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  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/0216—Solid or semisolid forms
  • A61K8/022—Powders; Compacted Powders
• • A—HUMAN NECESSITIES
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  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
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  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4816—Wall or shell material
  • A61K9/4825—Proteins, e.g. gelatin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2200/00—Function of food ingredients
  • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof

Definitions

• the present invention relates to powder solid dispersions comprising, phospholipids and a very to freely water soluble carrier.
• the invention also relates to a process for the preparation of said powder solid dispersions and pharmaceutical, nutraceutical and cosmetic compositions comprising said powder solid dispersions.
• Quercetin (namely 2-(3 ,4-Dihydroxyphenyl)-3 ,5 ,7-trihydroxy-4H-chromen-4-one) having formula (I), belongs to the chemical family of flavonols, a sub-class of flavonoids. Quercetin is a lipophilic citron yellow powder, substantially insoluble in water, but soluble in ethanol, methanol, acetone and other lipophilic organic solvents. Quercetin has a melting point of 316°C.
• Quercetin is present, mainly as quercetin glycosides, in many fruits and vegetables, including apples, grapes, onions, capers, berries, radish.
• Quercetin has many potential beneficial effects on human health, including antioxidant, anti-inflammatory, anti-allergy and anti-asthmatic effects.
• the anti-allergy and anti-asthmatic activities of quercetin are mediated by an inhibitory effect on histamine release by mast cell and basophils. Quercetin has been also studied for its potential anticancer effect due to different mechanisms of action.
• quercetin has gained growing attention as nutraceutical and pharmaceutical ingredient.
• the potential efficacy of quercetin is limited by its low and variable bioavailability which is mainly due to its very poor water solubility. Due to the low and variable oral bioavailability, high unitary doses of quercetin are required to guarantee its pharmacological activity.
• quercetin in- vivo absorption The high variability of quercetin in- vivo absorption is substantiated by many studies on animals, which have shown that different dietary factors can strongly influence quercetin absorption (Nishijima, T. et al. (2009). Journal of agricultural and food chemistry, 57(6), 2583-2587; Tamura, M. et al. (2007). Journal of food science, 72(9); Azuma, K. et al. (2003). Different approaches have been applied to improve quercetin absorption, including incorporation in micro and nano-emulsions (Gao, Y. et al. (2009).
• Colloids and Surfaces B Biointerfaces, 71(2), 306-314), solid lipid nanoparticles (Li, H., et al. (2009). Journal of Controlled Release, 133(3), 238-244), inclusion complexes of cyclodextrins (Aytac, Z., et al. (2016). Food chemistry, 197, 864-871), polymer nanoparticles (Patel, A. R., et al. (2012). Food Chemistry, 133(2), 423-429), but most of these approaches have many disadvantages including low encapsulation loading, complexity of manufacturing, lack of cost-effective industrial- scale production methods. Moreover most of these approaches have been applied only on laboratory scale and the potential improvement of quercetin oral bioavailability has been demonstrated only in- vitro or in-vivo animal studies.
• CN 1 813 677 A (UNIV SICHUAN [CN], published on August 9, 2006, relates to a quercetin liposome injection powder and its preparation method.
• the liposome powder is made of quercetin, polyglycol-phosphatidylethanolamine, lecithin, cholesterol and an excipient (such as sorbitol, mannitol, glucose, cane sugar or trehalose) and is prepared through a process comprising dissolution of quercetin, polyglycol- phosphatidylethanolamine, lecithin and cholesterol in chloroform and methanol, evaporation of the solvents to obtain a dry residue, addition of a sterile broth and an excipient to obtain a water solution which is subjected to ultra-sonic treatment and lyophilization to obtain a powder.
• an excipient such as sorbitol, mannitol, glucose, cane sugar or trehalose
• CN 10258011 IB (UNIV SICHUAN), published on April 9, 2014, discloses a liposome which comprises quercetin entrapped in a cyclodextrin.
• the liposome is prepared through a process comprising the addition of quercetin to a solution of hydroxypropyl-beta-cyclodextrin in a solvent selected from one or more of anhydrous alcohol, n-butyl alcohol and ether to obtain a solution; the addition of egg yolk lecithin or soybean phospholipid, cholesterol, polyethylene glycol-distearyl acid, phosphatidylethanolamine to the solution, followed by addition of the resulting solution to a water solution of sucrose and removal of the solvent by lyophilization.
• lecithin or soy phospholipids are used in excess with respect to quercetin; in greater detail, the weight ratio between quercetin and lecithin or soy phospholipid is from 1 :5 to 1 :50.
• CN 101 904 821 A (LINGMIN JIANG; LEI GAO), published on December 8, 2010 relates to a quercetin nano lyophilized powder having a mean diameter of less than 300 nm, preferably from 100 to 300 nm, and consisting of quercetin, a surfactant and a freeze drying protectant.
• the surfactant can be, inter alia, a phospholipid or soy lecithin, and the freeze drying protectant is a polysaccharide or a polyol.
• the quercetin powder is manufactured through a process carried out entirely in water; specifically, a surfactant is dispersed in water, then quercetin is added and the resulting suspension is homogenized under pressure and lyophilized.
• the freeze drying protectant can be added to the surfactant dispersion before addition of quercetin or before lyophilization.
• CN 1 813 677 A, CN 10258011 IB and CN 101 904 821 A disclose liposomes, whose preparation includes the use of water.
• the present invention relates to a powder solid dispersion comprising quercetin, phospholipids and a carrier very soluble to freely soluble in water.
• the invention also concerns a process for preparing the powder solid dispersion comprising dissolving or suspending in an anhydrous organic solvent and under heating quercetin, phospholipids and a water-soluble carrier and then removing the solvent to obtain the powder solid dispersion.
• compositions for oral administration comprising the powder solid dispersion and one o more pharmaceutically and food acceptable excipients.
• powder solid dispersions comprising, preferably consisting of, quercetin, phospholipids and a carrier very soluble to freely soluble in water are characterized by an improved solubility and oral bioavailability of quercetin in humans.
• quercetin is quercetin dihydrate.
• the phospholipids may be selected from the group consisting of lecithins from soy, sunflower or egg, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, or their mixtures, wherein the acyl groups, which may be the same or different, are mostly derived from palmitic, stearic, oleic, linoleic, linolenic acids.
• the lecithin is soy or sunflower lecithin; in a more preferred embodiment, the lecithin is sunflower lecithin.
• the quercetin to phospholipids weight ratio may range from 5: 1 to 1 : 1, preferably from 2: 1 to 1 : 1.
• the tern "very soluble” and the tern “freely soluble” have the meaning, as defined in the European Pharmacopeia 5.0, reported in the following scheme:
• carrier is used hereinafter to indicate "a carrier very soluble to freely soluble in water".
• the carrier may be selected from the group consisting of mono- and di- saccharides (such as sucrose, fructose, maltodextrins); polyalcohols (such as mannitol, sorbitol, xylitol); soluble oligo- and poly-saccharides (such as dextran, pullulan).
• the carrier is a maltodextrin.
• the quercetin to carrier weight ratio may range from 1 :5 to 5 : 1 , preferably from 1 :2 to 3:1.
• the solid dispersion of the invention has an average particle size distribution ranging from 100 ⁇ ⁇ 300 ⁇ .
• the solid dispersion of the invention consists only of quercetin, phospholipids and a carrier as defined above.
• the solid dispersion of the invention consists of quercetin, sunflower lecithin and maltodextrin; in another preferred embodiment, the solid dispersion of the invention consists of quercetin, sunflower lecithin and fructose.
• the carrier plays a fundamental role for the performance of the powder solid dispersion, promoting the fast dissolution rate of quercetin and contributing to promote its oral bioavailability. It is also believed that the soluble carrier also plays a relevant role in optimizing the physical properties of the final product.
• quercetin in particular quercetin dihydrate, can be incorporated in the phospholipids in high amount and that dissolution in water is fast even though X-rays of the solid dispersions of the invention show that a significant amount of crystalline is still present. Indeed, on the basis of the teaching of the aforementioned publications of Hong-Bo Yang, ET AL and of Sang Hyun Park ET AL one would expect that fast dissolution would be due to absence of quercetin in the crystalline form.
• the solid dispersions of the invention can be advantageously prepared with a process (or method) which avoids the use of chlorinated solvents and does not comprise any lyophilization steps and which can be easily scaled-up on pilot and industrial equipment.
• a further object of the invention is a process for preparing a powder solid dispersion according to the present invention comprising dissolving or suspending in an organic solvent comprising less than 5%wt water and under heating quercetin, phospholipids and a water-soluble carrier and then removing the solvent to obtain the powder solid dispersion.
• the process comprises the following steps:
• step c) contacting the solution of quercetin obtained in step a) with the solution/suspension of phospholipids obtained in step b) to provide a further solution or suspension [suspension or solution (S3)];
• step c) adding a carrier very soluble to freely soluble in water carrier to the solution or suspension obtained in step c) and
• the process comprises the following steps:
• the organic solvent is a food grade solvent having a boiling point at atmospheric pressure not higher than 80°C; preferably, the solvent is a C1 -C4 straight or branched alcohol, ethyl acetate or acetone, More preferably, the solvent is selected form the group comprising ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n-butanol, ethyl acetate, acetone. Even more preferably, the solvent is selected from ethanol and ethyl acetate.
• the process of the invention is carried out using solvents containing less than 5%wt of water and it does not comprise any steps of dissolution in water.
• the dissolution or suspension of quercetin, phospholipids and carrier is carried out under heating; in particular, steps a) to d) and a-1) and b-1) of the preferred embodiments are carried out under heating; typically, heating is carried out at a temperature ranging from 30°C to the solvent boiling temperature, preferably from 40°C to 80°C, more preferably from 50°C to 60°C, until or partial complete of quercetin, phospholipids and carrier.
• a person skilled in the art shall be able to determine the time necessary to obtain complete or partial solubilization (i.e. suspension) of quercetin, phospholipids and carrier.
• solution denotes a liquid composition which, upon visual inspection, is clear at the selected temperature;
• suspension denotes a liquid composition which, upon visual inspection, is opaque but nonetheless homogeneous.
• the powder solid dispersion may be calibrated, to obtain the desired particle size distribution within the aforementioned range of 100 ⁇ to 300 ⁇ and may be eventually mixed with pharmaceutically and food acceptable excipients, such as silicon dioxide, talc, magnesium stearate, to further improve its physical and technological properties.
• pharmaceutically and food acceptable excipients such as silicon dioxide, talc, magnesium stearate
• a high quercetin concentration in the absorption site is created, determining a high concentration gradient which is the driving force for the passive diffusion of quercetin through the absorption membranes of the gastro -intestinal tract.
• quercetin and phospholipids in the selected organic solvent during the process of the invention contributes to improve quercetin's solubility and oral bioavailability.
• a calorimetric analysis by Differential Scanning Calorimetry (DSC) was performed to determine, on the basis of the reduction of the enthalpy of fusion (J/g), the degree of amorphization of quercetin in the powder solid dispersion compared to the totally crystalline unformulated quercetin, in particular compared to quercetin dihydrate.
• quercetin, phospholipids, the carrier, weigh ratio and particle size apply to this object of the invention.
• the powder solid dispersion of the invention is easy to incorporate in conventional solid dosage forms, like tablets and capsules, but also in ready-to-use or extemporary liquid formulations, that are particularly useful and appealing in the sport nutrition sector, which represents one of the most important field of application of quercetin.
• Another object of the invention are formulations for oral administration containing the powder solid dispersions of the invention and one o more pharmaceutically and food acceptable excipients, such as disintcgrants, lubricants, binders, coating agents, colorants, absorption promoters, solubilizing agents, stabilizers, flavors, sweeteners, antiseptics, preservatives, antioxidants and the like.
• pharmaceutically and food acceptable excipients such as disintcgrants, lubricants, binders, coating agents, colorants, absorption promoters, solubilizing agents, stabilizers, flavors, sweeteners, antiseptics, preservatives, antioxidants and the like.
• formulations according to the invention may be prepared according to conventional techniques as described for example in Remington's Pharmaceutical Handbook, Mack Publishing Co., NY USA.
• dosage forms of the formulations of the invention include coated or uncoated tablets, chewable tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, extemporary and ready-to-use liquid formulation and combinations thereof.
• the improved solubility of quercetin contained in the powder solid dispersion of the invention was evaluated in simulated gastric and intestinal fluids.
• the oral bioavailability of the powder solid dispersions of quercetin was evaluated in humans compared to (unformulated, in free form) quercetin.
• the results show a significant improvement of oral bioavailability of quercetin in a powder solid dispersion according to the invention compared to (unformulated, in free form) quercetin dihydrate.
• a pharmacokinetic study on human subjects confirmed the improvement of oral bioavailability of about 50-times for quercetin of the powder solid dispersions of the invention in comparison with quercetin as such.
• the obtained powder solid dispersions of the invention are characterized by a high content of quercetin, by an improvement of quercetin solubility and dissolution rate, by an improvement of the oral bioavailability of quercetin in humans (AUC and Cmax), if compared to the quercetin as such. All this is surprising; indeed, while the DSC analysis of the powder solidi dispersions of the invention seemed to indicate an almost quantitative amorphization of quercetin, which was thought to be necessary to increase solubilization in body fluids and bioavailability, the X-ray analysis showed significant peaks of quercetin in a crystalline form different from the dihydrate form.
• Example 1 Preparation of a powder solid dispersion
• quercetin dihydrate 375 g are added to 13 L of ethyl alcohol, then heating at 60°C and mixing for about 15 minutes until complete dissolution.
• quercetin dihydrate 350 g of quercetin dihydrate to 12 L of ethyl acetate is added, then heating at 60°C and mixing for about 15 minutes until complete dissolution.
• Example 3 Characterization of the powder solid dispersion by DSC (Differential Scanning Calorimetry) and by X-ray analysis
• Example 1 The powder solid dispersion obtained in Example 1 was analyzed by DSC compared to (unformulated, in free form) quercetin dihydrate. The analysis was performed using a Mettler DSC1 System. Heat flow was recorded from 30 to 300°C with linear heating rate (10°C/min), using closed aluminum crucibles (40 ⁇ volume) with a pinhole, under a 50 ml/min nitrogen flow. About 5-10 mg of powder were used for each measurement. The thermal profiles were acquired and elaborated by a dedicate software. The disappearance of the endothermic peak of quercetin in the solid dispersion DSC curve seemed to indicate almost quantitative amorphization.
• the XRDP X-Ray Diffraction Pattern
• the solid dispersion of the invention still contains a significant amount of crystalline form that is, however, different from quercetin dihydrate as such or from quercetin dihydrate present in the physical mixture.
• the XRDP of quercetin dihydrate of this example is characterized by the most intense diffraction peak at 12.5 2 ⁇ angle with relative intensity of 100% (net intensity 7096 counts). In the physical mixture the same peak at 12.5 2 ⁇ angle remains the most intense (relative intensity 100%, net intensity 2577 counts), while in the solid dispersion at 12.5 2 ⁇ angle only noise baseline is detectable.
• Example 4 Characterization of the powder solid dispersion - solubility studies in simulated gastro -intestinal fluids
• Quercetin dihydrate, quercetin powder solid dispersion obtained in Example 1 and a mechanical (physical) mixture of the component of the said solid dispersion were subjected to comparative solubility experiments, in the presence of high excess of analyte, using the following simulated gastro -intestinal fluids:
• Fasted state simulated gastric fluid (pH 1.6)
• Fasted state simulated intestinal fluid (pH 6.5)
• Example 6 Formulation containing quercetin powder solid dispersion (film-coated tablets)
• Example 7 Formulation containing quercetin powder solid dispersion (soft gelatin capsules)
• Example 8 Formulation containing quercetin powder solid dispersion (granules for dispersion)
• Quercetin solid dispersion (Example 1) 500.0 mg

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