccharide (LPS) -mediated expression of CDbl 1 in BV-2 microglial cells as shown in FIG 1.
CDbl 1 was upregulated by LPS and the expression was reduced by 800 μg/ml OPP. In another embodiment of the present invention, the OPP extracts of the present invention inhibits the nitric oxide production as seen in EXAMPLE 2 below.
EXAMPLE 2
Inhibition of Nitric Oxide (NO) Production
In order to observe the inhibitory effect of oil palm phenolics (OPP) in accordance with the present invention, a culture medium of BV-2 microglial cells was used, with a stable metabolite of nitric oxide (NO) to provide the concentration of nitrite. In this experiment, cells were co-treated with LPS at 0.1, 1 , 2 and 5 μ^πιΐ and concentrations of OPP ranging from 100-800 μg/ml for a period of 24 hours. The nitrite levels were determined using Griess reagent. As seen in FIG 2, it is observed that the LPS at concentrations up to 5 μg/ml increased the NO production in the culture medium. It is further observed that the concentration of OPP inhibiting NO production by 50% (IC50) was approximately 100-400 μg/ml. It can be concluded that the inhibitory effect may level off at higher OPP concentrations. In one embodiment of the present invention, the OPP extracts do not affect the viability of the microglial cells as shown in the results for EXAMPLE 3 below.
EXAMPLE 3
Viability of OPP-treated BV-2 microglial cells
The viability of the microglial cells may be determined based on standard procedures available. For the purpose of the present invention, the CellTiter-GloTM Assay was used to examine the in vitro cytotoxicity. In the experiment, BV-2 cells 2 x 105/well in 1 ml of F 12/DMEM plus 10% FBS were plated in clear bottom 24 well plates. Cells were allowed to attach and grow for 18 hours. The medium was then replaced by F12/MEM with or without varying concentrations of OPP and subsequently incubated for 24 hours. Suitably, viability was assayed using the CellTiter-Glo Assay, and luminescence was measured with a Thermo plate reader. As seen in FIG 3, the results of the assay have shown that OPP did not increase the viability of microglial cells. Cell viability was suitably determined after 24 hours of growth in normal condition medium and medium supplemented with OPP. In one embodiment of the present invention, the OPP extracts showed significant activity in suppressing the protein expression of iNOS and COX-2. From the obtained results, it can be concluded that OPP extracts of the present invention can significantly reduce the protein levels of iNOS in LPS-activated cells. EXAMPLE 4
Protein Expression of iNOS and COX-2
In one embodiment of the present invention, the OPP extracts showed significant activity in suppressing the protein expression of iNOS and COX-2. From the obtained results, it can be concluded that OPP extracts of the present invention can significantly reduce the protein levels of iNOS in LPS-activated cells.
An experiment was conducted to detect the effects of OPP extracts on protein expression of iNOS and COX-2. Results were obtained and suitably plotted as seen in FIG 4 and FIG 5.
For this experiment, there were three samples prepared, whereby at least one sample comprises only media alone, at least one sample contained only LPS alone, one sample contained LPS mixed with OPP extracts at the concentration of 200 μg ml, at least one sample contained LPS mixed with OPP extracts at the concentration of 400 μg/ml and at least one sample contained LPS mixed with OPP extracts at the concentration of 800 μg/ml. Blotting was done against β-actin (130) where kDa was employed as a loading control - lower panel.
It is evident that at the lowest concentration, the extracts of the present invention did not reduce the LPS- stimulated iNOS protein expression. OPP treatment however showed substantial suppression activity and this reducing the protein levels of iNOS in LPS-activated cells at the concentration of 800 μg/ml.
It is further observed from the results that the OPP extracts of the present invention aids in suppressing COX-2 more effectively than that of Prostaglandin-2 than iNOS protein, as suitably shown in FIG 5.
In accordance with another embodiment of the present invention, the OPP extracts show significant activity in inhibiting the increase of LPS-induced NF-kB protein levels in a dose responsive manner.
EXAMPLE 5
Down Regulation of Nuclear Transcription factor NF-kB An experiment was performed to observe the down regulation of nuclear transcription factor based on the OPP extracts of the present invention. The results obtained was recorded and plotted as shown in FIG 6. It is seen that the OPP extracts treatment has significantly reduced the protein levels of NF-kB in LPS- activated cells. The synergistic effects of the OPP extracts can be evaluated by, but not limiting to; the following example:
EXAMPLE 6
Synergistic E ffects of OPP
Synergistic effects of the extracts of the present invention were evaluated. The anti- inflammation activity of the individual compounds effect added with that of the combined compounds at the same concentration were observed.
In this experiment, BV-2 microglia cells were co-treated with LPS (1 μg ml) and corresponding concentration of CS A (caffeoylshikimic acid) and OPP extracts, 1.2 μηι for a period of 24 hours. Nitrite levels in medium were determined. OPP-SgT, at 1.2 M, different doses of caffeolyshikimic acid, within 20, 40, 80, 160 M were prepared for experiments conducted in triplicate. Results based on the experiments were plotted as shown in FIG 7. It is observed that OPP extracts and caffeoylshikimic acid 1, 2, 3 and 1 , 2, 3 mixtures are anti-inflammation agents and that mixture of two compounds resulted in an additive effect of the anti-inflammatory capacities.
It is noted that for each compound, the anti-inflammatory capacity was calculated in GAE equivalents. DOSAGE AND FORMULATION
Generally, the composition comprising extracts from oil palm based materials may be prepared in various suitable forms for direct or oral administration for providing anti- inflammatory effects.
The compositions of the invention include those suitable for oral, rectal, optical, buccal (for example, sublingual), parenteral (for example, subcutaneous, intramuscular, intradermal and intravenous) and transdermal administration. The most suitable route in any given case will depend on the nature and severity of the condition being treated and the state of the patient in need thereof.
Compositions suitable for oral administration may be presented in discrete units, such as capsules, sachets, lozenges, or tablets, each containing a pre-determined amount of the extract: as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid. Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the extract of the present invention and one or more suitable carriers (which may contain one or more accessory ingredients as noted below). In general, the compositions of the invention are prepared by uniformly and intimately admixing the extract with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or moulding a powder or granules containing the extract, optionally with one or more accessory ingredients. Compressed tablets may be, optionally mixed with a binder, lubricant, inert diluents, and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder. Suitable carriers may be fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using for example, corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinylpyrrolidone, agar or algin acid or a salt thereof, such as sodium alginate.
Compositions may be prepared in a manner, and in a form/amount as is conveniently practiced. See, for example, Goodman & Gillman, The Pharmacological Basis of Therapeutics (7th Edition, 1985) and Remington's Pharmaceutical Science (Mack Publishing Company, 10th Edition), both of which are incorporated herein by reference.
Compositions may contain, for example, from 0.1 mg to 2g OPP such as 0.1 mg to 200mg, more particularly 15mg to 50mg OPP.
The compositions of the invention may also be administered to a human in a dietary supplement form. Dietary supplements incorporating the active composition can be prepared by adding the composition to a food in the process of preparing the food. An effective amount of the compositions of the present invention is administered to a human subject, a mammal or any animal species. The actual dosage levels will depend upon the number of factors, such as specific mode of administration, the condition being treated, the condition of the patient and the judgement of the health care giver.
The composition comprising extracts from oil palm based materials of the present invention may be prepared for use in a pharmaceutically effective or nutraceutically effective amount, solely on its own or in combination with other agents or compounds deemed appropriate by a person skilled in the art.
It is noted that the term 'pharmaceutically effective' and 'nutraceutically effective' amount includes a quantification that is acceptable for providing anti-inflammatory effects in a patient in need thereof.
In one embodiment the composition may be administered in form of doses, within a predetermined period of time, whereby it may be administered for example but not limiting to daily, weekly or monthly.
In another embodiment the composition may be provided in conventional treatment forms, pharmaceutical formulations or as nutritional supplement.
In one embodiment the composition of the present invention may be provided in a nutraceutical form. The compositions according to the present invention may include one or more pharmaceutically acceptable or nutraceutically acceptable carriers. Carriers are selected so as to be acceptable in the sense of being ingredients in the composition and must not be deleterious to the patient. The carriers may be solid or a liquid, or both, and may be formulated with extracts from oil palm based materials at the desired ratios.
Compositions may be prepared by any of the well known techniques of pharmacy, for example admixing the extract, optionally including excipients, diluents (for example water) and auxiliaries as are well known in the pharmaceutical field. The compositions may include one or more agents, such as vitamins (for example, Vitamin A, Vitamin B group, Vitamin C, Vitamin D, Vitamin E and Vitamin K), and minerals (for example magnesium, iron, zinc, calcium and manganese in the form of pharmaceutically or nutraceutically acceptable salts).
It is noted from the results of the studies referred herein as exemplifications evidently show that the composition of the present invention have anti-inflammatory properties.
It is understood by a person skilled in the art that the methods for experiments and studies are described as exemplifications herein and thus the results are not intended, however, to limit or restrict the scope of the invention in any way and should not be construed as providing conditions, parameters, agents or starting materials which must be utilized exclusively in order to practice the present invention. It is therefore understood that the invention may be practiced, within the scope of the appended claims, with equivalent methods for the experiments than as specifically described and stated in claims.

Claims

1. A composition used to provide anti-inflammatory effects and activities wherein said composition comprising extracts obtained from oil palm based materials.
2. The composition as claimed in Claim 1 for use in administering a mammal in need thereof.
3. The composition as claimed in Claim 1 for use in any animal species in need thereof.
4. The composition as claimed in Claim 1 wherein the composition is used to down regulate the production of Nitric Oxide (NO) produced by LPS-stimulated murine microglia cells.
5. The composition as claimed in Claim 1 wherein the composition inhibits LPS-induced increase in iNOS protein levels in LPS stimulated BV-2 cells.
6. The composition as claimed in Claim 1 wherein the composition inhibits the LPS- induced increase in NF-κΒ protein levels in LPS- stimulated BV-2 cells.
7. The composition as claimed in Claims 3 and 4 wherein the composition is provided in dose-dependent manner.
8. The composition as claimed in Claim 1 wherein the extracts obtained from oil palm based materials, said extracts comprises oil palm phenolics (OPP).
9. The composition as claimed in Claim 1 wherein the composition further comprising shikimic acid.
10. The composition as claimed in Claim 7 wherein the extracts comprises any one of the following compounds: protocatechuic acid, parahydyroxy benzoic acid, caffeic acid, 3-0- caffeoylshikimic acid, 4-0- caffeoylshikimic acid, and 5-O-caffeoylshikimic acid.
11. The composition as claimed in Claim 1 wherein the extracts are obtained from anyone of the following: palm oil mill effluent (POME); palm oil vegetation liquor, palm oil milling processes, oil palm based industries and oil palm based wastes materials.
12. The composition as claimed in Claim 1 wherein the extracts are obtained from any part of the oil palm tree for instance but not limiting to the stem, pulp, seed, trunk, fruitlet, fruitbunch, and frond.
13. The composition as claimed in Claim 1 wherein the composition is used to inhibit nitric oxide (NO) production by microglial cells without reducing the viability of said microglial cells.
14. The composition as claimed in Claim 1 wherein the composition provides therapeutic effects for inhibiting uncontrolled or elevated inflammatory responses in the brain.
15. The composition as claimed in Claim 1 wherein the composition is used to suppress the protein expression of iNOS and COX-2.
16. The composition as claimed in Claim 1 to 13 wherein said composition is provided in the form of at least one of the following: tablets, capsules, liquid, nutraceutical and food supplements.
17. A method for producing an anti-inflammatory composition comprising the step of obtaining extracts from from oil palm based materials.
18. The method as claimed in Claim 14 wherein the extracts comprise of oil palm phenolics (OPP).
19. The method as claimed in Claim 15 wherein the method further comprising the step of adding shikimic acid.
20. A method for providing anti-flammatory effects in mammals, comprising the steps of administering a composition comprising extracts from oil palm based materials to said mammal.
21. The method as claimed in Claim 18, wherein the composition comprises oil palm phenolics (OPP) obtained from extracts of oil palm based materials.
22. A method for down regulating the production of Nitric Oxide (NO) produced by stimulated murine microglia cells in mammals comprising the step of administering a composition comprising extracts obtained from oil palm based materials.
23. The method as claimed in Claim 20 wherein the composition comprises oil palm phenolics (OPP) and shikimic acid.
PCT/MY2011/000234 2010-11-16 2011-11-16 Compositions comprising extracts obtained from oil palm based materials for providing anti -inflammatory effects and method of producing thereof WO2012067491A2 (en)

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WO2014209100A3 (en) * 2013-06-28 2015-03-05 Malaysian Palm Oil Board (Mpob) Isolation of novel bioactive compound obtained from oil palm base materials
US20180264066A1 (en) * 2017-03-17 2018-09-20 Malaysian Palm Oil Board Antioxidant, Anti-Inflammatory Compositions and Uses Thereof
WO2018165780A1 (en) * 2017-03-17 2018-09-20 Malaysian Palm Oil Board Antioxidant, anti-inflammatory compositions and uses thereof
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EP3765052A4 (en) * 2018-03-08 2022-03-16 Malaysian Palm Oil Board (MPOB) Composition for delaying ageing process and increasing longevity in a subject and methods thereof
WO2021101370A1 (en) * 2019-11-22 2021-05-27 Malaysian Palm Oil Board Composition(s) comprising aqueous oil palm fruit extract for increasing tyrosine hydroxylase levels and improving brain health

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