BE1026269A1 - Anti-inflammatory formulation - Google Patents

Abstract

The present invention relates to a composition having anti-inflammatory properties.

Description

The present invention relates to a novel pharmaceutical, nutraceutical formulation (composition) (or a food additive for human or animal use) or a functional food formulation (composition) (for human or animal use) or a food supplement having an improved formulation of extracts. plants to increase the bioavailability of the active components present in this formulation (composition), and its use in the treatment and / or prevention of inflammation and of syndromes or disorders linked to inflammation.

State of the art

Many agents identified from fruits and vegetables can interfere with multiple cell signaling pathways. Agents include curcumin (turmeric), but also resveratrol (found in black grapes, peanuts and berries), genistein (found in soybeans), diallyl sulfide (found in varieties of Allium), S-allylcysteine (present in varieties of Allium), allicin (present in garlic), lycopene (present in tomato), capsaicin (present in red pepper), diosgenin (present in fenugreek), 6-gingerol (present in ginger), ellagic acid (present in pomegranate), ursolic acid (present in apple, pear, plum), silibinin (present in thistle- Marie), anethole (present in anise, camphor, and fennel), catechins (present in green tea), eugenol (present in cloves), indole-3-carbinol (found in cruciferous vegetables), limonene (found in citrus fruits), beta carotene (found in carrots), and fiber food (found in many fruits and vegetables).

In cell signaling pathways inhibited by curcumin appear to include one or more of the following biological factors

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BE2018 / 5305: NF-κΒ, AP-1, STAT3, Akt, Bcl-2, Bcl-XL, caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX.

Curcumin is the main curcuminoid of the popular Indian curry spice, turmeric. Curcuminoids are polyphenols and are responsible for the yellow color of turmeric.

Extensive work has been done in an attempt to establish the biological activities and pharmacological actions of curcumin, at least in vitro (including experiments carried out on cultured cells). Curcumin may be beneficial for its antitumor (cancer), antioxidant, anti-arthritic, anti-ischemic, anti-diabetic, anti-inflammatory, and anti-inflammatory effects, in addition to possible benefits for cardiovascular disease, neurological disease, and Crohn's disease. . However, at a neutral or basic pH, curcumin is rapidly degraded in vitro.

In addition, when it is eaten, curcumin is little (if at all) absorbed: curcumin undergoes a fervent intestinal metabolism and its intestinal absorption is low, which prevents it from reaching blood concentrations of curcumin compatible with the effects demonstrated in vitro.

It is assumed in the art that blood concentrations of curcumin (and its derivatives) of about 0.5 μΜ to about 6 μΜ are safe and compatible with the beneficial effects measured in vitro.

Aside from metabolism, rapid systemic elimination of curcumin may still contribute to the rather limited clinical effect.

To improve its bioavailability (at the plasma and tissue levels), many approaches have been undertaken. These approaches may involve the use of adjuvants such as piperine. Besides, piperine interferes with glucuronidation, a physiological mechanism (occurring in the liver and small intestine) of modification of compounds foreign to the normal biochemistry of an organism (such as pharmaceutical substances and poisons), in order to increase their solubility in water and their excretion.

Joint supplementation with 20 mg piperine (extracted from black pepper) may increase the plasma concentration of curcumin. However, due to its effects on the metabolism of substances

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BE2018 / 5305 pharmaceutical (i.e. inhibiting glucuronidation), piperine should be taken with caution (if taken) by individuals taking other medicines.

Alternatively, dissolving curcumin in hot water before ingestion, or in warm oily liquids, appears to increase its bioavailability, but this fact is not well established and heat instability of curcumin is frequently postulated.

The heat and light stability of curcumin appears to be increased by its encapsulation in cyclodextrin (Szente et al., 1998, Journal of inclusion Phenomena and Molecular Recognition in Chemistry, 32, 8189).

Other stable metabolites of curcumin, such as tetrahydrocurcumin, are used topically and are possibly found in vivo, but it is unclear whether they offer the same therapeutic activity as curcumin.

The presence of acids increases the stability of curcumin, but decreases its solubility. Conversely, a basic environment increases the solubility of curcumin, but at the expense of greatly reduced stability.

Therefore, care should be taken when formulating more bioavailable curcumin.

The compositions containing curcumin and an alginate or curcumin and gelatin have an increased solubility of> 104 times at pH 5. However, curcumin is not stabilized with respect to hydrolytic or photolytic degradation .

The use of curcumin in liposomes or nanoparticles of curcumin or a phospholipid complex of curcumin can be advantageous.

For example, nanoparticles comprising curcumin having a size of less than 100 nanometers on average are found to have an efficiency comparable to or greater than that of free curcumin in models of human cancer cell line. However, actual in vivo absorption has not been demonstrated with these nanoparticles.

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WO2007 / 101551 describes a method for increasing the bioavailability of curcumin, which involves a simple procedure creating a complex with soy phospholipids, however, the plasma concentration obtained from curcumin when using this formulation 'reaches 0.033 micromolar.

WO2006 / 130679 describes compositions containing chemicals having functional carbonyl groups for the treatment of allergic rhinitis.

This international application WO2006 / 130679 suggests that curcumin (which carries carbonyl groups) may possibly react in vitro with histamine via the formation of Schiff bases involving a carbonyl group of curcumin and the amine group of l histamine, and therefore it is believed that compounds having functional carbonyl groups may be of interest in the treatment of allergic rhinitis (in vivo).

In an example from patent application WO2006 / 130679, a commercial mixture of curcumin and polysorbate is used. However, in patent application WO2006 / 130679, the commercial composition of curcumin with polysorbate appears to be ineffective in a reaction with histamine. In addition, this prior art teaches that overly acidic mixtures should be avoided, since no Schiff base can be formed at an acidic pH.

Finally, patent application WO2006 / 130679 does not describe any data in vivo.

There is therefore a need for new methods resulting in an enhancement of the in vivo effect of curcumin to bring this promising natural product to the forefront of therapeutic agents for the treatment of various human diseases.

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Summary of the invention

The present invention provides a composition comprising a sufficient amount of curcumin, a sufficient amount of an emulsifier and a sufficient amount of citric acid, said composition being intended for use as a medicament or as a food supplement, in which the sufficient amount of curcumin is between 2 mg and 200 mg, in which

- either the emulsifier has a low viscosity at 25 ° C of 0.100 to 0.800 Nsm-2 (Pa.s), in combination with a medium to high hydro-lipophilic ratio, the average hydro-lipophilic ratio being from 6 to 10 and the high hydro-lipophilic ratio being from 11 to 25, and a sufficient quantity of said low viscosity emulsifier is between 400 mg and 700 mg, the sufficient quantity of curcumin is between 10 mg and 100 mg, the ratio of curcumin to the low viscosity emulsifier is between 5:95 and 15:85 (w / w), the citric acid being present at a concentration between 1 mg and 10 mg, the emulsifier being Polysorbate 80;

- either the emulsifier has a high viscosity at 50 ° C, between 75.0 and 175.0 Nsm-2 (Pa.s), in combination with a medium to high hydro-lipophilic ratio, the average hydro-lipophilic ratio being from 6 to 10 and the high hydro-lipophilic ratio being from 11 to 25, and a sufficient quantity of said high viscosity emulsifier is between 200 mg and 500 mg, the sufficient amount of curcumin is between 5 mg and 50 mg, the ratio of curcumin to high viscosity emulsifier is between 5:95 and 15:85 (w / w), citric acid being present in a content of between 1 mg and 10 mg, the emulsifier being Polysorbate 60.

Preferably, the composition is further encapsulated in a gelatin capsule.

Advantageously, the composition also comprises from 3% (w / w) to 30% (w / w) of an essential oil comprising more than 50% of terpene compounds.

Preferably, the composition comprises the low viscosity emulsifier, the sufficient quantity of said low viscosity emulsifier being between 600 mg and 700 mg.

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In a preferred embodiment, the composition comprises the low viscosity emulsifier, and the sufficient amount of curcumin is between 30 mg and 50 mg.

Advantageously, the composition comprises the emulsifier with low viscosity, and the ratio of curcumin to the emulsifier with low viscosity is between 5/95 and 12/88 (w / w).

Preferably, the composition comprises the emulsifier with low viscosity, and the citric acid is present at a concentration of between 2 mg and 5 mg.

In a preferred embodiment, the composition comprises the high viscosity emulsifier, and the sufficient quantity of said high viscosity emulsifier is between 300 mg and 500 mg.

Advantageously, the composition comprises the emulsifier with high viscosity, and the sufficient amount of curcumin is between 10 mg and 30 mg.

Preferably, the composition comprises the emulsifier with high viscosity, and the ratio of curcumin to the emulsifier with high viscosity is between 5/95 and 12/88 (w / w).

In a preferred embodiment, the composition comprises the high viscosity emulsifier, and the citric acid is present at a concentration of between 1 mg and 5 mg.

Advantageously, the composition comprises the emulsifier with high viscosity, and also comprises a desiccant chosen from the group consisting of cellulose, methylcellulose, hydroxypropylcellulose and SiO2.

Preferably, the composition is intended for use in the treatment or prevention of inflammation or diseases associated with inflammation.

In a preferred embodiment, the composition is for use in the treatment or prevention of osteoarthritis.

The present invention therefore provides a new composition and methods for obtaining it, and the use of this composition which does not have the drawbacks of the products of the prior art, in particular

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BE2018 / 5305 in particular a composition and methods which improve the bioavailability of curcumin in mammalian blood, in particular in human blood.

Furthermore, the invention provides a composition which comprises only food ingredients or elements which are compatible for administration as a food additive (for human or animal use) or in a food composition (for human or animal use). ) functional or in a food supplement.

Finally, the invention provides such a composition which can be used to improve the treatment and / or prevention of inflammation and / or syndromes or disorders linked to inflammation, while possibly requiring more administration doses. weak than for the composition known from the state of the art.

The inventors have found a method for increasing the bioavailability of an active compound which is curcumin, for administration to an animal (preferably a mammal, including a human) by supplying this curcumin in a composition containing an edible emulsifier ( and advantageously compatible with food).

Advantageously, the composition of the invention can also comprise an essential oil (preferably a mixture (without water) of monoterpenes and / or sesquiterpenes).

By supplying (administering) this composition to an animal, this concentration value of curcumin (including curcumin derivatives, preferably chosen from the group consisting of dihydrocurcumin, tetrahydrocurcumin and glucuronides and sulfate derivatives of curcumin, dihydrocurcumin and tetrahydrocurcumin) in the blood of this animal (preferably the blood of a mammal, including a human) is at least 0.5 μΜ.

Advantageously, in the process of the invention, from approximately 20 mg to approximately 500 mg of this curcumin (preferably from approximately 40 mg to approximately 120 mg of curcumin) present in this composition are given (administered) (orally) ) on a daily basis (to a human adult) so that a blood concentration of this curcumin and of derivatives of curcumin (including also glucuronides and sulphate derivatives of curcumin, is reached,

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BE2018 / 5305 and possibly tetrahydrocurcumin) of at least (approximately) 0.5 μΜ (in a human adult), preferably of at least (approximately) 1 μΜ.

Alternatively, from approximately 100 mg to approximately 250 mg of curcumin, preferably approximately 150 mg (alternatively approximately 168 mg) of curcumin present in the composition of the invention are given (administered) (orally) on a base daily to reach a blood concentration of this curcumin and curcumin derivatives (including also glucuronides and sulphate derivatives of curcumin, as well as possibly tetrahydrocurcumin) of at least (approximately) 1.5 μΜ (in a adult human), preferably at least (approximately) 2 μΜ.

Consequently, one aspect of the present invention relates to a pharmaceutical, nutraceutical (also called food additive composition for human (or animal)) or functional food composition for human or animal use or a food supplement comprising (or consisting of):

- optionally a suitable vehicle or diluent (compatible with a pharmaceutical compound or a food for human or animal use) and

- a sufficient amount of curcumin (E100), an emulsifier and possibly an essential oil (a mixture (without water) of more than 50% of terpene compounds: monoterpenes and / or sesquiterpenes);

this composition preferably being used as a medicament or as a food supplement, better still used for the treatment and / or prevention of an inflammation or of an syndrome or disorder linked to an inflammation, preferably for the treatment and / or prevention of osteoarthritis.

Advantageously, in the (pharmaceutical) composition according to the invention, the sufficient amount of curcumin (present in a capsule) is between approximately 2 mg and approximately 200 mg, preferably between approximately 2 mg and approximately 10 mg, better still between approximately 20 mg and about 50 mg, preferably is about 42 mg; alternatively is approximately 30 mg.

By inflammation-related syndrome or disorder is meant a disease of a mammal (human) caused by or in an inflamed state, including inflammation.

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More specifically, syndromes or disorders linked to inflammation include cancer, cardiovascular diseases, preferably chosen from the group consisting of atherosclerosis and ischemic heart disease (ischemia), asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivity, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, autoimmune diseases or an allergic disease, such as rhinitis, osteoarthritis (rheumatoid arthritis) , transplant rejection, angeitis, abdominal obesity and / or neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Huntington's chorea.

These syndromes or disorders also include allergic reactions formerly known as type 1 hypersensitivity (which are the result of an inappropriate immune response (inflammation-related disorder) triggering inflammation and other hypersensitivity reactions. (type 2 and type 3) mediated by antibody reactions that induce inflammation by attracting leukocytes, which damage surrounding tissue. These syndromes and disorders also include inflammatory myopathies due to an inappropriate attack on the immune system against a muscle, leading to muscle inflammation (which can occur in conjunction with other immune disorders, such as systemic sclerosis, and including dermatomyositis, polymyositis, and inclusion body myositis). These syndromes and disorders include also a high level of several markers linked to inflammation, preferably chosen in the group of IL-6, IL-8 and TNF-alpha, which are associated with obesity.

Prolonged inflammation (an inflammation-related disorder), called acute or chronic inflammation, leads to a gradual shift in the type of cells that are present at an inflammation site, and is characterized by simultaneous destruction and scarring of tissues due to the inflammatory process which can lead to known chronic diseases, syndromes or disorders, preferably chosen from the group consisting of obesity, diabetes mellitus, cardiovascular and cerebrovascular diseases such as hypertension or ischemia, autoimmune diseases (including inflammatory diseases such as arthritis or lupus), diseases of the

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BE2018 / 5305 brain (including neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, depression or schizophrenia), asthma, systemic sclerosis, allergies and cancer, one or all of the diseases identified above being treated and / or prevented by the composition of the invention.

Osteoarthritis is the disease which is especially preferred to be treated and / or prevented by the composition of the invention.

Another consequence of the disorders linked to an inflammation is pain, which will also be treated and / or prevented by the composition of the invention. Diseases involving pain in connective tissues, such as fibromyalgia, also constitute a syndrome or disorder treated and / or prevented by the present invention.

Consequently, in the present description, the applicant will use, for the same effect, the expressions chronic inflammation, disease associated with chronic inflammation and inflammatory disorders, which constitute a large and related group of syndromes and disorders collectively called syndrome or associated disorder. inflammation, underlying various mammalian (human) diseases.

Preferably, the pharmaceutical composition or the food supplement of the present invention may also comprise an acid component, preferably an organic acid, better still chosen from the group consisting of citric acid (E330), malic acid (E296 ), acetic acid (E260), tartaric acid (E334), lactic acid (E270), alginic acid (E400) or their mixtures.

Advantageously, the pharmaceutical composition or the food supplement of the present invention is combined with (encapsulated in) a suitable vehicle, preferably a capsule, a pearl, a pill or a tablet, which is preferably compatible with food, such as gelatin (capsule), and which can be better still coated with an element (compatible with food) which makes this composition resistant to gastric digestion in the stomach, better still this element being E904 (shellac).

The present invention also relates to a functional pharmaceutical, nutraceutical or food composition for human use or

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BE2018 / 5305 animal (including a food additive for human / animal use) or a food supplement, which is preferably a non-aqueous solution and which comprises (or consists of):

- possibly a suitable vehicle or diluent (compatible with a pharmaceutical compound or food) and

- a sufficient quantity of curcumin, a sufficient quantity of an emulsifier and a sufficient quantity of citric acid and possibly a sufficient quantity of an essential oil (a mixture (without water) of monoterpenes and / or sesquiterpenes), preferably for use as a medicament or as a food supplement and better still for use in the treatment and / or prevention of inflammation or of syndromes or disorders linked to inflammation, better still in the treatment and / or prevention osteoarthritis (rheumatoid arthritis).

Advantageously, the composition (in the form of either a non-aqueous solution or a solid composition and / or in a capsule) of the invention, comprising a sufficient amount of curcumin, a sufficient amount of an emulsifier and optionally a sufficient amount of an acid, is taken orally and is a composition (pharmaceutical or nutraceutical or functional food for human or animal use or a dietary supplement) per os.

Preferably, between approximately 2 mg and approximately 200 mg of curcumin, better still between approximately 2 mg and approximately 100 mg of curcumin, better still between approximately 20 mg and approximately 50 mg of curcumin, a sufficient quantity of an emulsifier and possibly a a sufficient amount of an acid are formulated in a capsule according to the present invention, this capsule being the pharmaceutical composition or the food supplement of the invention.

Advantageously, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10 capsules, preferably 1 to 6 capsules, better still 2 to 4 capsules of the invention are taken by a subject on a daily basis.

By approximately, it is preferably meant a variation of plus or minus 10%.

For example, about 5% means any real number ranging from 4.5% to 5.5%.

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Advantageously, this composition is suitable for being taken orally, one, two or three times a day.

The composition for oral use of the invention may also comprise a sufficient amount of an essential oil of plant. The preferred essential oils according to the invention are chosen from the group consisting of agar-agar essence, ajwain essence, anise essence, balsamine essence, parsley essence, the essence of bergamot, the essence of cardamom seed, the essence of carrot seed, the essence of chamomile, the essence of calamus, the essence of cinnamon, the essence of lemongrass, the essence of fennel seed, fenugreek essence, frankincense essence, galangal essence, geranium essence, ginger essence, grapefruit essence, henna essence, essence juniper, lavender essence, lemongrass essence, lemon balm essence, mint essence, myrrh essence, orange essence, oregano essence, essence iris, the essence of peppermint, the essence of pine, the essence of rose hips, the essence of sage, the essence of schizandra, jatamansi, the essence of tarragon, the essence of tea tree, thyme essence, turmeric essence, the essence of valerian, the essence of yarrow and the essence of zeodaire, and the essence of turmeric is more preferred.

Advantageously, in the composition of the invention, from approximately 3% (w / w) to approximately 30% (w / w), preferably from approximately 5% (w / w) to approximately 15% (w / w) ), better still about 7% (w / w) of essential oils are present (added (to the other elements of the composition of the invention)).

In the pharmaceutical (or nutraceutical) composition or in the food supplement of the invention, preferably from approximately 25 ml to approximately 200 ml, better still approximately 50 ml of essential oils (without water) can be added.

The term “essential oils” is understood to mean volatile and liquid (but not aqueous) aromatic compounds obtained from natural sources, usually from plants, having a poor solubility in water.

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Essential oils are usually prepared by extraction techniques, preferably selected from the group consisting of distillation (including steam distillation), cold pressing, extraction (maceration) and / or solvent extraction . The essential oils of the invention comprise more than 50% (consist essentially) of compounds (related to) terpenes, such as monoterpenes and / or sesquiterpenes, and are preferably without water.

By essentially consisting of compounds (related to) terpenes is meant that at least 50% (in moles), preferably at least 70%, better still at least 80% of essential oils, or all essential oils, consist of compounds (related to) terpenes and are preferably without water).

Terpenes are derived by biosynthesis from isoprene motifs. The monoterpenes are made up of two isoprene units and the sesquiterpenes are made up of three isoprene units. Additional hydrolysis and / or rearrangements and oxidations carried out on the isoprene framework (monoterpenes and / or sesquiterpenes) give the final terpene compounds of an essential oil.

As a variant, the most abundant molecules of an essential oil (terpene compounds originating from essential oils) can be used in the composition of the invention, in place of a complex essential oil, for example the compounds (related to ) terpenes, preferably chosen from the group consisting of ar-turmerone, turmerone, curlone, arcurcumene and p-cymene as well as their mixtures.

Advantageously, several emulsifiers are present and are combined (mixed) in the composition of the invention, provided that their average HLB, their viscosity, their content and their proportion are maintained within the ranges disclosed below.

Preferred emulsifiers according to one embodiment have low viscosity and good water solubility.

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Advantageously, the emulsifier (s) present in the composition according to the present invention have a low viscosity (at 25 ° C), of approximately 0.100 to 0.800 Pa.s, combined with an average hydro-lipophilic ratio (HLB) (6-10 ) to high (11-25), and it is preferably Polysorbate 80.

Advantageously, in the composition (in the form of a non-aqueous solution) according to the invention, a sufficient quantity of one or more low-viscosity emulsifiers is between approximately 200 mg and approximately 700 mg, better still between approximately 400 mg and about 700 mg, more particularly between about 600 mg and about 700 mg, preferably between about 600 mg and about 650 mg.

Advantageously, in the composition (in the form of a non-aqueous solution) according to the invention, a sufficient amount of curcumin is between approximately 5 mg and approximately 200 mg, preferably between approximately 10 mg and approximately 100 mg, better still between about 30 mg and about 50 mg, more preferably is about 40 mg (alternatively about 42 mg).

Preferably, the ratio of curcumin to low viscosity emulsifier (s) is between about 1/99 and about 30/70 (w / w), more preferably between about 5/95 and about 15/85 (w / w) , more particularly between approximately 5/95 and approximately 12/88 (w / w), even more particularly is approximately 6/94 (w / w).

Advantageously, in the composition (in non-aqueous solution) according to the invention, the acid component (preferably citric acid) is present in an amount of between approximately 0.5 mg and approximately 35 mg, better still between approximately 1 mg and about 10 mg, more preferably between about 2 mg and about 5 mg, more preferably is about 3 mg (alternatively, is preferably about 3.5 mg).

The composition (in non-aqueous solution) according to the invention may optionally also comprise a sufficient amount of one or more essential oils (monoterpenes and / or sesquiterpenes).

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As a variant, in another embodiment of the invention, the emulsifier or emulsifiers present in the (solid) composition according to the present invention have a high viscosity (at 50 ° C.), of between approximately 75.0 and approximately 175, 0 Pa.s, combined with a medium (6-10) to high (11-15) hydro-lipophilic (HLB) ratio, this emulsifier preferably being Polysorbate 60.

Advantageously, in the composition (solid) according to the invention, a sufficient quantity of the emulsifier or emulsifiers with high viscosity is between approximately 100 mg and approximately 700 mg, better still between approximately 200 mg and approximately 500 mg, more particularly between approximately 300 mg and about 500 mg, and more preferably about 300 mg (or alternatively about 260 mg).

Advantageously, in the composition (solid) according to the invention, a sufficient amount of curcumin is between approximately 2 mg and approximately 100 mg, preferably between approximately 5 mg and approximately 50 mg, better still between approximately 10 mg and approximately 30 mg, better still is around 16 mg.

Preferably, the ratio of curcumin to emulsifiers or to high viscosity present in the composition is between approximately 1/99 and approximately 20/80 (w / w), better still between approximately 5/95 and approximately 15/85 ( w / w), more particularly between about 5/95 and about 12/88 (w / w), more particularly is about 6/94 (w / w).

Advantageously, in the composition (solid) according to the invention, the acid component is present at a concentration (content) of between approximately 0.25 mg and approximately 35 mg, better still between approximately 1 mg and approximately 10 mg, better still between about 1 mg and about 5 mg, better still is 1.5 mg.

The composition (solid) according to the invention can also optionally comprise a sufficient amount of one or of a mixture of several essential oils (monoterpenes and / or sesquiterpenes).

Advantageously, the composition (solid) comprises a sufficient amount of curcumin, one or more emulsifiers with high viscosity, an acid, and a siccative.

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The siccative present in the composition is any substance (inert and compatible with food) capable of absorbing (and consequently allowing a solid appearance such as a powder) the emulsifier (s) with high viscosity and it is of preferably selected from the group consisting of cellulose, methylcellulose, hydroxypropylcellulose (and combinations thereof), and SiO2.

The preferred drier according to the invention is SiO2.

Advantageously, the amount of the siccative (preferably particles of S1O2) present in the composition is between approximately 50 mg and approximately 400 mg, preferably between approximately 100 mg and approximately 300 mg, better still is approximately 120 mg.

Preferably, this siccative (preferably S1O2) is added to the pharmaceutical composition in a ratio of 1/10 to about 5/10, more preferably about 3/10 (w / w). Preferably, the particles of S1O2 added to the composition of the invention are made of silica having a high absorption capacity.

Preferably, the particles of S1O2 added to the composition of the invention are made of silica having a small particle size, with an average diameter situated in the range ranging from approximately 5 μm to approximately 100 μm, optionally sold under the name Sipemat 50S .

Preferably, the S1O2 of the invention is not derived.

Another aspect of the present invention relates to a method of treating an inflammatory disease by the step of administering a sufficient amount of the composition of the invention to a mammalian subject (preferably a human patient), possibly suffering from 'one of the disorders, syndromes and diseases mentioned above.

More preferably, in the method of the invention, from about 20 mg to about 500 mg of curcumin (preferably from about 40 mg to about 170 mg of curcumin; alternatively from about 40 mg to about 120 mg) are administered on a daily basis to this mammalian subject (preferably to an adult human patient) so that the blood concentration of this curcumin and of curcumin derivatives reaches a concentration value of at least (approximately) 0.5 μΜ (in a adult human).

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A final aspect of the invention is a process for obtaining the composition of the invention, comprising (consisting of) the steps of:

- preparation or obtaining of practically pure curcumin,

- dissolution of the practically pure curcumin in an adequate quantity of an emulsifier, preferably with an organic acid,

- possibly addition of a sufficient quantity of one or a mixture of essential oils (monoterpenes and / or sesquiterpenes),

- optionally mixing the composition consisting of this curcumin and this emulsifier on a dryer and grinding the particles,

filling a capsule (of gelatin) with this composition comprising (consisting of) this curcumin and this emulsifier and optionally this siccative,

- possibly obtaining an enteric coating (with the addition of one or more layers of E904) of this capsule (of gelatin) and

- recovery of the composition of the invention.

Preferably, the capsule (of gelatin) makes it possible to condition from approximately 700 mg to approximately 1000 mg of the composition (liquid) of the invention.

Preferably, the capsule (of gelatin) makes it possible to package approximately 400 mg of the composition (solid) of the invention.

Detailed description of the invention Definitions

Curcumin is also known as [1,7-bis (4hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione, diferuloylmethane or food additive E100.

The present invention encompasses curcumin, including its keto and enol forms, but preferably neither the chemically derived forms of curcumin nor the di-tetra- or hexahydrocurcumin.

Polysorbate 80, E433, Tween®80 or sorbitan monooleate

PEG 20 is an emulsifier.

Polysorbate 60, E435, Tween®60, sorbitan monostearate

PEG 20 is an emulsifier.

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By viscosity is meant the dynamic viscosity, expressed in Pa * s.

By emulsifier is meant an edible compound which is amphiphilic and therefore has the potential to reduce the tension at the interface between a hydrophobic compound (such as curcumin) and water by adsorption at the liquid-liquid interface. The emulsifiers of the present invention can assemble into aggregates, such as micelles which can encapsulate the hydrophobic compound of the invention.

The inventors have surprisingly found that acid mixtures of curcumin with the emulsifiers and possibly with essential oils (monoterpenes and / or sesquiterpenes) according to the invention result in better curcumin stability and sustained solubility under duodenal conditions. (for example in a phosphate buffer at pH 6.8, 37 ° C, bioavailability and a clinical effect.

Examples Example 1

Commercial curcumin having a purity of at least 90% is used (the inventors have preferably selected batches of curcumin having a purity of at least 95% or 96% and preferably close to 100%). These batches were obtained after extraction with ethanol and recrystallization from methanol.

Preparation of the liquid extract

The curcumin preparation is carried out using curcumin powder having a small particle size (having a preferred and advantageous particle size of between approximately 100 and approximately 200 μm). First, the citric acid crystals (having an advantageous particle size of less than 150 μm) are mixed with the curcumin. The resulting mixture is stirred in Polysorbate 80. After heating to 30 ° C for adequate homogenization, this complete mixture is mixed for 45 minutes. Then all the mixture is ground in a three roller mill (preferably a Coball mill) and the enclosure is aerated with nitrogen to remove the air present. We encapsulate

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BE2018 / 5305 then the preparation briefly in gelatin capsules, preferably at the rate of approximately 700 mg per capsule.

The inventors used uncoated capsules and also enteric coated capsules with the addition of E904 (shellac).

The concentration of pure curcumin is preferably 6%, with 0.5% citric acid, the complement to 100% being Polysorbate 80.

Example 2

The preparation is carried out as in Example 1, but using a high viscosity emulsifier, preferably Polysorbate 60. Then S1O2 is added to a final percentage of 10% to 60%, preferably from 30% to 40% maximum (better still around 30%) in a planetary mixer or in a mixer with high shear speed, until a fluid and homogeneous powder is obtained. This powder can be compressed into a tablet or filled with hard capsules (preferably 400 mg per capsule).

The concentration of pure curcumin in the final composition is preferably 4%, with 0.35% citric acid and a final concentration of SiO2 preferably 30%.

All percentages are by weight (w / w).

Example 3

The solubility of curcumin in the liquid composition of Example 1 is measured by shaking 1.4 g (equivalent to a dosage of 2 capsules of 700 mg per day) of this preparation (containing 84 mg of curcumin) in 900 ml of phosphate buffer, pH 6.8, for 1 hour at 37 ° C.

For comparison, the same amount (84 mg) of curcumin is dissolved in phosphate buffer, pH 6.8, for 1 hour at 37 ° C.

After one hour, the solution is filtered through a 0.2 μm filter and the solubilized curcumin is quantified. Curcumin dissolved in the liquid composition of Example 1: 35% of the initial dose.

Curcumin in the composition of Example 1 is 8750 times more soluble than curcumin without polysorbate and citric acid.

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The solubility of curcumin in the powder composition of [Example 2 is measured by shaking 1.2 g (equivalent to a dosage of 3 capsules of 400 mg per day) of this preparation (containing 48 mg of curcumin) in 900 ml of phosphate buffer, pH 6.8, for 1 hour at 37 ° C.

By way of comparison, the same quantity (48 mg) of curcumin is dissolved in phosphate buffer, pH 6.8, for 1 hour at 37 ° C. After one hour, the solution is filtered through a 0.2 μm filter and the solubilized curcumin is quantified. Curcumin dissolved in the liquid composition of [Example 2: 30% of the initial dose.

Curcumin in the composition of [Example 2 is 6000 times more soluble than curcumin without polysorbate and citric acid.

Example 4

Composition

Curcumin preparation is carried out as in [Example using curcumin powder having a small particle size (100-200 μm). First, citric acid crystals (having an advantageous particle size of less than 150 μm) are mixed with the curcumin. The resulting mixture is stirred in Polysorbate 80 and essential oil of turmeric, extracted from rhizomes of Curcuma longa L. by supercritical extraction. It contains at least 60% of total turmerones (aromatic turmerones, alpha-turmerone and beta-turmerone). It is also possible to apply hydrodistillation or steam distillation to extract said essential oil. After heating the complete mixture to 30 ° C, it is mixed for 45 minutes. Then all the mixture is ground in a Coball mill (preferably a three roller mill) and the enclosure is aerated with nitrogen. The preparation is then briefly encapsulated in gelatin capsules, preferably provided with an enteric coating, preferably at the rate of 700 mg per capsule.

The resulting composition consists of 6% (w / w) curcumin,

0.5% (w / w) citric acid and 7.14% (w / w) essential oil of turmeric, the complement to 100% being Polysorbate 80 (86.36%; w / w).

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Solubility

The solubility of curcumin in the liquid composition of Example 4 is measured by shaking 1.4 g (equivalent to a dosage of 2 capsules of 700 mg per day) of this preparation (containing 84 mg of curcumin) in 900 ml of phosphate buffer, pH 6.8, for 1 hour at 37 ° C.

For comparison, the same amount (84 mg) of the curcumin preparation of Example 1 is dissolved in phosphate buffer, pH 6.8, for 1 hour at 37 ° C.

After one hour, the solution is filtered through a 0.2 μm filter and the solubilized curcumin is quantified. Solubilized curcumin from Example 1: 35% of the initial dose. Solubilized curcumin from Example 4 (with the addition of essential oil): 50% of the initial dose.

The inventors repeated the same experiment but replacing the essential oils of turmeric with the same amount of essential oil of peppermint, and they obtained the same improved solubility compared to the composition of curcumin comprising only an emulsifier.

As witnesses, the inventors mixed curcumin with essential oils, and measured only a poor solubility of curcumin, close to the solubility of pure curcumin.

The inventors conclude that curcumin in a composition comprising an emulsifier and supplemented with an essential oil is 500 times more soluble than a composition of curcumin with essential oils but without emulsifier, and 1.5 times more soluble than a composition of curcumin with an emulsifier and citric acid (without essential oils), although the amount of emulsifier is reduced in the composition of curcumin with citric acid, an emulsifier and essential oils.

Example 5

Oral bioavailability test

The inventors first evaluated the acute toxicity of the formulation of the invention.

The inventors observed no toxicity. Rats were administered a predefined high dose (5000 mg / kg) of the formulation of Example 1 in

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BE2018 / 5305 a single oral dose. The animals were observed daily for at least 14 days.

Then the formulation of Example 1 was studied in human volunteers to assess the relative oral bioavailability. Twenty-four healthy volunteers, aged 18 to 55, were selected for the study. The following treatments have been administered as single doses (once a day): 1 enteric-coated capsule (6 men and 6 women), and 2 enteric-coated capsules (6 men and 6 women). The enteric coated capsule is a gelatin capsule coated with shellac and filled with 700 mg of a mixture of curcumin (6%; 42 mg), citric acid (0.5%; 3.5 mg) and, as an emulsifier, Polysorbate 80. Blood samples were taken at midnight and periodically at hour or half hour intervals for 12 hours (0, 0.5, 1, 1.5 , 2, 3, 4, 6, 8 and 12 hours after administration). At each sample collection, 6 ml of blood were sampled in heparin tubes. After centrifugation, the plasma was transferred to two labeled tubes. An internal standard (pipenbuterol) was pipetted into the first tube and extracted with methanol and acetonitrile. The extract was analyzed by UPLC-MS / MS on a BEH-C18 column (100 x 2.1 mm, particle size 1.7 μm) using water + formic acid and acetonitrile + formic acid as as solvent. The flow rate of the eluent was 0.6 ml / min, and detection was carried out using an electron beam ionization (ESI) source operating in positive ionic mode. The effectiveness of the extraction procedure for recovering curcumin from blood samples was determined by recovering curcumin from normal blood samples. The recovery of curcumin was calculated at three different concentration levels with at least 5 repetitions by comparing the peak area for curcumin with that obtained by direct injection of reference solutions in triplicate at the same concentration levels.

No quantifiable trace of non-metabolized curcumin was observed regardless of subject, time point, and dose.

The blood samples were then analyzed after hydrolysis of potential conjugated metabolites of curcumin using b-glucuronidase and arylsulfatase. We measured the curcumin and its conjugates in the

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BE2018 / 5305 samples after incubating the plasma samples with the enzymes bglucuronidase and sulfatase. For these assays, 200 μΙ of plasma samples were mixed with 20 μΙ of 1 étate acetate buffer (pH 5.5), 5 μΙ of bglucuronidase and arylsulfatase solution, and 20 μΙ of internal standard solution (clenbuterol; 2 μg / ml). The samples were incubated at 37 ° C for 3 hours (determination after a test run).

The samples were extracted with 1 ml ethyl acetate / methanol (95/5; v / v). After centrifugation, the supernatant was slowly evaporated to dryness under a stream of nitrogen at room temperature and it was reconstituted in 100 μΙ of methanol and 50 μΙ of water, and 7.5 μΙ were injected into the system. UPLC.

After this treatment with b-glucuronidase and with arylsulfatase, the inventors observed Cmax values of curcumin in the blood of 196 ng / ml and 333 ng / ml (Table 1).

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Table 1 - Summary of statistics for curcumin derivatives (measured as curcumin after hydrolysis of curcumin derivatives); pharmacokinetic parameters per dose

AUC (O-inf) (ng * h / ml) AUC (O-t) (ng X h / ml) Cmax (Ng / ml) Tlag (H) Tmax (H) T1 / 2 (H) 1 capsule not 11 12 12 12 11 Average (AND.) 888.974 (571.7139) 724603 (479.7565) 195.742 (136.6893) 3,167 (2.1567) 5,000 (2.9233) 2697 (0.8636) Average CV% 64.312 66.210 69.831 68.11 58.465 32.018 Geo Average 658.000 539.480 145.981 2.4626 4,219 2584 Average geo CV% 119.7742 116.4587 110.6014 103.23 72.3560 30.7865 Median 1057.820 661.815 176.600 3,000 4,000 2,370 [Mm; Max] [117.86; 1900.67] [87.80; 1704.48] [29,70, 480.90] [0.50; 8.00] [1.00; 12,00] [173 4,53] 2 capsules not 10 12 12 12 12 10 Average (AND.) 1938.345 (1090.9189) 1330.797 (945.9549) 333.033 (252.9666) 2,792 (1.6020) 5,042 (2.2203) 3,148 (0.9816) Average CV% 56281 71082 75.958 57.38 44.040 31.181 Geo Average 1625.572 957.501 241.916 2,368 4,364 3,015 Average geo CV% 75.1433 123.9572 112.0137 67.794 71.8203 31.6947 Median 1594.145 1231.100 269.950 2,500 6,000 2,860 [Min; Max] [540.89; 3804.92] [135.30; 3338.43] [45.50; 847.80] [1.00; 6,00] [1.00; 8.00] [1.78; 4,66]

Various articles have demonstrated that these low doses of curcumin for oral use (unformulated) (42 or 84 mg of curcumin) were not at all bioavailable, even in metabolized forms (glucuronides or sulfates of curcumin).

The inventors have also confirmed this aspect by giving the same amount of curcumin in a 700 mg capsule without emulsifier. They did not measure curcumin in the blood, even after treatment with bglucuronidase and arylsulfatase, as above.

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The inventors then compared enteric coated capsules with uncoated capsules comprising the same amount of curcumin and emulsifier.

After treatment with b-glucuronidase and arylsulfatase as above, the inventors observed similar maximum blood values, with a Cmax value of curcumin in the blood of approximately 300-350 ng / ml in both cases (2 capsules had been administered).

Overall, the inventors conclude that the composition they have developed is bioavailable, and have mainly measured curcumin derivatives.

Example 6

Clinical tests

The inventors then evaluated the compositions of the invention (preferably the composition of Example 1) in the treatment of osteoarthritis.

The inventors selected 280 patients suffering from osteoarthritis of the knee and randomized them (50/50) into a placebo group and a treated group.

The treated group received 4 capsules (one capsule: 42 mg curcumin; 3.5 mg citric acid and, as an emulsifier, Polysorbate 80) of the invention per day, for 14 days, while the placebo group received 4 (visually) identical capsules without curcumin.

The study was double blind and was carried out at several sites and monitored by expert rheumatologists.

Patients were selected according to inclusion criteria such as age (40-80 years), the presence of knee osteoarthritis associated with pain (by means of a similar visual scale; VAS; typically the patients had had a VAS> 50 mm over 24 hours without taking an analgesic), and exclusion criteria such as the coexistence of other rheumatoid diseases or another medication (except paracetamol).

Lequesne's index (overall pain and physical capacity index of the patient) was measured on day 0 and day 14, as well as pain (VAS) and the pictorial representation of their knee affected by arthritis.

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Patients were asked to rate their pain rating on the Likert scale (0: no pain at all; 10: maximum pain) on a daily basis and, if they were taking paracetamol, the amount (maximum 4 g per day, with the exception of days 13-14 when paracetamol was not authorized). During the study, patients were also asked not to take anti-inflammatory or analgesic compounds (other than paracetamol).

The inventors have also monitored the appearance of any undesirable effects.

On day 14, the pain estimate (VAS), the Lequesne index, and all the data collected by the patients (patient assessment of pain on the Likert scale, amount taken of paracetamol) were collected.

When all the patients had finished the 14-day treatment, the inventors made the data open.

There was no difference in adverse events between the placebo and treated groups.

The main difference compared to the placebo group was a reduction in pain (VAS and / or Likert scale) and / or Lequesne's score, measured by the doctor and / or by the patients between day 0 and day 14 and / or consumption of paracetamol between days 1 and 12.

Overall, the inventors conclude that the patients who received the capsules according to the invention (containing curcumin, an organic acid and an emulsifier) presented a reduction in pain and an improvement in capacities. They therefore conclude that the formulation they have developed is effective in the treatment of osteoarthritis and / or its symptoms.

The present invention has been described in relation to specific embodiments, which have a purely illustrative value and should not be considered as limiting. In general, it will be obvious to a person skilled in the art that the present invention is not limited to the examples illustrated and / or described above. The presence of reference numbers in the drawings cannot be considered to be limiting, including when these numbers are indicated in the claims.

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The use of the verbs "to understand", "to include", "to include", or any other variant, as well as their conjugations, cannot in any way exclude the presence of elements other than those mentioned.

The use of the indefinite article "a", "an", or of the definite article 5 "le", "la" or "I '", to introduce an element does not exclude the presence of a plurality of these elements.

Claims (14)

1. Composition containing a sufficient quantity of curcumin, a sufficient quantity of an emulsifier and a sufficient quantity of citric acid, said composition being intended for use as a medicament or as a food supplement, the sufficient quantity of curcumin being between 2 mg and 200 mg, in which either the emulsifier has a low viscosity at 25 ° C of 0.100 to 0.800 NsmW -2 (Pa.s), in combination with a medium to high hydro-lipophilic ratio, the average hydrolipophilic ratio being from 6 to 10 and the high hydro-lipophilic ratio being from 11 to 25, and a sufficient amount of said low viscosity emulsifier is between 400 mg and 700 mg, the sufficient amount of curcumin is between 10 mg and 100 mg, the ratio of curcumin to low viscosity emulsifier is between 5:95 and 15:85 (w / w), citric acid being present at a concentration between 1 mg and 10 mg, the Emulation sifier being Polysorbate 80; either the emulsifier has a high viscosity at 50 ° C, between 75.0 and 175.0 Nsm-2 (Pa.s), in combination with a medium to high hydro-lipophilic ratio, the average hydro-lipophilic ratio being from 6 to 10 and the high hydro-lipophilic ratio being from 11 to 25, and a sufficient amount of said high viscosity emulsifier is between 200 mg and 500 mg, the sufficient amount of curcumin is between 5 mg and 50 mg, the ratio of curcumin to high viscosity emulsifier is between 5:95 and 15:85 (w / w), citric acid being present in a content of between 1 mg and 10 mg, the emulsifier being the Polysorbate 60. 2. A composition for use according to claim 1, which is further encapsulated in a gelatin capsule. 2018/5305 BE2018 / 5305 3. Composition for use according to claims 1 or 2, further comprising from 3% (w: w) to 30% (w: w) of an essential oil comprising more than 50% of terpene compounds. 4. Composition for use according to any one of the preceding claims, comprising the low viscosity emulsifier, in which the sufficient quantity of said low viscosity emulsifier is between 600 mg and 10,700 mg. 5. Composition for use according to any one of the preceding claims, comprising the low viscosity emulsifier, in which the sufficient amount of curcumin is between 30 mg and 50 mg. 6. Composition for use according to any one of the preceding claims, comprising the low viscosity emulsifier, in which the ratio of curcumin to the low viscosity emulsifier is between 5:95 and 12:88 (p / w). 7. Composition for use according to any one of the preceding claims, comprising the emulsifier with low viscosity, in which the citric acid is present at a concentration of between 2 mg and 5 mg. 8. Composition for use according to any one of claims 1 to 3, comprising the high viscosity emulsifier, in which the sufficient quantity of said high viscosity emulsifier is between 300 mg and 500 mg. 9. Composition for use according to any one of claims 1 to 3 or 8, comprising the high viscosity emulsifier, in which the sufficient amount of curcumin is between 10 mg and 30 mg. 2018/5305 BE2018 / 5305 10. Composition for use according to any one of claims 1 to 3 or 8 to 9, comprising the high viscosity emulsifier, in which the ratio of curcumin to the high viscosity emulsifier is between 5:95 and 12:88 (w / w). 11. Composition for use according to any one of claims 1 to 3 or 8 to 10, comprising the emulsifier with high viscosity, in which the citric acid is present at a concentration of between 1 mg and 5 mg. 12. Composition for use according to any one of claims 1 to 3 or 8 to 11, comprising the high viscosity emulsifier, further comprising a desiccant selected from the group consisting of cellulose, methylcellulose, hydroxypropylcellulose and SiO2. 13. Composition according to any one of the preceding claims, for use in the treatment or prevention of inflammation or of diseases associated with inflammation. 14. The composition for use according to claim 13, for which the disease associated with inflammation is osteoarthritis. PATENT COOPERATION TREATY INTERNATIONAL-TYPE RESEARCH REPORT DRAWN UP UNDER ARTICLE XI.23., §10 OF THE CODE OF BELGIAN ECONOMIC LAW IDENTIFICATION OF THE INTERNATIONAL APPLICATION REFERENCE OF THE DEPOSITOR OR REPRESENTATIVE T800BE prio Belgian national application n ° 201805305 Date of filing 09-05-2018 Priority date claimed Submitter (Name) TILMAN SA Date of the request for an international type search 02-06-2018 Number assigned by the international search administration to the request for an international search SN71350 I. CLASSIFICATION OF THE SUBJECT OF THE REQUEST (in the case of several symbols of the classification, indicate them all) According to the International Patent Classification (IPC) or both according to the national classification and the IPC A61K9 / 48; A61K31 / 12; A61P29 / 00 II. RESEARCH AREAS Minimum documentation consulted Classification system Classification symbols CPI A61K Documentation consulted other than the minimum documentation insofar as these documents form a large part of the fields consulted III. | JlL HAS BEEN ESTIMATED THAT SOME CLAIMS CANNOT BE SEARCHED (Comments on additional sheet) IV. THE ABSENCE OF UNITY OF THE INVENTION AND / OR FINDING RELATING TO THE SCOPE OF THE RESEARCH (Comments on the additional sheet)