EP3256141A1 - Multipartikuläre formulierung mit kräuterextrakten - Google Patents

Multipartikuläre formulierung mit kräuterextrakten

Info

Publication number
EP3256141A1
EP3256141A1 EP16703546.8A EP16703546A EP3256141A1 EP 3256141 A1 EP3256141 A1 EP 3256141A1 EP 16703546 A EP16703546 A EP 16703546A EP 3256141 A1 EP3256141 A1 EP 3256141A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
spray
anyone
dried
form according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16703546.8A
Other languages
English (en)
French (fr)
Inventor
Jose VEREEKEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP3256141A1 publication Critical patent/EP3256141A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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)
    • A61K36/51—Gentianaceae (Gentian family)
    • A61K36/515—Gentiana
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to multiparticulate formulations comprising herbal extracts, in particular spray-dried herbal extracts, said multiparticulate formulations being prepared by extrusion-spheronization.
  • said multiparticulate formulations comprise colloidal silicon dioxide at a total concentration of about 1 % w/w to about 5% w/w.
  • the present invention relates to the use of such formulations in human or veterinary medicine as well as methods for preparing such formulations.
  • Formulations comprising herbal extracts are frequently used in traditional Chinese medicine and also gain more and more interest in the Western Civilization.
  • Zingiberis, Gentian and/or Matricaria extracts are suitable for use in the treatment of gastro-intestinal complaints/disorders, including flatulence, motion sickness, travel sickness, loss of appetite, ...
  • These extracts are mostly formulated in powder form or tablets, which need to be swallowed with water.
  • water may not always be available to the patient (eg. while driving a car), and it may thus be difficult to administer such powders or tablets to the patient in need thereof.
  • a possible solution for this problem is to formulate the herbal extracts in a multiparticulate formulation, comprising small particles. These particles can easily be administered to a patient and due to their small size, they can be swallowed without the need of water. Furthermore, such particles can be coated in order to mask the bad taste of the included herbal extracts without the addition of taste masking agents, in contrast to formulations provided in powder form.
  • a multiparticulate formulation comprising ginger extracts is for example known from Deol et al., 2013. Said formulation is prepared by entrapping alginate beads with ginger extracts followed by Eudragit S100 coating.
  • Calcium alginate beads are water-insoluble gelatinous beads prepared by addition of aqueous calcium chloride to aqueous sodium alginate, and they are often used for entrapping macromolecules such as enzymes.
  • the entrapped active ingredient is only very slowly released (e.g. less than 0% in the first 5 h, see Deol et al). Therefore, this type of formulation is not suitable for use in indications in which a very fast relief of symptoms is desired such as for example in case of nausea or motion sickness.
  • multiparticulate herbal formulations prepared by extrusion-spheronization can be used (e.g.
  • US2003206978 discloses solid dosage forms comprising an active agent, such as a spray dried plant extract
  • WO03047551 discloses agglomerated particles including spray- dried herbal extract
  • Soares et al., 2005 discloses tablets comprising spray-dried plant extracts
  • WO03048666 discloses spray-drying processes for preparing agglomerated particles containing an herbal extract.
  • none of these publications discloses said formulations to be in the form of extrudates, or extrusion-spheronization processes for preparing such formulation.
  • the inventors have surprisingly found that the addition of a small amount of colloidal silicon dioxide (about 1 % w/w to about 5% w/w) to the spray-dried herbal extracts before the extrusion-spheronization step, avoids such shark skiming and significantly increases the yield, thereby resulting in a herbal extract preparation suitable for extrusion-spheronization.
  • colloidal silicon dioxide Low amounts of colloidal silicon dioxide (0.1 to 0.5% by weight) are often used in tablets and capsules as a glidant.
  • large amounts (up to about 40%) of colloidal silicon dioxide, in combination with a surfactant and/or a plasticizer were used during extrusion-spheronization of a (non-herbal extract) formulation, in order to replace the classically used microcrystalline cellulose as an excipient (WO2008001 140).
  • WO2008001 140 classically used microcrystalline cellulose as an excipient
  • colloidal silicon dioxide were needed in combination with a surfactant and/or a plasticizer, in order for the formulations to be suitable for extrusion-spheronization.
  • These formulations have the major disadvantage that the total amount of active ingredient to be incorporated in the final product is significantly reduced due to the high amounts of colloidal silicon dioxide.
  • the inventors have now found that the addition of a moderate amount (about 1 % w/w to about 5% w/w) of silicon dioxide, before the extrusion-spheronization process, is very suitable for the preparation of multiparticulates comprising significant amounts of spray-dried herbal extracts, even in the absence of surfactants or plasticizers.
  • the present invention provides a multiparticulate pharmaceutical dosage form, wherein each particle comprises:
  • the dosage form according to this invention comprises a combination of at least 2 or more spray-dried herbal extracts.
  • said spray-dried herbal extracts are selected from the list comprising Zingiberis extracts, Gentian extracts, and Matricaria extracts.
  • said extrusion spheronization aid is selected from the list comprising microcrystalline cellulose, celluloses, starch and derivatives thereof, chitosan, K- Carrageenan, pectin ic-acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, and cross-linked PVP.
  • said disintegrant is a superdisintegrant selected from the list comprising cross-linked cellulose, cross-linked polyvinylpyrrolidone (PVPP), cross-linked starch or cross-linked alginic acid; more in particular PVPP.
  • PVPP polyvinylpyrrolidone
  • the dosage form core (i.e. before application of an optional coating layer), does not contain a surfactant or a plasticizer.
  • the dosage form, i.e. the multiparticulates, according to this invention is coated.
  • Said coating is preferably a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Gentian Extract. In another specific embodiment, the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Matricaria Extract.
  • the present invention provides the dosage form according to this invention for use in human or veterinary medicine, more in particular for use in the treatment and/or prevention of gastro-intestinal disorders; such as for example in the treatment and/or prevention of spasmodic gastrointestinal complaints including bloating and flatulence, motion sickness, travel sickness, mild dyspeptic/gastrointestinal disorders, temporary loss of apetite, gastro-intestinal complaints such as minor spasm, or epigastric distension.
  • the present invention provides a method for the preparation of a solid multiparticulate pharmaceutical dosage form according to this invention comprising the steps of:
  • the method according to this invention may further comprise the step of coating said multiparticulate dosage form, with a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • the present invention provides a multiparticulate pharmaceutical dosage form, wherein each particle comprises:
  • said Si0 2 is present at a total concentration of about 1 % w/w to about 5% w/w; and in that the pharmaceutical dosage form is an extrudate.
  • each particle may have a diameter of from about 0.1 mm to about 5.0 mm, e.g. from about 0.5 mm to about 5.0 mm, in particular from about 0.5 mm to about 2.5mm, more particularly from about 0.5 mm to about 1 .0 mm, more in particular about 0.75 mm.
  • These particles may subsequently be formulated in sachets or capsules for easy dosing and administration.
  • the multiparticulate pharmaceutical dosage form comprises an agent to facilitate the extrusion spheronization process (i.e. extrusion spheronization aid).
  • extrusion spheronization aid i.e. microcrystalline cellulose (CMC) is the most widely used extrusion spheronization aid, and is also preferred in the formulations according to the invention, other suitable extrusion spheronization aids may also be used such as for example celluloses, starch and derivatives thereof, chitosan, K-Carrageenan, pectinic-acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, and cross-linked PVP.
  • the extrusion/spheronization process in general comprises 5 steps including dry mixing, wet granulation, extrusion, spheronization and drying.
  • First, the materials are dry mixed to achieve a homogeneous powder dispersion and then wet granulated to produce a sufficiently plastic wet mass.
  • the wet mass is extruded to form rod-shaped particles of uniform diameter that are charged into a spheronizer and rounded off into spherical particles.
  • the spherical particles are then dried to achieve the desired moisture content.
  • the resulting end products of such an extrusion/spheronization process according to the present invention are termed 'extrudates'.
  • the pharmaceutical dosage form of the present invention is characterized in being an extrudate, by being produced using the described extrusion/spheronization process.
  • the multiparticulate pharmaceutical dosage form comprises an agent to facilitate disintegration (disintegrant) after administration to the patient. Disintegrants expand when wetted, causing the particles to break apart in the digestive tract, and thereby releasing the active ingredient(s).
  • the disintegrant is preferably a superdisintegrant.
  • superdisintegrants are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength.
  • superdisintegrants Upon contact with water, superdisintegrants swell, hydrate, change volume or form, and produce a disruptive change in the particles.
  • Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs.
  • Superdisintegrants suitable in the formulations according to this invention, may be selected from the list comprising cross-linked cellulose, cross-linked polyvinylpyrrolidone (PVPP), cross- linked starch or cross-linked alginic acid; more in particular PVPP.
  • the multiparticulate pharmaceutical dosage form comprises colloidal silicon dioxide (CSD), which is a very fine particulate (colloidal) form of silicon dioxide (Si0 2 ).
  • colloidal silicon dioxide may or may not be used during the preparation of the herbal extracts, it is essential in the context of the present invention, that colloidal silicon dioxide is added to the herbal extracts, before the extrusion-spheronization thereof.
  • the formulations of the current invention in particular comprise one or more spray-dried herbal extracts.
  • Spray-drying is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
  • a spray dryer takes a liquid stream and separates the solute or suspension as a solid and the solvent into a vapor.
  • the liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporised. Solids form as moisture quickly leaves the droplets.
  • the solid is usually collected in a drum or cyclone.
  • a nozzle is usually used to make the droplets as small as possible, maximising heat transfer and the rate of water vaporisation. Droplet sizes can range from 10 to 500 ⁇ depending on the nozzle.
  • Spray dryers can dry a product very quickly compared to other methods of drying. They also turn a solution, or slurry into a dried powder in a single step, which can be advantageous for profit maximization and process simplification.
  • a carrier can be used such as for example maltodextrin, gum arabic or waxy starch.
  • spray-dried herbal extracts prepared using maltodextrin as a carrier are preferred.
  • the dosage form according to this invention preferably does not comprise other ingredients than the ones listed above.
  • the dosage form according to this invention preferably does not contain a surfactant or a plasticizer in the core of the particles.
  • an optional coating which does not affect the loading of the active ingredient, may further comprise a surfactant or plasticizer.
  • the multiparticulates according to this invention may optionally be coated.
  • a coating is advantageous in for example masking the bad taste of the herbal extracts.
  • this coating is preferably a fast-dissolving coating.
  • the optional coating is preferably a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • the spray-dried herbal extracts may be selected from the list comprising Zingiberis extracts, Gentian extracts, and Matricaria extracts. These extracts are generally known to be particularly suitable for treating or relieving the gastro-intestinal disorders or complaints according to this invention. However, any other suitable type of spray- dried herbal extracts may be used in the formulations according to the present invention.
  • the dosage form according to this invention may comprises a combination of at least 2 spray-dried herbal extracts, such as for example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 spray-dried herbal extracts.
  • the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Gentian Extract; or a combination of spray-dried Zingiberis Extract and spray-dried Matricaria Extract.
  • Zingiberis extracts are generally known for the symptomatic treatment of mild, spasmodic gastrointestinal complaints including bloating and flatulence or for the symptomatic relief of motion sickness.
  • Gentian extracts may be used for the symptomatic treatment of mild dyspeptic/gastrointestinal disorders, and/or in temporary loss of appetite.
  • Matricaria extracts may in turn be used for the relief of gastrointestinal complaints such as minor spasm, epigastric distension, or travel sickness.
  • the present invention provides the dosage forms according to this invention for use in human or veterinary medicine, more in particular for use in the treatment and/or prevention of gastro-intestinal disorders; such as for example in the treatment and/or prevention of spasmodic gastrointestinal complaints including bloating and flatulence, motion sickness, travel sickness, mild dyspeptic/gastrointestinal disorders, temporary loss of apetite, gastro-intestinal complaints such as minor spasm, or epigastric distension.
  • the present invention provides a method for the preparation of a solid multiparticulate pharmaceutical dosage form (i.e. extrudate) according to this invention comprising the steps of:
  • the method according to this invention may further comprise the step of coating said multiparticulate dosage form, with a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.
  • the spheres were air dried (can also be dried at 40-50° C in fluid bed dryer).

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
EP16703546.8A 2015-02-09 2016-02-09 Multipartikuläre formulierung mit kräuterextrakten Withdrawn EP3256141A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15154400 2015-02-09
PCT/EP2016/052704 WO2016128386A1 (en) 2015-02-09 2016-02-09 Multiparticulate formulation comprising herbal extracts

Publications (1)

Publication Number Publication Date
EP3256141A1 true EP3256141A1 (de) 2017-12-20

Family

ID=52477590

Family Applications (1)

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EP16703546.8A Withdrawn EP3256141A1 (de) 2015-02-09 2016-02-09 Multipartikuläre formulierung mit kräuterextrakten

Country Status (2)

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EP (1) EP3256141A1 (de)
WO (1) WO2016128386A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111228224B (zh) * 2018-11-28 2022-05-20 鲁南制药集团股份有限公司 一种首荟通便微丸制剂及其制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE29613932U1 (de) * 1996-08-12 1997-02-13 Nestmann Andreas Magenbitterrezeptur
AU2002219964A1 (en) 2001-11-29 2003-06-17 Penwest Pharmaceutical Company Agglomerated particles including an active agent coprocessed with silicified microcrystalline cellulose
EP1481211B1 (de) 2001-11-29 2009-04-22 J. Rettenmaier & Söhne GmbH + Co. KG Verfahren zum co-sprühtrocknen flüssiger kräuterextrakte mit trockener silifizierter mcc
US20030206978A1 (en) 2001-11-29 2003-11-06 Bob Sherwood Agglomerated particles including an active agent coprocessed with silicified microcrystalline cellulose
US20190083399A9 (en) * 2006-04-03 2019-03-21 Isa Odidi Drug delivery composition
GB0612809D0 (en) 2006-06-28 2006-08-09 Univ Sunderland Formulation
EP2709593A4 (de) * 2011-05-16 2014-10-29 Sun Pharma Advanced Res Co Ltd Pharmazeutische zusammensetzung aus mehreren partikeln

Also Published As

Publication number Publication date
WO2016128386A1 (en) 2016-08-18

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