WO2022201022A1 - A formulation in form of microgranules comprising an extract or molecule of plant origin having gastrolesive effects or instability at acidic ph, and a gastro-resistant matrix - Google Patents

A formulation in form of microgranules comprising an extract or molecule of plant origin having gastrolesive effects or instability at acidic ph, and a gastro-resistant matrix Download PDF

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WO2022201022A1
WO2022201022A1 PCT/IB2022/052606 IB2022052606W WO2022201022A1 WO 2022201022 A1 WO2022201022 A1 WO 2022201022A1 IB 2022052606 W IB2022052606 W IB 2022052606W WO 2022201022 A1 WO2022201022 A1 WO 2022201022A1
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extract
gastro
microgranules
formulation
plant origin
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PCT/IB2022/052606
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French (fr)
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Valeria CURTI
Rita Paola PETRELLI
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Kolinpharma S.P.A.
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Publication of WO2022201022A1 publication Critical patent/WO2022201022A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/68—Plantaginaceae (Plantain Family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present invention relates to formulations in form of microgranules for an oral gastro-resistant administration comprising at least one extract of plant origin ( botanical ) or at least one molecule of plant origin, having gastrolesive effects and/or an instability at acidic pH, and a gastro-resistant matrix (enteric), wherein said matrix coats and/or embeds said extract of plant origin.
  • a gastro-resistant matrix enteric
  • the presence of said gastro-resistant matrix allows said at least one extract or molecule of plant origin to overcome the gastric tract without generating unwanted effects and without undergoing changes, and, furthermore, it allows said at least one extract to be mainly released into the intestinal tract.
  • Said formulations in form of microgranules comprising at least one gastro-protected extract or molecule of plant origin according to the present invention may be used for the preparation of dietary supplements, foods for special medical purposes (FSMPs), compositions for medical devices or pharmaceutical compositions.
  • FSMPs special medical purposes
  • gastric wall level gastric wall, the surface which delimits the stomach cavity
  • Extracts of plant origin such as extracts of plant portions such as leaves, seeds, roots and/or rhizomes, or molecules of plant origin are widely used as active components both in dietary supplements (or Foods for Special Medical Purposes FSMPs) and in compositions for medical devices or pharmaceutical compositions, for the therapeutic or non-therapeutic treatment (for example cosmetic) of various problems.
  • said side effects are stomach and/or intestinal disorders due to the presence of molecules which have a lesive effect on the gastric mucosa. Said lesive effect on the gastric mucosa could cause gastric acidity, affect the gastroenteric motility and/or cause nausea, vomiting and/or gastric discomfort. Further side effects caused by extracts or molecules of plant origin or by the compounds containing them are gastric disorders caused by their bitter taste, such as for example nausea, vomiting, loss of appetite and/or gastric discomfort.
  • Document US2018/339006 A1 relates to a method for preparing granules containing plant extracts, for example with high concentration.
  • Document W02009/112054 A1 relates to a pharmaceutical compositions or compositions for dietary supplements containing an extract of Mangosteen ( Garcinia Mangostana pericarp) and characterised by high bioavailability. Furthermore, the compositions may contain oligosaccharides in an amount by weight comprised from 5% to 50% with respect to the Mangosteen extract.
  • Document US2008/038362 A1 relates to a composition for an enteric coating for natural products containing lecithin.
  • NSAIDs non steroidal anti-inflammatory drugs
  • gastrolesiveness weakens the defence and functional recovery capacity of the gastric mucosa. Numerous studies show that gastric acidity could play a significant role in facilitating this gastrointestinal toxicity. Flowever, as mentioned above, gastrolesiveness could also be triggered or caused by other substances, not drugs. It is therefore important to be able to reduce the gastrolesiveness caused by non-drug substances.
  • These substances may be present in compositions for dietary supplements, medical devices (Reg. 745/20017) or foods for special medical purposes (FSMPs).
  • the expression extract or molecule of plant origin with "gastrolesive effects” is used to indicate an extract or molecule of plant origin which - at the doses used in the treated subject - not only causes beneficial effects but also unwanted side effects on the gastric system as defined in the context of the present invention (side effects known or unknown from the literature). Said side effects may be due to the extract as a whole or to one or more of the components or molecules thereof present in said extract.
  • the expression extract or molecule of plant origin with "instability at acidic pH” is used to indicate an extract of plant origin which - at the acidic pH of the stomach (for example, pH comprised from 1 to 3, preferably comprised from 1.5 to 2.5) - undergoes a structural change such to alter or reduce the beneficial properties (efficacy) thereof for which it is administered to the subject (instability known or unknown from the literature).
  • Said structural change may relate to the extract or one or more components of the extract.
  • tannins and triterpene saponins preferably are of interest for the present invention.
  • Tannins are polyphenols with a high affinity for proteins. They are classified in hydrolysable tannins, condensed tannins (procyanidins, proanthocyanidins) and tannoids. At contact with the mucosa of the gastrointestinal tract, tannins exert an astringent function, making the mucosa scarcely permeable and reducing the enzymatic secretion thereof. In particular, at gastric level tannins reduce secretions and inhibit the activity of hyaluronidase (an enzyme which participates in the phlogistic process releasing histamine). Over time, these activities of tannins on the gastrointestinal mucous membranes can irritate the digestive tract and they could cause hepatotoxicity.
  • hyaluronidase an enzyme which participates in the phlogistic process releasing histamine
  • Tannins are contained, for example, in two extracts widely used in dietary supplements or in foods for special medical purposes (FSMPs), such as the Arctostaphylos uva-ursi (Linnaeus) (or bearberry) extract and the Thea sinensis (Linnaeus) (or tea plant) extract.
  • FSMPs special medical purposes
  • Triterpene saponins are among the most common saponins in the plant kingdom. Thanks to their surfactant capacity, when administered in small amounts triterpene saponins dissolve and stimulate the secretion of a fluid bronchial mucus, facilitating sputum and causing cough. In particular, this latter effect seems to be due to an irritant action of saponins at the level of the gastric mucosa which, by reflected action, determines an increase in bronchial secretion.
  • the irritant effect of saponins on the mucous membranes of the gastrointestinal tract is also used to improve the absorption of some drugs: the triggered irritation causes an imbalance in the intestinal mucosa, reducing the resistance and filtering barrier effect thereof toward exogenous substances.
  • saponins have an unwanted purgative and/or emetic effect (emetic, which causes "emesis” that is it capable of stimulating vomiting).
  • triterpene saponins are contained in extracts of plant origin widely used in the food and pharmacological industry, such as for example the Bacopa monnieri extract, the Aesculus hippocastanum (L.) extract and the extract of a ginseng (for example, Panax ginseng (C.)).
  • Extracts of plant origin which cause gastric problems, of interest for the present invention are for example the extracts of Zingiber officinale and Andrographis paniculata.
  • the technical problem addressed and solved by the present invention lies in providing formulations for oral use comprising extracts or molecules of plant origin ( botanicals ) having unwanted gastrolesive effects or instability at acidic pH, wherein said formulations are capable of releasing said extracts or molecules directly into the intestinal tract (controlled release with bypass of the gastric tract) without side effects at the gastric level (for example due to the bitter taste or to a lesive effect of the extract on the gastric mucosa) and/or without degradation or changes in the active molecules (for example changes due to the acidic pH of the gastric tract or to specific enzymes present in the gastric tract).
  • the Applicant provides formulations in form of microgranules for oral administration comprising at least one extract or molecule of plant origin ( botanical) and a g astro-resistant matrix, wherein said matrix coats or embeds said extract or molecule, allowing said at least one extract or molecule of plant origin to overcome the gastric tract without generating unwanted effects and without undergoing changes, and allowing said at least one extract or molecule of plant origin to be released directly into the intestinal tract, preferably into the tract of the digestive system.
  • the formulations of the invention in form of microgranules comprising gastro-protected extracts or molecules of plant origin, showing a high safety profile, can be used by a broad category of subjects, such as adults, the elderly, paediatric subjects, subjects with comorbidities and sportsmen and sportswomen.
  • Said formulations of the present invention are easy to prepare and cost-effective, in particular the microencapsulation step.
  • Figure 1 graphically shows the structure of a microgranule of the formulation subject of the present invention: core/shell structure A and structure B of microbeads dispersed in the matrix.
  • a first aspect of the present invention relates to a formulation in form of microgranules for oral gastro- resistant administration, wherein a microgranule comprises at least one extract or a molecule of plant origin having gastrolesive effects (or a composition thereof) and a gastro-resistant matrix wherein said gastro-resistant matrix coats and/or embeds said at least one extract or molecule of plant origin (or a composition thereof).
  • a second aspect of the present invention relates to a composition
  • a composition comprising at least one formulation in form of microgranules of the present invention and at least one acceptable pharmaceutical or food grade additive and/or excipient.
  • a third aspect of the present invention relates to said formulation or composition of the present invention for use as medicament, such as formulation or composition for use in a treatment method or method for treatment by administering said formulation or composition to a subject in need.
  • a fourth aspect of the present invention relates to the non-therapeutic (or cosmetic) use of the formulation or composition of the present invention in a healthy subject.
  • a fifth aspect of the present invention relates to a process for the preparation of said formulation in form of microgranules of the present invention.
  • a sixth aspect of the present invention relates to said formulation in form of microgranules of the present invention which can be obtained through the process of the invention.
  • a last aspect of the present invention relates to the use of said formulation or composition of the present invention for the preparation of a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
  • FSMP special medical purposes
  • Forming an object of the present invention is a formulation in form of microgranules (or a microgranule) for oral gastro-resistant administration (in short formulation of the present invention), wherein a microgranule comprises:
  • a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or one molecule of plant origin having gastrolesive effects and/or instability at acidic pH, and (b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or embeds said (a) mixture (or core).
  • said (a.1) at least one extract or molecule of plant origin may be selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax extract (e.g.
  • Panax ginseng Zingiber officinale extract, Andrographis paniculata extract, and a mixture thereof; preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata; more preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Zingiber officinale, Andrographis paniculata.
  • said (a.1) at least one extract of plant origin may be selected from an extract comprising or, alternatively, consisting of at least one triterpene saponin (for example, aescin or ginsenosides) and/or at least one tannin.
  • said (a.1) at least one molecule of plant origin may be selected from at least one triterpene saponin (for example, aescin or ginsenosides) and/or at least one tannin.
  • the Arctostaphylos uva-ursi (L.) (or bearberry) extract is mainly a leaf extract.
  • the main components of Arctostaphylos uva-ursi are: phenolic glycosides, in particular arbutin and methyl arbutin, tannins (about 15-20%), flavonoids (about 1-2% including quercetin and isoquercetin), triterpenes (for example, ursolic acid and the corresponding uvaol alcohol).
  • the herb should contain not less than 6% (w/w) of hydroquinone derivatives, calculated as arbutoside.
  • the Arctostaphylos uva-ursi extract has traditionally been used for the relief of symptoms associated with infections of the low urinary tract in women, such as burning sensation during urination and/or frequent urination.
  • the posology varies and depends both on the extent of the symptom to be alleviated, and on the type of preparation and extraction intended to be used (for example, in the case of dry extract, about 400 mg of extract in ethanol 60% v/v up to 3-4 times a day).
  • the Arctostaphylos uva-ursi extract is considered a safe substance for the subjects to whom it is administered, given the high tannin content, adverse events such as nausea, vomiting and cramps could manifest themselves due to irritation of the mucous membranes of the stomach, especially in particularly sensitive and predisposed subjects (for example, subjects with gastric diseases or disorders, such as for example, indigestion, heartburn, nausea, cramps or vomiting, etc.).
  • adverse events such as nausea, vomiting and cramps could manifest themselves due to irritation of the mucous membranes of the stomach, especially in particularly sensitive and predisposed subjects (for example, subjects with gastric diseases or disorders, such as for example, indigestion, heartburn, nausea, cramps or vomiting, etc.).
  • the use of an Arctostaphylos uva-ursi extract for prolonged periods for example, more than seven days is not recommended.
  • Tea contains tannins (about 8 to 20%) including epigallocatechin-3-O- gallate (EGCG), caffeine (about 2.5-5.5%), theobromine (about 0.07-0.17%), theophylline (about 0.002- 0.013%), a volatile oil; furthermore, vitamins (of group B), poly-flavonoid compounds (for example theaflavin and thearubigin).
  • EGCG epigallocatechin-3-O- gallate
  • caffeine about 2.5-5.5%
  • theobromine about 0.07-0.17%
  • theophylline about 0.002- 0.0137%
  • vitamins of group B
  • poly-flavonoid compounds for example theaflavin and thearubigin
  • Possible unwanted effects at the level of the gastrointestinal system or of the gastroenteric system after taking tea may be due to high tannic content, such as stomach disorders and cramps, nausea, flatulence, dyspepsia and abdominal pain, while disorders such as dizziness, headache and increased heart rate can be associated with the caffeine content.
  • the extract of Bacopa monnieri (plant belonging to the botanical family of Scrofulariaceae) comprises, as active compounds responsible for the biological activity thereof, alkaloids (for example brahmin, nicotine and erpestin), triterpene saponins (for example bacosides A and B) and sterols (for example beta- sitosterol and stigmasterol).
  • alkaloids for example brahmin, nicotine and erpestin
  • triterpene saponins for example bacosides A and B
  • sterols for example beta- sitosterol and stigmasterol.
  • the standardised Bacopa monnieri extract is used in traditional medicine to combat anxiety disorders, depression, and the improvement of cognitive functions.
  • the use of Bacopa monnieri extract has some side effects. Subjects involved in clinical studies subjected to treatments with preparations based on Bacopa monnieri have often experienced adverse effects at the level of the gastrointestinal tract, mainly diarrhoea, nausea and abdominal cramps.
  • Bacopa monnieri the cholinergic action thereof at the intestinal level exerts a spasmolytic action, a relaxation of the smooth muscle, contractions with greater tone related to a stimulation of secretory activity, which could translate into nausea, constipation or diarrhoea in some subjects due to relaxation of the sphincters.
  • the Bacopa monnieri extract has a direct effect on the modulation of gastric secretions, especially due to the high saponin content, and this effect could irritate the stomach.
  • the Aesculus hippocastanum (L.) seed extract comprises aescin, a triterpene saponin.
  • the Aesculus hippocastanum seed extract as of date authorised by the European Medicines Agency (EMA) is a dry extract of hydroalcoholic derivation (40-80% v/v) standardised and containing from 6.5% to 10% (w/w) of triterpene glycosides, calculated as protoaescigenin.
  • the main components of Aesculus hippocastanum are triterpene saponins (whose mixture is called aescin), flavonoids (for example quercetin, kaempferol and rutin), coumarins and tannins (present in the bark and in the trunk and therefore lost during the seed extraction process).
  • aescin is known to have antiphlogistic, anti-edematous, anti-exudative and venotonic properties with particular effectiveness in the early stages of the inflammatory process.
  • Experimental evidence shows an interference of the extract with lysosomal enzymes by hindering the activity of hyaluronidase, but not elastase, and with the synthesis of autacoids (eicosanoids and serotonin).
  • autacoids eicosanoids and serotonin.
  • clinically recognised uses of aescina relate to the treatment of chronic venous insufficiency symptoms, including pain, feeling of heavy legs, nocturnal cramps in calves, pinching and oedema.
  • the recommended dosage ranges from 250 mg to 312 mg twice a day of an standardised powdered extract of unprocessed herb (corresponding to 100 mg of aescin) containing 16%-20% (w/w) triterpene saponins calculated in aescin.
  • an standardised powdered extract of unprocessed herb corresponding to 100 mg of aescin
  • the aescin content cannot exceed 75 mg as daily dose.
  • aescin has shown unwanted effects at the gastrointestinal level, in particular nausea and stomach disorders.
  • a high content of triterpene saponins can cause irritation to the gastric mucosa.
  • ginseng extract or “Panax extract” is used to indicate the extract obtained from the root of at least one of the eleven different species of plants belonging to the genus Panax, each typical of a different region of the world.
  • the most common ginseng derives from the root of Panax ginseng (C. Meyer).
  • the ginseng root extract (or Panax root extract) or Panax ginseng comprises triterpene or pentacyclic saponins, related to oleanolic acid (for example ginsenosides, panaxosides, chikusetsusaponins), polysaccharides (for example panaxans), sterols and vitamin D.
  • Ginseng is useful in case of asthenia, fatigue, malaise, to improve concentration at work and when studying, and in convalescence periods (dose 1-2 g per day for a maximum period of 3 months). It is also traditionally used to treat impotence, lower diabetes, prevent hepatotoxicity and treat ulcers and gastritis.
  • the side effects observed following the use of a ginseng extract mainly affect the gastrointestinal system, such as nausea, irritation of the gastric mucosa, epigastralgia, vomiting, diarrhoea constipation. These gastrointestinal disorders could be due to the high content of triterpene saponins of ginseng extract, which are called ginsenosides.
  • ginseng and “Panax” are used in the context of the present description as interchangeable synonyms.
  • Zingiber officinale (Roscoe, 1807; common name ginger) is a herbaceous plant of the family Zingiberaceae. Ginger or Zingiber officinale extract derives from the rhizome of the plant.
  • the main components of ginger are contained in oleoresin which contains gingerols (about 30-35%), shogaols and zingerone.
  • the other components of ginger are carbohydrates (starch about 50%), lipids (fatty acids 6-8%) and essential oil (about 1-3%).
  • EMA European Medicines Agency
  • Said ginger functions are mainly due to 6-gingerol and shogaols. These compounds appear to be able to inhibit nausea and vomiting, given that they normalise gastric motility and inhibit vasopressin release. However, these gastric effects also manifest themselves as side effects.
  • the monograph by EMA reports that the use of ginger can cause minor gastrointestinal disorders in particular such as stomach-ache, eructation, dyspepsia and nausea.
  • Andrographis paniculata (Burm. f.; Wall, ex Nees) is an annual herbaceous plant of the family Acanthaceae used to reduce the duration and symptoms of common cold and in the treatment of symptoms of upper respiratory tract infections. It is known that high oral dosages of Andrographidis paniculata dry extract can cause gastric disorders, vomiting and loss of appetite. These side effects seem to be due to the bitter taste thereof.
  • the content of tannins and/or triterpene saponins or of any other molecule of interest (i.e. active component or active molecule) in one of said extracts of plant origin can be determined by means of titration methods (for example titration by means of UV or HPLC technique) and standard equipment known to the person skilled in the art.
  • Forming an object of the present invention is a formulation in form of microgranules for oral gastro- resistant administration, wherein a microgranule comprises:
  • a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or at least one molecule of plant origin having at least one gastrolesive effect and/or an instability at acidic pH, and
  • said (a.1) at least one extract of plant origin is selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax, preferably Panax ginseng, extract, Zingiber officinale extract, Andrographis paniculata extract, an extract comprising at least one triterpene saponin, preferably aescin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof;
  • said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt and/or a mixture thereof.
  • said (a.1) is at least one extract of plant origin and it is selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata.
  • said (b) is a gastro-resistant matrix and it may comprise or, alternatively, consist of (b.1) at least one gastro- resistant component selected from the group comprising or, alternatively, consisting of: a lipid, preferably a phospholipid, a polymer other than an alginate salt, and/or a mixture thereof.
  • said microgranules have an average particle diameter comprised from about 100 m to about 600 pm, preferably comprised from about 150 pm to about 400 pm.
  • the extracts of plant origin of the present invention are preferably dry extracts.
  • dry extract in the context of the present invention is used to indicate an extract in powdered form having a water content in a percentage by weight from 0.05% to 15% (for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 14%), preferably from 0.05% to 10% or from 0.05% to 5%.
  • the extracts of plant origin of the present invention can be extracts of one or more parts of the plant, such as for example leaves, roots, seeds, pistils, bark, and/or fruits.
  • the extracts (or dry extracts) of plant origin which can be used in the formulations of the present invention are extracts obtained and identified according to methods and equipment known to the person skilled in the art.
  • an Artostaphylos Uva-ursi leaf extract (bearberry leaf extract) can be obtained as a dry extract by extraction in an aqueous solvent or in an alcohol solvent (for example ethanol, 60% v/v) or as a liquid extract by extraction in an alcohol solvent (for example ethanol, 25% v/v), and identified by means of spectroscopic techniques;
  • a Bacopa monnieri leaf extract or a Zingiber officinale extract can be obtained by extraction in an alcohol solvent (for example ethanol);
  • a ginseng or Panax ginseng root extract is produced by means of standard extraction methods using alcohol solvents (for example ethanol or methanol) in different concentration ratio with water;
  • an Aesculus hippocastanum seed extract can be obtained by extraction in an alcohol solvent (for example ethanol, 40% v/v );
  • a Panax ginseng root extract can be obtained by extraction in an alcohol solvent (for example ethanol, 95% v/v);
  • an Andrographis paniculata root extract
  • the microgranules of the formulation subject of the present invention have an average particle diameter comprised from about 1 pm to about 950 pm (for example 10 pm, 20 pm, 50 pm, 80 pm, 100 pm, 200 pm, 300 pm, 400 pm, 500 pm, 600 pm, 700 pm, 800 pm o 900 pm), preferably from 100 pm to 600 pm, more preferably from about 150 pm to about 400 pm.
  • Microencapsulation or coating generally refers to technologies which allow to embed/coat one or more compounds into an individualised small particle structure having an average diameter in a range comprised from about 1 pm to about 1000 pm (for example 10 pm, 50 pm, 100 pm, 200 pm, 400 pm, 600 pm, or 800 pm). Depending on the process applied, these microparticles obtained from the encapsulation or coating process may have different sizes, shapes and specific structures.
  • the advantage of microencapsulation lies in the fact that the material of the core is fully coated and isolated from the external environment (for example, the acidic pH environment of the stomach). Furthermore, microencapsulation potentially does not affect the properties of the materials of the core.
  • microgranules of the formulation subject of the present invention may have a core/shell structure A or a matrix structure B or a mixed structure A+B.
  • the mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of plant origin forms the core, while the gastro-resistant matrix (b) constitutes the shell which coats (a).
  • a multitude of microgranules of mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of plant origin is dispersed or embedded in the gastro-resistant matrix (b) (i.e., n microgranules of active ingredient embedded in the gastro-resistant matrix to form a microgranule of the invention).
  • structure A+B a multitude of core/shell structures A are dispersed or embedded into the gastro- resistant matrix (b).
  • microgranules of the formulation subject of the present invention may have various shapes without any limitation such as, for example, spherical, ellipsoid, cubic, parallelepiped, or flakes or pellets.
  • said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof.
  • said (b.1) at least one gastro-resistant component consists of a lipid selected from the group comprising or, alternatively, consisting of:
  • a phospholipid preferably a phosphoglyceride, more preferably a phosphoglyceride selected from the group comprising or, alternatively, consisting of 1,2-diacyl-phospholipid, 1 -alkyl-2-acyl-phospholipid, 1- alkenyl-2-acyl-phospholipid; even more preferably a diacyl-phospholipid selected from the group comprising or, alternatively, consisting of: phosphatidylcholine or lecithin for example (E322), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid and mixtures thereof; preferably the phosphatidylcholine or the lecithin for example (E322), are advantageously allergen free and/or in form of powder or granules; more preferably, the sunflower, corn or soy lecithin for example (E322) is selected; and 2) a lipid of plant origin selected from the group comprising or, alternatively
  • sucrose fatty acid esters preferably mixtures of mono- di- or tri- sucrose fatty acid esters; wherein said saturated or unsaturated fatty acids both free and esterified with glycerol or mono-alcohols or di-alcohols or sucrose, have a number of carbon atoms comprised in the range from C12 to C28, more preferably from C14 to C24, for example C16, C18, C20 and/or C22.
  • said (b.1) at least one gastro-resistant component consists of an alginate salt selected from the group comprising or, alternatively, consisting of: sodium alginate, potassium alginate, magnesium alginate, ammonium alginate, calcium alginate and mixtures thereof; preferably sodium alginate.
  • Sodium alginate is a chemical compound formed from the alginic acid sodium salt, with minimum formula NaC 6 H70 6 .
  • Sodium alginate is extracted from the cell walls of algae and it has a rubber-like appearance.
  • the sodium alginate generally used in the food or pharmaceutical industry is an alginate E401 (E401 means: food additive permitted by European legislation and regulated by the Italian Ministerial Decree D.M.1996).
  • Alginic acid also called algin, is a polysaccharide widely present in the cell walls of brown algae (for example, brute or molecular formula (CsHsOs), ! molecular mass (u or Da) from 10.000 to 600.000).
  • said (b.1) at least one gastro-resistant component consists of a polymer other than an alginate, wherein said polymer has the technical characteristics suitable for coating and/or embedding said (a) mixture and ensuring a gastroprotection thereof.
  • a polymer other than an alginate which can be used in the context of the present invention are ethyl cellulose and polyvinyl alcohol.
  • said (a) mixture (or core) may further comprise (a.2) at least one acceptable pharmaceutical or food grade mixture additive and/or excipient known to the person skilled in the art.
  • said (b) gastro-resistant matrix may further comprise (b.2) at least one acceptable pharmaceutical or food grade matrix additive and/or excipient known to the person skilled in the art.
  • ancillary substances known to the person skilled in the art such as for example, diluents, solvents, solubilizers, thickeners, sweeteners, flavour
  • Non limiting examples of such substances are phosphate buffers (for example, dicalcium phosphate), alkali or alkali-earth metal stearate (for example of magnesium), silicon dioxide, mono- and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch or corn starch, natural or artificial flavours.
  • phosphate buffers for example, dicalcium phosphate
  • alkali or alkali-earth metal stearate for example of magnesium
  • silicon dioxide silicon dioxide
  • mono- and diglycerides of fatty acids microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch or corn starch, natural or artificial flavours.
  • said (a) mixture or core (for example (a.1) or (a.1)+(a.2)) and said (b) gastro-resistant matrix (for example (b.1) or (b.1)+(b.2)) may be in an [(a):(b)] by weight ratio from 100:1 to 1:1 (for example 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1) or 1:1 to 1:100 (for example, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).
  • said (a.1) at least one extract of plant origin and said (b.1) gastro-resistant component may be in an [(a.1):(b.1)] by weight ratio from 100:1 to 1:1 (for example, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1) or 1:1 to 1:100 (for example, 5:1, 2:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).
  • 100:1 to 1:1 for example, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1
  • 1:1 to 1:100 for example, 5:1, 2:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).
  • the formulation in form of microgranule of the present invention may comprise said (a) mixture, comprising or consisting of (a.1) at least one extract or molecule of plant origin in a percentage by weight with respect to the total weight of the formulation comprised from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%), preferably from 20% to 40% (for example about 25-30%).
  • the formulation in form of microgranule of the present invention may comprise said (b) gastro- resistant matrix in a percentage by weight, with respect to the total weight of the formulation comprised from 10% to 99% (for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%), preferably from 60% to 80% (for example about 70-85 %).
  • the formulation in form of microgranule of the present invention may comprise said (a.1) at least one extract of plant origin in a percentage by weight with respect to the total weight of the formulation comprised from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%), preferably from 20% to 40% (for example about 25-30%).
  • the formulation in form of microgranule of the present invention may comprise said (b.1) at least one gastro-resistant component (for example a lipid or an alginate salt or a polymer) in a percentage by weight with respect to the total weight of the formulation comprised from 10% to 99% (for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%), preferably from 60% to 80% (for example about 70-85 %).
  • gastro-resistant component for example a lipid or an alginate salt or a polymer
  • compositions in form of microgranules of the invention are suitable for oral administration.
  • the oral dosage form of said formulations in form of microgranules of the invention may be a solid form, such as a capsule comprising microgranules, microgranules to be dissolved in water or a water-based liquid, or mouth dissolvable microgranules; or a semi-solid form, such as a soft-gel capsule comprising microgranules; or a liquid form, such as a suspension or dispersion comprising or deriving from microgranules; preferably the composition of the invention is for oral use in solid form.
  • a solid form such as a capsule comprising microgranules, microgranules to be dissolved in water or a water-based liquid, or mouth dissolvable microgranules
  • a semi-solid form such as a soft-gel capsule comprising microgranules
  • a liquid form such as a suspension or dispersion comprising or deriving from microgranules
  • the composition of the invention is for oral use in solid form.
  • compositions comprising at least one formulation in form of microgranules of the present invention and at least one acceptable pharmaceutical or food grade additive and/or excipient.
  • Said formulations in form of microgranules or the relative compositions of the present invention may consist of or, alternatively, be comprised in a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), and/or a pharmaceutical composition.
  • FSMP food for special medical purposes
  • EU Medical Device Regulation
  • MDR Medical Device Regulation
  • Forming an object of the present invention is the use of the formulation in form of microgranules of the present invention comprising said at least one extract or a molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) or compositions of the present invention for preparing a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), and/or a pharmaceutical composition.
  • FSMP Food for special medical purposes
  • EU Medical Device Regulation
  • MDR Medical Device Regulation
  • Forming an object of the present invention is the formulation in form of microgranules of the present invention comprising said at least one extract or molecule of plant origin ( botanical) and said gastro- resistant matrix (according to any one of the described embodiments or aspects) or the compositions of the present invention for use as medicament in a subject in need.
  • the formulations in form of microgranules of the present invention comprising said at least one extract or molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) or the compositions of the present invention are formulations or compositions for use in a method for the treatment of a disease and/or symptom defined based on the properties of said extract or molecule of plant origin, wherein said treatment method provides for administering a therapeutically effective amount to a subject in need.
  • diseases or symptoms which can be treated using the formulations of the present invention are for example: muscle pain, joint pain, circadian cycle disorders (sleep disorders), menstrual disorders, gastrointestinal disorders (nausea, diarrhoea, vomiting, stomach and/or intestinal discomfort), gastric reflux disease (GERD), metabolic dysfunctions (obesity, overweight, diabetes).
  • the present invention provides methods for the treatment of a disease and/or symptom by administering a therapeutically effective amount of a formulation or composition of the present invention to a subject in need, wherein said disease and/or symptom are defined based on the properties of said extract or molecule of plant origin.
  • the formulations of the present invention may be for use in the treatment of a disease or symptom or disorder both as a single treatment and as an adjuvant of further treatments.
  • Forming an object of the present invention is the cosmetic use or non-therapeutic use of the formulations in form of microgranules or of the relative compositions according to the present invention, wherein said non-therapeutic use is a use on healthy subjects to increase or enhance or implement physical and/or mental performance.
  • Forming an object of the present invention is a process (in short microencapsulation process of the invention) for the preparation of said formulation in form of microgranules of the invention comprising said at least one extract or molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) comprising the steps of: (1) preparing the mixture (a) to be microencapsulated and the gastro-resistant matrix (b) as the coating matrix of the mixture (a); (2) coating (a) with (b) or embedding (a) in (b) according to the structure A or B or A+B, wherein said structures are as described in the present invention, to obtain microgranules of (a) coated or embedded in (b) (or formulations in form of microgranules of the present invention); (3) optionally, applying to the microgranules obtained from step 2 a drying step, to obtain the formulations in form of microgranules of the present invention.
  • Said microencapsulation process of the present invention may be carried out using methods and procedures known to the person skilled in the art.
  • the microencapsulation process of the present invention is performed by means of a fluid bed system, that is a microencapsulation system comprising a fluid bed process chamber (for example, a fluid bed chamber according to standard processes and machines).
  • a fluid bed process chamber for example, a fluid bed chamber according to standard processes and machines.
  • the particles (or microparticles) of the mixture (a) comprising or consisting of (a.1) at least one extract of plant origin) to be microencapsulated are in motion in a gas flow and, simultaneously, the gastro-resistant matrix (b) of the present invention is applied to said particles of mixture (a) in said fluid bed chamber, for example by means of a spray method (for example, spray emitted from a nozzle arranged in the fluid bed chamber).
  • microencapsulation of the mixture (a) in the gastro- resistant matrix (b) to obtain the formulation in form of microgranules according to the invention.
  • Said microencapsulation in a fluid bed is preferably carried at a process temperature comprised from 20°C to 80°C (for example 25°C, 35°C, 40°C, 50°C, 60°C, or 70°C), preferably from 30°C to 60°C.
  • the formulation in form of microgranules of the present invention can be obtained by means of the process of the present invention.
  • the expression "subject/s” is used to indicate mammalian subjects (animals and/or humans), preferably human subjects.
  • terapéuticaally effective amount is used to indicate the amount of mixture or compound or formulation which elicits the biological or medicinal response in a tissue, system or subject which is sought and defined by a person skilled in the art.
  • the expression mixture or composition comprises a component in an amount "comprised in a range from x to y” is used to indicate that said component can be present in the composition in all the amounts present in said range, even though not specified, extremes of the range comprised.
  • Preferred embodiments FRn of the present invention are reported below.
  • a formulation in form of microgranules for oral gastro-resistant administration, wherein a microgranule comprises:
  • a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or at least one molecule of plant origin having at least one gastrolesive effect and/or an instability at acidic pH, and
  • FR2 The formulation according to FR1, wherein said microgranules have an average particle diameter comprised from about 100 m to about 600 pm, preferably comprised from about 150 pm to about 400 pm.
  • FR3 The formulation according to FR1 or FR, wherein said (a.1) at least one extract of plant origin is selected from the group comprising, or alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax, preferably Panax ginseng, extract, Zingiber officinale extract, Andrographis paniculata extract, an extract comprising at least one triterpene saponin, preferably aescin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof;
  • Arctostaphylos uva-ursi Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata.
  • gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof; preferably a lipid, more preferably a phospholipid.
  • FR5 The formulation according to any one of FR1-4, wherein said microgranules have a core/shell structure, wherein the core comprises or, alternatively, consists of said mixture (a) and wherein the shell comprises or, alternatively, consists of said gastro-resistant matrix (b).
  • FR6 The formulation according to any one of FR1-5, wherein said microgranules have a matrix structure, wherein a multitude of microgranules of said mixture (a) is dispersed or embedded in said gastro-resistant matrix (b).
  • a composition comprising: at least one formulation in form of microgranules according to any one of FR1-6, and at least one acceptable pharmaceutical or food grade additive and/or excipient; preferably wherein said composition is a dietary supplement composition, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
  • FSMP food for special medical purposes
  • FR8 The formulation in the form of microgranules or the composition according to any one of FR1-7 for use as medicament.
  • FR9 Cosmetic use or non-therapeutic use of the formulation according to any one of FR1-6 or of the composition according to FR7 in healthy subjects to increase the physical and/or mental performance.
  • FR10 Use of the formulation in the form of microgranules according to any one of FR1-6 or of the composition according to FR7 to prepare a dietary supplement composition, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
  • FSMP special medical purposes

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Abstract

The present invention relates to formulations in form of microgranules for oral administration comprising at least one extract of plant origin (botanical) having gastrolesive effects or an instability at acidic pH and a gastro-resistant matrix (enteric) which coats and/or embeds 5 said extract, allowing said at least one extract to be released directly into the intestinal tract overcoming the gastric tract without generating unwanted effects and without undergoing changes.

Description

DESCRIPTION of the invention having the title:
“A FORMULA TION IN FORM OF MICROGRANULES COMPRISING AN EXTRACT OR MOLECULE OF PLANT ORIGIN HAVING GASTROLESIVE EFFECTS OR INSTABILITY AT ACIDIC PH, AND A GASTRO-RESISTANT MA TRIX’ .
The present invention relates to formulations in form of microgranules for an oral gastro-resistant administration comprising at least one extract of plant origin ( botanical ) or at least one molecule of plant origin, having gastrolesive effects and/or an instability at acidic pH, and a gastro-resistant matrix (enteric), wherein said matrix coats and/or embeds said extract of plant origin. The presence of said gastro-resistant matrix allows said at least one extract or molecule of plant origin to overcome the gastric tract without generating unwanted effects and without undergoing changes, and, furthermore, it allows said at least one extract to be mainly released into the intestinal tract.
Said formulations in form of microgranules comprising at least one gastro-protected extract or molecule of plant origin according to the present invention may be used for the preparation of dietary supplements, foods for special medical purposes (FSMPs), compositions for medical devices or pharmaceutical compositions.
Furthermore, the present invention relates to a process for the preparation of said formulations in form of microgranules for an oral gastro-resistant administration, said microgranules comprising at least one extract, or one molecule of plant origin, said process being capable of conferring a protection to said at least one extract, or one molecule of plant origin, at gastric level (gastric = relating to or regarding the stomach) and at the gastric wall level (gastric wall, the surface which delimits the stomach cavity). The process confers a gastroprotection to said at least one extract, or one molecule of plant origin, gastro- protecting them.
Extracts of plant origin (or botanicals), such as extracts of plant portions such as leaves, seeds, roots and/or rhizomes, or molecules of plant origin are widely used as active components both in dietary supplements (or Foods for Special Medical Purposes FSMPs) and in compositions for medical devices or pharmaceutical compositions, for the therapeutic or non-therapeutic treatment (for example cosmetic) of various problems.
Nevertheless, some extracts or molecules of plant origin could cause unpleasant side effects for the subject using them to an extent of having them suspended from taking them.
In most cases, said side effects are stomach and/or intestinal disorders due to the presence of molecules which have a lesive effect on the gastric mucosa. Said lesive effect on the gastric mucosa could cause gastric acidity, affect the gastroenteric motility and/or cause nausea, vomiting and/or gastric discomfort. Further side effects caused by extracts or molecules of plant origin or by the compounds containing them are gastric disorders caused by their bitter taste, such as for example nausea, vomiting, loss of appetite and/or gastric discomfort.
Document US2018/339006 A1 relates to a method for preparing granules containing plant extracts, for example with high concentration.
Document W02009/112054 A1 relates to a pharmaceutical compositions or compositions for dietary supplements containing an extract of Mangosteen ( Garcinia Mangostana pericarp) and characterised by high bioavailability. Furthermore, the compositions may contain oligosaccharides in an amount by weight comprised from 5% to 50% with respect to the Mangosteen extract.
Document US2006/165794 A1 relates to gastro-resistant beads comprising a core containing one or more active substances, and a coating film comprising an enteric polymer or a mixture of saturated and/or unsaturated polyglycolysed glycerides.
Document US2008/038362 A1 relates to a composition for an enteric coating for natural products containing lecithin.
Gastrolesive or gastrolesiveness are terms used with reference to drugs, for example a gastrolesive drug (from Greek gastros, gaster= stomach) is a drug that causes inflammatory processes in the stomach or in subjects already suffering from gastric ulcers if not even haemorrhage. The gastrolesiveness of non steroidal anti-inflammatory drugs (NSAIDs), as well as other substances (not drugs) is known. Generally, gastrolesiveness weakens the defence and functional recovery capacity of the gastric mucosa. Numerous studies show that gastric acidity could play a significant role in facilitating this gastrointestinal toxicity. Flowever, as mentioned above, gastrolesiveness could also be triggered or caused by other substances, not drugs. It is therefore important to be able to reduce the gastrolesiveness caused by non-drug substances. These substances may be present in compositions for dietary supplements, medical devices (Reg. 745/20017) or foods for special medical purposes (FSMPs).
In the context of the present invention, the expression extract or molecule of plant origin with "gastrolesive effects” is used to indicate an extract or molecule of plant origin which - at the doses used in the treated subject - not only causes beneficial effects but also unwanted side effects on the gastric system as defined in the context of the present invention (side effects known or unknown from the literature). Said side effects may be due to the extract as a whole or to one or more of the components or molecules thereof present in said extract.
In the context of the present invention, the expression extract or molecule of plant origin with "instability at acidic pH” is used to indicate an extract of plant origin which - at the acidic pH of the stomach (for example, pH comprised from 1 to 3, preferably comprised from 1.5 to 2.5) - undergoes a structural change such to alter or reduce the beneficial properties (efficacy) thereof for which it is administered to the subject (instability known or unknown from the literature). Said structural change may relate to the extract or one or more components of the extract.
Among molecules which cause or trigger gastric problems the most tannins and triterpene saponins preferably are of interest for the present invention.
Tannins are polyphenols with a high affinity for proteins. They are classified in hydrolysable tannins, condensed tannins (procyanidins, proanthocyanidins) and tannoids. At contact with the mucosa of the gastrointestinal tract, tannins exert an astringent function, making the mucosa scarcely permeable and reducing the enzymatic secretion thereof. In particular, at gastric level tannins reduce secretions and inhibit the activity of hyaluronidase (an enzyme which participates in the phlogistic process releasing histamine). Over time, these activities of tannins on the gastrointestinal mucous membranes can irritate the digestive tract and they could cause hepatotoxicity.
Tannins are contained, for example, in two extracts widely used in dietary supplements or in foods for special medical purposes (FSMPs), such as the Arctostaphylos uva-ursi (Linnaeus) (or bearberry) extract and the Thea sinensis (Linnaeus) (or tea plant) extract.
Triterpene saponins are among the most common saponins in the plant kingdom. Thanks to their surfactant capacity, when administered in small amounts triterpene saponins dissolve and stimulate the secretion of a fluid bronchial mucus, facilitating sputum and causing cough. In particular, this latter effect seems to be due to an irritant action of saponins at the level of the gastric mucosa which, by reflected action, determines an increase in bronchial secretion. The irritant effect of saponins on the mucous membranes of the gastrointestinal tract is also used to improve the absorption of some drugs: the triggered irritation causes an imbalance in the intestinal mucosa, reducing the resistance and filtering barrier effect thereof toward exogenous substances. Disadvantageously, in large amounts saponins have an unwanted purgative and/or emetic effect (emetic, which causes "emesis” that is it capable of stimulating vomiting). For example, triterpene saponins are contained in extracts of plant origin widely used in the food and pharmacological industry, such as for example the Bacopa monnieri extract, the Aesculus hippocastanum (L.) extract and the extract of a ginseng (for example, Panax ginseng (C.)).
Further extracts of plant origin which cause gastric problems, of interest for the present invention, are for example the extracts of Zingiber officinale and Andrographis paniculata.
The technical problem addressed and solved by the present invention lies in providing formulations for oral use comprising extracts or molecules of plant origin ( botanicals ) having unwanted gastrolesive effects or instability at acidic pH, wherein said formulations are capable of releasing said extracts or molecules directly into the intestinal tract (controlled release with bypass of the gastric tract) without side effects at the gastric level (for example due to the bitter taste or to a lesive effect of the extract on the gastric mucosa) and/or without degradation or changes in the active molecules (for example changes due to the acidic pH of the gastric tract or to specific enzymes present in the gastric tract).
In order to overcome said technical problems, following an intense research and development activity, the Applicant provides formulations in form of microgranules for oral administration comprising at least one extract or molecule of plant origin ( botanical) and a g astro-resistant matrix, wherein said matrix coats or embeds said extract or molecule, allowing said at least one extract or molecule of plant origin to overcome the gastric tract without generating unwanted effects and without undergoing changes, and allowing said at least one extract or molecule of plant origin to be released directly into the intestinal tract, preferably into the tract of the digestive system.
The formulations of the invention in form of microgranules comprising gastro-protected extracts or molecules of plant origin, showing a high safety profile, can be used by a broad category of subjects, such as adults, the elderly, paediatric subjects, subjects with comorbidities and sportsmen and sportswomen. Said formulations of the present invention are easy to prepare and cost-effective, in particular the microencapsulation step.
These and other objects which will be apparent from the detailed description that follows are achieved by the formulations and the processes of the present invention thanks to the technical characteristics present in description and in the attached claims.
FIGURES
Figure 1 graphically shows the structure of a microgranule of the formulation subject of the present invention: core/shell structure A and structure B of microbeads dispersed in the matrix. SUMMARY OF THE INVENTION
A first aspect of the present invention relates to a formulation in form of microgranules for oral gastro- resistant administration, wherein a microgranule comprises at least one extract or a molecule of plant origin having gastrolesive effects (or a composition thereof) and a gastro-resistant matrix wherein said gastro-resistant matrix coats and/or embeds said at least one extract or molecule of plant origin (or a composition thereof).
A second aspect of the present invention relates to a composition comprising at least one formulation in form of microgranules of the present invention and at least one acceptable pharmaceutical or food grade additive and/or excipient.
A third aspect of the present invention relates to said formulation or composition of the present invention for use as medicament, such as formulation or composition for use in a treatment method or method for treatment by administering said formulation or composition to a subject in need.
A fourth aspect of the present invention relates to the non-therapeutic (or cosmetic) use of the formulation or composition of the present invention in a healthy subject.
A fifth aspect of the present invention relates to a process for the preparation of said formulation in form of microgranules of the present invention.
A sixth aspect of the present invention relates to said formulation in form of microgranules of the present invention which can be obtained through the process of the invention.
A last aspect of the present invention relates to the use of said formulation or composition of the present invention for the preparation of a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
Forming an object of the present invention is a formulation in form of microgranules (or a microgranule) for oral gastro-resistant administration (in short formulation of the present invention), wherein a microgranule comprises:
(a) a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or one molecule of plant origin having gastrolesive effects and/or instability at acidic pH, and (b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or embeds said (a) mixture (or core).
In the formulation of the present invention, said (a.1) at least one extract or molecule of plant origin may be selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax extract (e.g. Panax ginseng), Zingiber officinale extract, Andrographis paniculata extract, and a mixture thereof; preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata; more preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Zingiber officinale, Andrographis paniculata.
Furthermore, in the formulation of the present invention, said (a.1) at least one extract of plant origin may be selected from an extract comprising or, alternatively, consisting of at least one triterpene saponin (for example, aescin or ginsenosides) and/or at least one tannin.
Alternatively, in the formulation of the present invention, said (a.1) at least one molecule of plant origin may be selected from at least one triterpene saponin (for example, aescin or ginsenosides) and/or at least one tannin.
The Arctostaphylos uva-ursi (L.) (or bearberry) extract is mainly a leaf extract. The main components of Arctostaphylos uva-ursi are: phenolic glycosides, in particular arbutin and methyl arbutin, tannins (about 15-20%), flavonoids (about 1-2% including quercetin and isoquercetin), triterpenes (for example, ursolic acid and the corresponding uvaol alcohol). For the official pharmacopoeia, the herb should contain not less than 6% (w/w) of hydroquinone derivatives, calculated as arbutoside. The Arctostaphylos uva-ursi extract has traditionally been used for the relief of symptoms associated with infections of the low urinary tract in women, such as burning sensation during urination and/or frequent urination. The posology varies and depends both on the extent of the symptom to be alleviated, and on the type of preparation and extraction intended to be used (for example, in the case of dry extract, about 400 mg of extract in ethanol 60% v/v up to 3-4 times a day). Although the Arctostaphylos uva-ursi extract is considered a safe substance for the subjects to whom it is administered, given the high tannin content, adverse events such as nausea, vomiting and cramps could manifest themselves due to irritation of the mucous membranes of the stomach, especially in particularly sensitive and predisposed subjects (for example, subjects with gastric diseases or disorders, such as for example, indigestion, heartburn, nausea, cramps or vomiting, etc.). In the light of the above, the use of an Arctostaphylos uva-ursi extract for prolonged periods (for example, more than seven days) is not recommended. The extract of leaves and/or flowers of Thea sinensis (Linnaeus) (or tea plant). Conventionally Thea sinensis is taken as an infusion, and traditionally the use thereof is associated with resistance to fatigue and to combat feeling of malaise. Tea contains tannins (about 8 to 20%) including epigallocatechin-3-O- gallate (EGCG), caffeine (about 2.5-5.5%), theobromine (about 0.07-0.17%), theophylline (about 0.002- 0.013%), a volatile oil; furthermore, vitamins (of group B), poly-flavonoid compounds (for example theaflavin and thearubigin). Possible unwanted effects at the level of the gastrointestinal system or of the gastroenteric system after taking tea may be due to high tannic content, such as stomach disorders and cramps, nausea, flatulence, dyspepsia and abdominal pain, while disorders such as dizziness, headache and increased heart rate can be associated with the caffeine content.
The extract of Bacopa monnieri (plant belonging to the botanical family of Scrofulariaceae) comprises, as active compounds responsible for the biological activity thereof, alkaloids (for example brahmin, nicotine and erpestin), triterpene saponins (for example bacosides A and B) and sterols (for example beta- sitosterol and stigmasterol). The standardised Bacopa monnieri extract is used in traditional medicine to combat anxiety disorders, depression, and the improvement of cognitive functions. The use of Bacopa monnieri extract has some side effects. Subjects involved in clinical studies subjected to treatments with preparations based on Bacopa monnieri have often experienced adverse effects at the level of the gastrointestinal tract, mainly diarrhoea, nausea and abdominal cramps. These adverse effects have been associated with some specific characteristics of Bacopa monnieri : the cholinergic action thereof at the intestinal level exerts a spasmolytic action, a relaxation of the smooth muscle, contractions with greater tone related to a stimulation of secretory activity, which could translate into nausea, constipation or diarrhoea in some subjects due to relaxation of the sphincters. As regards the adverse effect at gastric level, it has been demonstrated that the Bacopa monnieri extract has a direct effect on the modulation of gastric secretions, especially due to the high saponin content, and this effect could irritate the stomach.
The Aesculus hippocastanum (L.) seed extract comprises aescin, a triterpene saponin. The Aesculus hippocastanum seed extract as of date authorised by the European Medicines Agency (EMA) is a dry extract of hydroalcoholic derivation (40-80% v/v) standardised and containing from 6.5% to 10% (w/w) of triterpene glycosides, calculated as protoaescigenin. The main components of Aesculus hippocastanum are triterpene saponins (whose mixture is called aescin), flavonoids (for example quercetin, kaempferol and rutin), coumarins and tannins (present in the bark and in the trunk and therefore lost during the seed extraction process). Traditionally, aescin is known to have antiphlogistic, anti-edematous, anti-exudative and venotonic properties with particular effectiveness in the early stages of the inflammatory process. Experimental evidence shows an interference of the extract with lysosomal enzymes by hindering the activity of hyaluronidase, but not elastase, and with the synthesis of autacoids (eicosanoids and serotonin). According to the monograph by the World Health Organization, clinically recognised uses of aescina relate to the treatment of chronic venous insufficiency symptoms, including pain, feeling of heavy legs, nocturnal cramps in calves, pinching and oedema. The recommended dosage ranges from 250 mg to 312 mg twice a day of an standardised powdered extract of unprocessed herb (corresponding to 100 mg of aescin) containing 16%-20% (w/w) triterpene saponins calculated in aescin. In Italy, to date, the aescin content cannot exceed 75 mg as daily dose. As a matter of fact, aescin has shown unwanted effects at the gastrointestinal level, in particular nausea and stomach disorders. As known, a high content of triterpene saponins can cause irritation to the gastric mucosa.
The expression "ginseng extract” or “Panax extract” is used to indicate the extract obtained from the root of at least one of the eleven different species of plants belonging to the genus Panax, each typical of a different region of the world. The most common ginseng derives from the root of Panax ginseng (C. Meyer). The ginseng root extract (or Panax root extract) or Panax ginseng comprises triterpene or pentacyclic saponins, related to oleanolic acid (for example ginsenosides, panaxosides, chikusetsusaponins), polysaccharides (for example panaxans), sterols and vitamin D. Ginseng is useful in case of asthenia, fatigue, malaise, to improve concentration at work and when studying, and in convalescence periods (dose 1-2 g per day for a maximum period of 3 months). It is also traditionally used to treat impotence, lower diabetes, prevent hepatotoxicity and treat ulcers and gastritis. The side effects observed following the use of a ginseng extract mainly affect the gastrointestinal system, such as nausea, irritation of the gastric mucosa, epigastralgia, vomiting, diarrhoea constipation. These gastrointestinal disorders could be due to the high content of triterpene saponins of ginseng extract, which are called ginsenosides. The expressions "ginseng” and "Panax” are used in the context of the present description as interchangeable synonyms.
Zingiber officinale (Roscoe, 1807; common name ginger) is a herbaceous plant of the family Zingiberaceae. Ginger or Zingiber officinale extract derives from the rhizome of the plant. The main components of ginger are contained in oleoresin which contains gingerols (about 30-35%), shogaols and zingerone. The other components of ginger are carbohydrates (starch about 50%), lipids (fatty acids 6-8%) and essential oil (about 1-3%). The monograph by the European Medicines Agency (EMA) indicates that oral consumption of ginger is useful in preventing disorders associated with nausea and vomiting in kinetosis. Furthermore, the traditional use thereof is also associated with mild intestinal disorders such as flatulence and bloating. Said ginger functions are mainly due to 6-gingerol and shogaols. These compounds appear to be able to inhibit nausea and vomiting, given that they normalise gastric motility and inhibit vasopressin release. However, these gastric effects also manifest themselves as side effects. The monograph by EMA, reports that the use of ginger can cause minor gastrointestinal disorders in particular such as stomach-ache, eructation, dyspepsia and nausea.
Andrographis paniculata (Burm. f.; Wall, ex Nees) is an annual herbaceous plant of the family Acanthaceae used to reduce the duration and symptoms of common cold and in the treatment of symptoms of upper respiratory tract infections. It is known that high oral dosages of Andrographidis paniculata dry extract can cause gastric disorders, vomiting and loss of appetite. These side effects seem to be due to the bitter taste thereof.
The content of tannins and/or triterpene saponins or of any other molecule of interest (i.e. active component or active molecule) in one of said extracts of plant origin can be determined by means of titration methods (for example titration by means of UV or HPLC technique) and standard equipment known to the person skilled in the art.
Forming an object of the present invention is a formulation in form of microgranules for oral gastro- resistant administration, wherein a microgranule comprises:
(a) a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or at least one molecule of plant origin having at least one gastrolesive effect and/or an instability at acidic pH, and
(b) a g astro-resistant matrix, wherein said gastro-resistant matrix coats and/or embeds said (a) mixture;
- wherein said (a.1) at least one extract of plant origin is selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax, preferably Panax ginseng, extract, Zingiber officinale extract, Andrographis paniculata extract, an extract comprising at least one triterpene saponin, preferably aescin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof;
- wherein said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt and/or a mixture thereof.
Preferably, in said formulation, said (a.1) is at least one extract of plant origin and it is selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata. Preferably, in said formulation, said (b) is a gastro-resistant matrix and it may comprise or, alternatively, consist of (b.1) at least one gastro- resistant component selected from the group comprising or, alternatively, consisting of: a lipid, preferably a phospholipid, a polymer other than an alginate salt, and/or a mixture thereof. Preferably, in said formulation, said microgranules have an average particle diameter comprised from about 100 m to about 600 pm, preferably comprised from about 150 pm to about 400 pm.
The extracts of plant origin of the present invention are preferably dry extracts.
The expression "dry extract” in the context of the present invention is used to indicate an extract in powdered form having a water content in a percentage by weight from 0.05% to 15% (for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 14%), preferably from 0.05% to 10% or from 0.05% to 5%.
The extracts of plant origin of the present invention can be extracts of one or more parts of the plant, such as for example leaves, roots, seeds, pistils, bark, and/or fruits.
The extracts (or dry extracts) of plant origin which can be used in the formulations of the present invention are extracts obtained and identified according to methods and equipment known to the person skilled in the art.
For example, an Artostaphylos Uva-ursi leaf extract (bearberry leaf extract) can be obtained as a dry extract by extraction in an aqueous solvent or in an alcohol solvent (for example ethanol, 60% v/v) or as a liquid extract by extraction in an alcohol solvent (for example ethanol, 25% v/v), and identified by means of spectroscopic techniques; a Bacopa monnieri leaf extract or a Zingiber officinale extract can be obtained by extraction in an alcohol solvent (for example ethanol); a ginseng or Panax ginseng root extract is produced by means of standard extraction methods using alcohol solvents (for example ethanol or methanol) in different concentration ratio with water; an Aesculus hippocastanum seed extract can be obtained by extraction in an alcohol solvent (for example ethanol, 40% v/v ); a Panax ginseng root extract can be obtained by extraction in an alcohol solvent (for example ethanol, 95% v/v); an Andrographis paniculata root extract can be obtained by extraction in a water/ethanol solvent (for example water, 20/ethanol, 80 v/v).
Advantageously, the microgranules of the formulation subject of the present invention have an average particle diameter comprised from about 1 pm to about 950 pm (for example 10 pm, 20 pm, 50 pm, 80 pm, 100 pm, 200 pm, 300 pm, 400 pm, 500 pm, 600 pm, 700 pm, 800 pm o 900 pm), preferably from 100 pm to 600 pm, more preferably from about 150 pm to about 400 pm.
Microencapsulation or coating generally refers to technologies which allow to embed/coat one or more compounds into an individualised small particle structure having an average diameter in a range comprised from about 1 pm to about 1000 pm (for example 10 pm, 50 pm, 100 pm, 200 pm, 400 pm, 600 pm, or 800 pm). Depending on the process applied, these microparticles obtained from the encapsulation or coating process may have different sizes, shapes and specific structures. The advantage of microencapsulation lies in the fact that the material of the core is fully coated and isolated from the external environment (for example, the acidic pH environment of the stomach). Furthermore, microencapsulation potentially does not affect the properties of the materials of the core.
The microgranules of the formulation subject of the present invention may have a core/shell structure A or a matrix structure B or a mixed structure A+B.
In the core/shell structure A, the mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of plant origin forms the core, while the gastro-resistant matrix (b) constitutes the shell which coats (a).
In the matrix structure B, a multitude of microgranules of mixture (a) comprising or, alternatively, consisting of (a.1) at least one extract or mixture of plant origin is dispersed or embedded in the gastro-resistant matrix (b) (i.e., n microgranules of active ingredient embedded in the gastro-resistant matrix to form a microgranule of the invention).
In structure A+B, a multitude of core/shell structures A are dispersed or embedded into the gastro- resistant matrix (b).
The microgranules of the formulation subject of the present invention may have various shapes without any limitation such as, for example, spherical, ellipsoid, cubic, parallelepiped, or flakes or pellets.
In the formulation of the present invention, said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof.
According to an aspect, in the formulation in form of microgranules comprising (a) and (b), subject of the present invention, said (b.1) at least one gastro-resistant component consists of a lipid selected from the group comprising or, alternatively, consisting of:
1) a phospholipid, preferably a phosphoglyceride, more preferably a phosphoglyceride selected from the group comprising or, alternatively, consisting of 1,2-diacyl-phospholipid, 1 -alkyl-2-acyl-phospholipid, 1- alkenyl-2-acyl-phospholipid; even more preferably a diacyl-phospholipid selected from the group comprising or, alternatively, consisting of: phosphatidylcholine or lecithin for example (E322), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid and mixtures thereof; preferably the phosphatidylcholine or the lecithin for example (E322), are advantageously allergen free and/or in form of powder or granules; more preferably, the sunflower, corn or soy lecithin for example (E322) is selected; and 2) a lipid of plant origin selected from the group comprising or, alternatively, consisting of:
- glycerols or mono-alcohols or di-alcohols mono-, di- or tri-esterified with saturated or unsaturated fatty acids (e.g. monounsaturated);
- saturated or unsaturated free fatty acids (e.g. monounsaturated);
- sucrose fatty acid esters (sucresters), preferably mixtures of mono- di- or tri- sucrose fatty acid esters; wherein said saturated or unsaturated fatty acids both free and esterified with glycerol or mono-alcohols or di-alcohols or sucrose, have a number of carbon atoms comprised in the range from C12 to C28, more preferably from C14 to C24, for example C16, C18, C20 and/or C22.
According to another aspect, in the formulation in form of microgranules comprising (a) and (b) subject of the present invention, said (b.1) at least one gastro-resistant component consists of an alginate salt selected from the group comprising or, alternatively, consisting of: sodium alginate, potassium alginate, magnesium alginate, ammonium alginate, calcium alginate and mixtures thereof; preferably sodium alginate. Preferably, said alginate salt, present in the (b) gastro-resistant matrix, has an average molecular weight comprised in the range from 10.000 Da to 600.000 Da (for example, 50.000 Da, 100.000 Da, 150.000 Da, 200.000 Da, 250.000 Da, 300.000 Da, 350.000 Da, 400.000 Da, 450.000 Da, 500.000 Da, or 550.000 Da; Da = Dalton), preferably from 100.000 Da to 400.000 Da, more preferably from 150.000 Da to 300.000 Da.
Sodium alginate is a chemical compound formed from the alginic acid sodium salt, with minimum formula NaC6H706. Sodium alginate is extracted from the cell walls of algae and it has a rubber-like appearance. The sodium alginate generally used in the food or pharmaceutical industry is an alginate E401 (E401 means: food additive permitted by European legislation and regulated by the Italian Ministerial Decree D.M.1996).
Alginic acid, also called algin, is a polysaccharide widely present in the cell walls of brown algae (for example, brute or molecular formula (CsHsOs),! molecular mass (u or Da) from 10.000 to 600.000).
According to an aspect, in the formulation in form of microgranules comprising (a) and (b) subject of the present invention, said (b.1) at least one gastro-resistant component consists of a polymer other than an alginate, wherein said polymer has the technical characteristics suitable for coating and/or embedding said (a) mixture and ensuring a gastroprotection thereof. Examples of a polymer other than an alginate, which can be used in the context of the present invention are ethyl cellulose and polyvinyl alcohol.
Besides said (a.1) at least one extract or molecule of plant origin, in the formulation of the present invention said (a) mixture (or core) may further comprise (a.2) at least one acceptable pharmaceutical or food grade mixture additive and/or excipient known to the person skilled in the art. Besides said (b.1) at least one gastro-resistant component, in the formulation of the present invention said (b) gastro-resistant matrix may further comprise (b.2) at least one acceptable pharmaceutical or food grade matrix additive and/or excipient known to the person skilled in the art.
Said (a.2) at least one pharmaceutical or food grade additive and/or excipient, comprised in the (a) mixture/core of the invention together with said (a.1) at least one extract or molecule of plant origin (botanical), or said (b.2) at least one pharmaceutical or food grade additive and/or excipient, comprised in the (b) gastro-resistant matrix together with said (b.1) gastro-resistant component, consists of substances devoid of therapeutic or cosmetic (or non-therapeutic) activity suitable for pharmaceutical or food use selected from the group of ancillary substances known to the person skilled in the art such as for example, diluents, solvents, solubilizers, thickeners, sweeteners, flavour enhancement agents, dyes, lubricants, surfactants, antimicrobials, antioxidants, preservatives, pH stabilising buffers and mixtures thereof. (Non limiting) examples of such substances are phosphate buffers (for example, dicalcium phosphate), alkali or alkali-earth metal stearate (for example of magnesium), silicon dioxide, mono- and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch or corn starch, natural or artificial flavours.
In the formulation of the present invention, said (a) mixture or core (for example (a.1) or (a.1)+(a.2)) and said (b) gastro-resistant matrix (for example (b.1) or (b.1)+(b.2)) may be in an [(a):(b)] by weight ratio from 100:1 to 1:1 (for example 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1) or 1:1 to 1:100 (for example, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).
In the formulation of the present invention, said (a.1) at least one extract of plant origin and said (b.1) gastro-resistant component may be in an [(a.1):(b.1)] by weight ratio from 100:1 to 1:1 (for example, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1) or 1:1 to 1:100 (for example, 5:1, 2:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80 or 1:90).
The formulation in form of microgranule of the present invention ((a) + (b)) may comprise said (a) mixture, comprising or consisting of (a.1) at least one extract or molecule of plant origin in a percentage by weight with respect to the total weight of the formulation comprised from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%), preferably from 20% to 40% (for example about 25-30%).
The formulation in form of microgranule of the present invention ((a) + (b)) may comprise said (b) gastro- resistant matrix in a percentage by weight, with respect to the total weight of the formulation comprised from 10% to 99% (for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%), preferably from 60% to 80% (for example about 70-85 %).
It should be understood that the percentages of said (a) mixture and of said (b) gastro-resistant matrix mentioned above are mutually connected and interdependent.
The formulation in form of microgranule of the present invention ((a) + (b)) may comprise said (a.1) at least one extract of plant origin in a percentage by weight with respect to the total weight of the formulation comprised from 1% to 90% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%), preferably from 20% to 40% (for example about 25-30%).
The formulation in form of microgranule of the present invention ((a) + (b)) may comprise said (b.1) at least one gastro-resistant component (for example a lipid or an alginate salt or a polymer) in a percentage by weight with respect to the total weight of the formulation comprised from 10% to 99% (for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%), preferably from 60% to 80% (for example about 70-85 %).
It should be understood that the percentages of said (a.1) at least one extract of plant origin and of said (b.1) at least one gastro-resistant component mentioned above are mutually connected and interdependent.
The formulations in form of microgranules of the invention are suitable for oral administration.
The oral dosage form of said formulations in form of microgranules of the invention may be a solid form, such as a capsule comprising microgranules, microgranules to be dissolved in water or a water-based liquid, or mouth dissolvable microgranules; or a semi-solid form, such as a soft-gel capsule comprising microgranules; or a liquid form, such as a suspension or dispersion comprising or deriving from microgranules; preferably the composition of the invention is for oral use in solid form.
Forming an object of the present invention are compositions (in short compositions of the present invention) comprising at least one formulation in form of microgranules of the present invention and at least one acceptable pharmaceutical or food grade additive and/or excipient.
Said formulations in form of microgranules or the relative compositions of the present invention may consist of or, alternatively, be comprised in a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), and/or a pharmaceutical composition.
Forming an object of the present invention is the use of the formulation in form of microgranules of the present invention comprising said at least one extract or a molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) or compositions of the present invention for preparing a dietary supplement, a food for special medical purposes (FSMP), a composition for medical devices (Medical Device Regulation (EU) 2017/745 (MDR)), and/or a pharmaceutical composition.
Forming an object of the present invention is the formulation in form of microgranules of the present invention comprising said at least one extract or molecule of plant origin ( botanical) and said gastro- resistant matrix (according to any one of the described embodiments or aspects) or the compositions of the present invention for use as medicament in a subject in need.
Advantageously, the formulations in form of microgranules of the present invention comprising said at least one extract or molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) or the compositions of the present invention are formulations or compositions for use in a method for the treatment of a disease and/or symptom defined based on the properties of said extract or molecule of plant origin, wherein said treatment method provides for administering a therapeutically effective amount to a subject in need.
Examples of diseases or symptoms which can be treated using the formulations of the present invention are for example: muscle pain, joint pain, circadian cycle disorders (sleep disorders), menstrual disorders, gastrointestinal disorders (nausea, diarrhoea, vomiting, stomach and/or intestinal discomfort), gastric reflux disease (GERD), metabolic dysfunctions (obesity, overweight, diabetes).
Furthermore, the present invention provides methods for the treatment of a disease and/or symptom by administering a therapeutically effective amount of a formulation or composition of the present invention to a subject in need, wherein said disease and/or symptom are defined based on the properties of said extract or molecule of plant origin.
The formulations of the present invention may be for use in the treatment of a disease or symptom or disorder both as a single treatment and as an adjuvant of further treatments.
Forming an object of the present invention is the cosmetic use or non-therapeutic use of the formulations in form of microgranules or of the relative compositions according to the present invention, wherein said non-therapeutic use is a use on healthy subjects to increase or enhance or implement physical and/or mental performance.
Forming an object of the present invention is a process (in short microencapsulation process of the invention) for the preparation of said formulation in form of microgranules of the invention comprising said at least one extract or molecule of plant origin ( botanical ) and said gastro-resistant matrix (according to any one of the described embodiments or aspects) comprising the steps of: (1) preparing the mixture (a) to be microencapsulated and the gastro-resistant matrix (b) as the coating matrix of the mixture (a); (2) coating (a) with (b) or embedding (a) in (b) according to the structure A or B or A+B, wherein said structures are as described in the present invention, to obtain microgranules of (a) coated or embedded in (b) (or formulations in form of microgranules of the present invention); (3) optionally, applying to the microgranules obtained from step 2 a drying step, to obtain the formulations in form of microgranules of the present invention.
Said microencapsulation process of the present invention may be carried out using methods and procedures known to the person skilled in the art.
According to a preferred aspect, the microencapsulation process of the present invention is performed by means of a fluid bed system, that is a microencapsulation system comprising a fluid bed process chamber (for example, a fluid bed chamber according to standard processes and machines). In said fluid bed chamber the particles (or microparticles) of the mixture (a) (comprising or consisting of (a.1) at least one extract of plant origin) to be microencapsulated are in motion in a gas flow and, simultaneously, the gastro-resistant matrix (b) of the present invention is applied to said particles of mixture (a) in said fluid bed chamber, for example by means of a spray method (for example, spray emitted from a nozzle arranged in the fluid bed chamber). The result is the microencapsulation of the mixture (a) in the gastro- resistant matrix (b) to obtain the formulation in form of microgranules according to the invention. Said microencapsulation in a fluid bed is preferably carried at a process temperature comprised from 20°C to 80°C (for example 25°C, 35°C, 40°C, 50°C, 60°C, or 70°C), preferably from 30°C to 60°C.
The formulation in form of microgranules of the present invention can be obtained by means of the process of the present invention.
In the context of the present invention, the expression "subject/s” is used to indicate mammalian subjects (animals and/or humans), preferably human subjects.
The expression "therapeutically effective amount” is used to indicate the amount of mixture or compound or formulation which elicits the biological or medicinal response in a tissue, system or subject which is sought and defined by a person skilled in the art.
Unless otherwise specified, the expression mixture or composition comprises a component in an amount "comprised in a range from x to y” is used to indicate that said component can be present in the composition in all the amounts present in said range, even though not specified, extremes of the range comprised. Preferred embodiments FRn of the present invention are reported below.
FR1. A formulation in form of microgranules for oral gastro-resistant administration, wherein a microgranule comprises:
(a) a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or at least one molecule of plant origin having at least one gastrolesive effect and/or an instability at acidic pH, and
(b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or embeds said (a) mixture.
FR2. The formulation according to FR1, wherein said microgranules have an average particle diameter comprised from about 100 m to about 600 pm, preferably comprised from about 150 pm to about 400 pm.
FR3. The formulation according to FR1 or FR, wherein said (a.1) at least one extract of plant origin is selected from the group comprising, or alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax, preferably Panax ginseng, extract, Zingiber officinale extract, Andrographis paniculata extract, an extract comprising at least one triterpene saponin, preferably aescin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof;
Preferably Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata.
FR4. The formulation according to any one of FR1-3, wherein said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt, a polymer other than an alginate salt, and a mixture thereof; preferably a lipid, more preferably a phospholipid.
FR5. The formulation according to any one of FR1-4, wherein said microgranules have a core/shell structure, wherein the core comprises or, alternatively, consists of said mixture (a) and wherein the shell comprises or, alternatively, consists of said gastro-resistant matrix (b).
FR6. The formulation according to any one of FR1-5, wherein said microgranules have a matrix structure, wherein a multitude of microgranules of said mixture (a) is dispersed or embedded in said gastro-resistant matrix (b).
FR7. A composition comprising: at least one formulation in form of microgranules according to any one of FR1-6, and at least one acceptable pharmaceutical or food grade additive and/or excipient; preferably wherein said composition is a dietary supplement composition, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
FR8. The formulation in the form of microgranules or the composition according to any one of FR1-7 for use as medicament.
FR9. Cosmetic use or non-therapeutic use of the formulation according to any one of FR1-6 or of the composition according to FR7 in healthy subjects to increase the physical and/or mental performance.
FR10. Use of the formulation in the form of microgranules according to any one of FR1-6 or of the composition according to FR7 to prepare a dietary supplement composition, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.

Claims

1. A formulation in form of microgranules for oral gastro-resistant administration, wherein a microgranule comprises:
(a) a mixture (or core) comprising or, alternatively, consisting of (a.1) at least one extract of plant origin or at least one molecule of plant origin having at least one gastrolesive effect and/or an instability at acidic pH, and
(b) a gastro-resistant matrix, wherein said gastro-resistant matrix coats and/or embeds said (a) mixture;
- wherein said (a.1) at least one extract of plant origin is selected from the group comprising, or alternatively, consisting of: Arctostaphylos uva-ursi extract, Thea sinensis extract, Bacopa monnieri extract, Aesculus hippocastanum extract, ginseng or Panax, preferably Panax ginseng, extract, Zingiber officinale extract, Andrographis paniculata extract, an extract comprising at least one triterpene saponin, preferably aescin or ginsenosides, an extract comprising at least one tannin, and a mixture thereof;
- wherein said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, an alginate salt and/or a mixture thereof.
2. The formulation according to claim 1, wherein said (a.1) at least one extract of plant origin is selected from the group comprising or, alternatively, consisting of: Arctostaphylos uva-ursi, Thea sinensis, Bacopa monnieri, Aesculus hippocastanum, Zingiber officinale, Andrographis paniculata.
3. The formulation according to claim 1 or 2 wherein said (b) gastro-resistant matrix may comprise or, alternatively, consist of (b.1) at least one gastro-resistant component selected from the group comprising or, alternatively, consisting of: a lipid, preferably a phospholipid, a polymer other than an alginate salt and/or a mixture thereof.
4. The formulation according to any one of claims 1- 3, wherein said microgranules have an average particle diameter comprised from about 100 m to about 600 pm, preferably comprised from about 150 pm to about 400 pm.
5. The formulation according to any one of claims 1-4, wherein said microgranules have a core/shell structure, wherein the core comprises or, alternatively, consists of said mixture (a) and wherein the shell comprises or, alternatively, consists of said gastro-resistant matrix (b).
6. The formulation according to any one of claims 1-5, wherein said microgranules have a matrix structure, wherein a multitude of microgranules of said mixture (a) is dispersed or embedded in said gastro-resistant matrix (b).
7. A composition comprising: at least one formulation in form of microgranules according to any one of the preceding claims, and at least one acceptable pharmaceutical or food grade additive and/or excipient; preferably wherein said composition is a dietary supplement composition, a food for special medical purposes (FSMP), a composition for medical devices and/or a pharmaceutical composition.
8. The formulation in the form of microgranules or the composition according to any one of the preceding claims for use as medicament.
9. Cosmetic use or non-therapeutic use of the formulation according to any one of claims 1-6 or of the composition according to claim 7 in healthy subjects to increase the physical and/or mental performance.
10. Use of the formulation in the form of microgranules according to any one of claims 1-6 or of the composition according to claim 7 to prepare a dietary supplement composition, a food for special medical purposes (FSMP), a medical device composition and/or a pharmaceutical composition.
PCT/IB2022/052606 2021-03-22 2022-03-22 A formulation in form of microgranules comprising an extract or molecule of plant origin having gastrolesive effects or instability at acidic ph, and a gastro-resistant matrix WO2022201022A1 (en)

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IT102021000006893A IT202100006893A1 (en) 2021-03-22 2021-03-22 A FORMULATION IN THE FORM OF MICROGRANULES INCLUDING AN EXTRACT OR MOLECULE OF VEGETABLE ORIGIN HAVING GASTROLESIVE EFFECTS OR INSTABILITY TO ACID PH, AND A GASTRO-RESISTANT MATRIX
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Citations (6)

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US20060165794A1 (en) * 2002-10-04 2006-07-27 Ethypharm Spheroids, preparation method thereof and pharmaceutical compositions
US20080038362A1 (en) * 2003-06-12 2008-02-14 Won-Bong Park Composition For An Enteric Coating Of Natural Product Containing Lectin
WO2009112054A1 (en) * 2008-03-10 2009-09-17 Phf S.A. High bioavailability formulation of mangosteen and manufacturing process thereof
RU2564896C2 (en) * 2013-12-11 2015-10-10 Александр Александрович Кролевец Tannin encapsulation method
WO2016094810A2 (en) * 2014-12-12 2016-06-16 Ojai Energetics Pbc Microencapsulated cannabinoid compositions
US20180339006A1 (en) * 2012-06-19 2018-11-29 Aribio Co., Ltd Method for preparing granules or pills containing extracts in high concentration

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060165794A1 (en) * 2002-10-04 2006-07-27 Ethypharm Spheroids, preparation method thereof and pharmaceutical compositions
US20080038362A1 (en) * 2003-06-12 2008-02-14 Won-Bong Park Composition For An Enteric Coating Of Natural Product Containing Lectin
WO2009112054A1 (en) * 2008-03-10 2009-09-17 Phf S.A. High bioavailability formulation of mangosteen and manufacturing process thereof
US20180339006A1 (en) * 2012-06-19 2018-11-29 Aribio Co., Ltd Method for preparing granules or pills containing extracts in high concentration
RU2564896C2 (en) * 2013-12-11 2015-10-10 Александр Александрович Кролевец Tannin encapsulation method
WO2016094810A2 (en) * 2014-12-12 2016-06-16 Ojai Energetics Pbc Microencapsulated cannabinoid compositions

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