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WO2024246566A1 - Pastille enrobée gastro-résistante contenant du bicarbonate de sodium, production associée, préparation pharmaceutique et complément alimentaire contenant celle-ci, et leur utilisation - Google Patents

Pastille enrobée gastro-résistante contenant du bicarbonate de sodium, production associée, préparation pharmaceutique et complément alimentaire contenant celle-ci, et leur utilisation Download PDF

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Publication number
WO2024246566A1
WO2024246566A1 PCT/HU2024/050036 HU2024050036W WO2024246566A1 WO 2024246566 A1 WO2024246566 A1 WO 2024246566A1 HU 2024050036 W HU2024050036 W HU 2024050036W WO 2024246566 A1 WO2024246566 A1 WO 2024246566A1
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WO
WIPO (PCT)
Prior art keywords
pellet
coating
gastro
sodium bicarbonate
coated
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Pending
Application number
PCT/HU2024/050036
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English (en)
Inventor
Pál FEKETE
Fruzsina NACSA
Lívia Gál
Zsolt ŐSZI
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Meditop Gyogyszeripari Kft
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Meditop Gyogyszeripari Kft
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Publication of WO2024246566A1 publication Critical patent/WO2024246566A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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
    • 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
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • Gastro-resistant coated pellet containing sodium bicarbonate production thereof , pharmaceutical preparation and food supplement containing thereof , and their use
  • the obj ect of the invention relates to a gastro-resistant pellet containing sodium bicarbonate as the only active ingredient which pellet is suitable for the manufacture of a pharmaceutical preparation and food supplement , to a method for the manufacture of such coated pellet , to pharmaceutical preparations and food supplements produced from such coated pellets , and to their use .
  • the obj ect of the present invention relates to gastro- resistant coated pellets containing sodium bicarbonate .
  • Sodium hydrogencarbonate is mentioned in the literature as sodium bicarbonate or bicarbonate of soda, in the present speci fication the term sodium bicarbonate will be used .
  • Sodium bicarbonate is administered orally for the treatment of mild metabolic acidosis and chronic kidney disease .
  • it is also used for neutralising the unpleasant symptoms caused by overeating, bloating, nausea, hiccoughing and acidic foods .
  • Sodium bicarbonate on its own and pharmaceutical preparations and food supplements containing this without a gastro- resistant coating are less suitable for therapeutic purposes .
  • the reason for this is that sodium bicarbonate decomposes in the acidic medium of the stomach while producing carbon dioxide , which, on the one hand, involves an uncomfortable side-ef fect originating from the formation of gas , and, on the other hand, the sudden reduction of the acidity of the stomach may cause so-called acid rebound ( excessive acid formation) .
  • the desired ef fect may only be achieved temporarily with sodium bicarbonate on its own or without a gastro-resistant coating, and with its use in this way the symptoms of acid reflux may occur even more intensively than before .
  • Sodium bicarbonate that may be used for therapeutic purposes and is currently available in commerce in the form of gastro- resistant tablets including, for example , bicaNorm tablets and Nephrotrans gastro-resistant soft gelatine capsules ( J . Breitkreutz et al . : Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance : an exception from the rule? , JPP 2007 , 59 , 59- 65 . ) .
  • J . Breitkreutz et al . following the general manufacturing method for gastro- resistant coated pellets , first applied a water-soluble film coating to sodium bicarbonate pellets , then applied a film coating that does not dissolve in the gastric j uice but does dissolve in the intestinal juice above pH 5.5. They found that the use of at least a 60% coating material was required to form a suitable gastro-resistant pellet.
  • Hajnal, P. et al. recommend the use of an at least four-layer film coating when producing gastro-resistant coated pellets containing sodium bicarbonate (Hungarian patent no HU230560) .
  • the pellets are first coated with a cationic polymer coating that is insoluble above pH 5, then with an anionic polymer coating that dissolves above pH 6, then after this with an insoluble polymer coating independent of pH, and finally with an anionic polymer coating that dissolves above pH 4.5 or pH 5.5.
  • the coating material applied to the pellets in this case also exceeds 50%.
  • coating materials that do not dissolve in the gastric juice have acidic character, i.e. the polymer chains contain groups with acidic character, as a result of which these coatings are substantially insoluble in the acidic medium of the stomach, while in the higher pH medium of the small and large intestines they dissolve while forming salts.
  • These coating materials may be divided into three groups :
  • Materials belonging to the first two groups are usually used as the gastro-resistant coating of pharmaceutical preparations, the materials belonging to group 2 may be used in the case of food supplements, while the polymers belonging to group 3 dissolving at a pH value of over 7 . 0 do not even dissolve in the small intestine , these are used for transporting active ingredients directly into the large intestine .
  • the acidic character groups of the gastro- resistant polymers may cause the decomposition of the active ingredients during the manufacture and storage of the preparations . Therefore , in order to create a pharmaceutical preparation or food supplement of the appropriate stability an intermediate insulating coating must be used between the pellet containing the active ingredient and the gastro- resistant coating .
  • this intermediate insulating coating usually contains a water-soluble filmforming material (US 6379705B1 , US 6228400B1 ) , to which, optionally, sucrose (WO2021126098A1 ) , or mannitol ( CN102631327B ) is added .
  • sucrose WO2021126098A1
  • mannitol CN102631327B
  • additives that do not dissolve in water talc : EP3292862A1 , polydimethylsiloxane : WO9852564A1
  • melts of fat-like materials (HU226580B1 ) is also described .
  • the amount of the coatings is higher than in the case of the pharmaceutical forms of tablets and capsules , due to the smaller particle si ze of pellets and, therefore , their greater speci fic surface area .
  • the amount of the intermediate insulating coating calculated with respect to the mass of the pellet is generally 10 to 20% , while the amount of the gastro-resistant coating may even be 10 to 40% (EP3292862A1 ) .
  • Figure 1 presents the pH-increasing ef fect of uncoated pellets and of pellets with various coatings when dissolved in a 0 . 01 N HC1 solution, where the ethylcellulose is a Surelease® coating, shellac is a Bonulac® coating and the methacrylate is an Eudraguard® biotic coating .
  • Figure 2 presents the pH-increasing ef fect elicited in various pH dissolving mediums of coated pellets containing an intermediate insulating coating ( 15% Surelease®) on the pellet that does not dissolve in water and a gastro-resistant coating applied to this , where the shellac is a Bonulac® coating and the methacrylate is an Eudraguard® biotic coating .
  • Figure 3 presents the pH-increasing ef fect of the dissolution of sodium bicarbonate in various buf fers , in the case of an intermediate insulating coating that dissolves in water ( 15% Nutraf inish®) , where the methacrylate is an Eudraguard® biotic coating .
  • these latter coating materials are required in order to delay dissolution in an acidic medium, and, on the other part , surprisingly they permit the dissolution of sodium bicarbonate and thereby the release of the sodium bicarbonate into the small intestine within approximately 60 minutes even in a medium with a pH of 4 . 5 , and so the preparation is suitable for neutralising the acidic medium in the small intestine , and thereby promoting the digestion process performed in the small intestine .
  • the obj ect of the present invention relates to a coated pellet suitable for the manufacture of a pharmaceutical preparation and/or food supplement that contains sodium bicarbonate as active ingredient , and that contains at least two coating layers , and which coated pellet contains sodium bicarbonate as the only active ingredient , where the one coating layer is the intermediate insulating coating surrounding the pellet , and the other coating layer is the gastro-resistant coating surrounding the intermediate insulating coating, which gastro- resistant coating contains shellac or anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7 . 0 .
  • the coated pellet has a total of two coating layers , the intermediate insulating coating and the gastro-resistant coating surrounding the intermediate insulating coating .
  • the diameter of the coated pellet is between 0 . 5 and 2 mm, preferably between 1 . 0 and 2 . 0 mm .
  • the sodium bicarbonate content of the pellet is 70 to 95 mass! of the mass of the pellet .
  • the sodium bicarbonate content of the coated pellet is at least 50 mass! of the mass of the coated pellet .
  • the intermediate insulating coating of the coated pellet is between 10 and 20 mass! of the mass of the pellet .
  • the gastro-resistant coating of the coated pellet is between 10 to 30 mass! of the mass of the pellet .
  • the intermediate insulating coating of the coated pellet contains either a polymer that does not dissolve in water that is selected from the following list : ethylcellulose or neutral methacrylate copolymer, or it contains a water-soluble polymer that is selected from the following list : hydroxypropyl methylcellulose , polyvinyl alcohol , hydroxypropyl cellulose , hydroxypropyl starch, polyvinylpyrrolidone .
  • anionic methacrylate copolymer dissolving in an aqueous medium at a pH of over 7 . 0 is used as the gastro- resistant polymer of the gastro-resistant coating of the coated pellet .
  • the obj ect of the present invention also relates to a method for the manufacture of a coated pellet according to the above , which method contains the following steps : a ) producing the pellet containing sodium bicarbonate ; b ) coating the pellet containing sodium bicarbonate obtained in step a ) with an intermediate insulating coating ; c ) applying a gastro-resistant coating surrounding the intermediate insulating coating to the pellet obtained in step b ) provided with an intermediate insulating coating, where the amount of the gastro-resistant coating is 10 to 30% of the mass of the pellet , and where shellac or anionic methacrylate copolymer dissolving at a pH of over 7 . 0 is used in the form of an aqueous dispersion as the gastro-resistant coating .
  • the pellet produced in step a ) contains at least 70% sodium bicarbonate with respect to the mass of the pellet ; and/or in step b ) 10 to 20% intermediate insulating coating that does not dissolve in water is used with respect to the mass of the pellet , and ethylcellulose , or neutral methacrylate copolymer is used as the intermediate insulating coating in the form of an aqueous dispersion; or in step b ) 10 to 20% hydroxypropyl methylcellulose , or polyvinyl alcohol with respect to the mass of the pellet is used as the water-soluble intermediate insulating coating in the form of an aqueous dispersion, then in step c ) anionic methacrylate copolymer dissolving in an aqueous medium at a pH of over 7 . 0 is used as the gastro- resistant coating in the form of an aqueous dispersion .
  • the obj ect of the present invention also relates to a pharmaceutical preparation and/or food supplement containing sodium bicarbonate as the only active ingredient , which is provided in the form of a tablet , a capsule or a storage unit and contains the coated pellet according to the above .
  • the obj ect of the present invention also preferably relates to a pharmaceutical preparation and/or food supplement containing sodium bicarbonate as the only active ingredient in the form of tablet or capsule , which contains between 300 mg and 1000 mg of sodium bicarbonate , preferably between 300 mg and 600 mg of sodium bicarbonate .
  • the obj ect of the present invention relates to the use of the coated pellet according to the above for the manufacture of tablets or capsules .
  • the obj ect of the present invention relates to the use of the coated pellet according to the above or the pharmaceutical preparation according to the above in the treatment of mild metabolic acidosis , chronic kidney disease or heartburn/ref lux, where the pharmaceutical preparation is preferably a tablet or a capsule .
  • the obj ect of the present invention also relates to the use of the coated pellet according to the above or the food supplement according to the above in the treatment of digestion problems , heartburn, acidic digestion disorders and stomach complaints , where the food supplement is preferably a tablet or a capsule .
  • the food supplement is preferably a tablet or a capsule .
  • % (percent) in the present specification is understood to mean mass percent (mass%)
  • ratios are understood to mean mass ratios of the given components .
  • pellet is understood to mean particles produced using granulation with a diameter of between 0.5 to 2.0 mm that are spherical or nearly perfectly spherical. With respect to structure, the pellets are solid, their surface is even and smooth, which is preferable in the interest of even active ingredient release in the case of the manufacture of a coated pharmaceutical form.
  • the particle size distribution of pellets is homogenous and falls within a narrow range, it is between 0.5 and 2.0 mm in case of pellets used usually in the pharmaceuticals industry.
  • pelletisation processes known to the person skilled in the art may be used to produce the pellets, which procedures include matrix pellet manufacture procedures, such as vortex granulation, fluid bed rotogranulation, and the extrusion spheronization process, and build-up processes, such as hot-melt extrusion and the centrifugal granulation method.
  • matrix pellet manufacture procedures such as vortex granulation, fluid bed rotogranulation, and the extrusion spheronization process
  • build-up processes such as hot-melt extrusion and the centrifugal granulation method.
  • pellet is understood to mean a pellet not containing a coating.
  • such a pellet is provided with at least one intermediate insulating coating and one gastro-resistant coating and in this way the coated pellet according to the present invention is obtained.
  • mass! proportion of active ingredient or a coating layer is given with respect to the mass of the pellet, then this is understood to mean that the mass! proportion of the given component is given with respect to the mass of the coated pellet without the mass of the coating layers.
  • the most frequent method for producing gastro-resistant pellets is the coating of the pellets.
  • Coating procedures known to the person skilled in the art may be used for coating the pellets, such as fluidized bed spray granulation methods in Wurster or Ventilus apparatuses, and pan coating, respectively. These procedures belong to the compulsory knowledge of the person skilled in the art, and descriptions of these processes may be found in specialist books and specialist articles (including: Revesz P. : Gyogyszertechnologia (Pharmaceutical Technology) , JATE Press, 2009; Developing Solid Oral Dosage Forms (Pharmaceutical Theory & Practice ) Second Edition, Edited by Yihong Qiu and others , Elsevir, 2017 .
  • Our invention is directed at producing gastro-resistant coated pellets containing sodium bicarbonate as the only active ingredient with the use of a coating system having a smaller amount of coating and a coating system with a simpler structure as compared to the currently known methods .
  • the basis of the invention is the surprising recognition that in the case of pellets containing sodium bicarbonate as the only active ingredient , not only can the polymer mixtures be used that dissolve or partially dissolve at a pH value of under 6 . 0 as usually used in the case of other active ingredients but also gastro-resistant polymers that dissolve above pH 7 . 0 , which actually serve for realising active ingredient release in the large intestine in the case of other active ingredients .
  • These coatings dissolving above pH 7 . 0 which used at an amount of 10 to 30% with respect to the mass of the pellet prevent the release of the sodium bicarbonate in the acidic medium of the stomach (pH 1 to 2 ) , surprisingly already at a pH of above 4 . 5 make it possible for the sodium bicarbonate to be dissolved and therefore terminate the unfavourable pH value in the small intestine .
  • the basis of the present invention is also the surprising recognition that in the case of a gastro-resistant polymer coating that dissolves above pH 7 . 0 , a water-soluble polymer or a polymer that does not dissolve in water constituting 10 to 20% of the mass of the pellet may both be used as the intermediate insulating coating .
  • the solution according to our invention is then that , as compared to the solutions according to the state of the art , a smaller amount of coating ( 20 to 50% ) with respect to the amount of the pellets and with a simpler coating structure ( two coatings ) enables the manufacture of pellets with a gastro-resistant coating containing sodium bicarbonate as the only active ingredient .
  • the obj ect of the present invention relates to gastro-resistant coated pellets containing sodium bicarbonate as the only active ingredient suitable for the manufacture of a pharmaceutical preparation and/or food supplement , where the coated pellet contains at least two coating layers , the intermediate insulating coating surrounding the pellet and the gastro-resistant coating surrounding the intermediate insulating coating, the latter of which contains shellac or anionic methacrylate copolymer coating material dissolving at a pH above 7 . 0 .
  • the coated pellets according to the present invention are suitable for the manufacture of pharmaceutical preparations and food supplements , in other words these pellets are such so that pharmaceutical preparations and food supplements ( e . g .
  • tablets , capsules , sachets primarily for human use , may be manufactured from them .
  • the aforementioned pharmaceutical preparation and food supplement are designed for human use , their use in animals is not excluded in a given case , because , as is obvious for a person skilled in the art , animals may have illnesses that require the use of gastro- resistant pharmaceutical preparations containing the active ingredient of sodium bicarbonate .
  • the coated pellet according to the present invention contains coating layers .
  • the first layer or coating that surrounds the pellet is the intermediate insulating coating .
  • the function of this layer is to separate the pellet and the gastro- resistant coating .
  • the intermediate insulating coating ensures that the sodium bicarbonate content of the coated pellet according to the present invention remains stable during manufacture and storage .
  • the gastro-resistant coating surrounds the non-water-soluble intermediate insulating coating from the outside with respect to the pellet .
  • the gastro-resistant coating (which contains shellac or anionic methacrylate copolymer coating material dissolving at a pH above 7 . 0 ) contains acid character groups , due to this it does not dissolve in the acidic medium of the stomach . Its task is to protect the coated pellet containing sodium bicarbonate from undesired dissolution in the stomach, but to enable the release of the active ingredient in the intestines . In general , the latter takes place in such a way that the external gastro-resistant coating, or a part of it, is dissolved in the nearly neutral pH of the intestines during salt formation .
  • coated pellet according to the present invention may also optionally contain other layers , coatings .
  • the present invention provides a gastro- resistant coated pellet containing sodium bicarbonate as the only active ingredient .
  • the coated pellet exclusively contains the two coating layers described above .
  • the coated pellet does not contain additional layers , so its manufacture is simple , and the active ingredient content of the pellets obtained is higher than the currently known gastro-resistant pellets containing sodium bicarbonate .
  • the diameter of the coated pellet according to the present invention is preferably between 0 . 5 and 2 mm, even more preferably between 1 . 0 and 2 . 0 mm .
  • This is the si ze range within which the pellet with the composition and structure described above may be economically manufactured using the known pelleting methods , and it is from pellets of this si ze that pharmaceutical products or food supplement products ( e . g . tablets or capsules ) may be formulated simply and in a known way .
  • it is preferable i f the si ze of the pellet does not approach the lower limit .
  • the speci fic surface area of the pellets increases in the case of pellets of a smaller diameter, and as a consequence of this there will also be a greater coating layer demand, which would not be economical from the point of view of coating .
  • the sodium bicarbonate content of the pellet is 70 to 95 mass! of the mass of the pellet (we note that the concept of pellet within the context of the present speci fication is understood to mean the form without coating ) .
  • the pellet also contains other excipients apart from the active ingredient generally used in the pharmaceutical industry, e . g . microcrystalline cellulose , polyvinylpyrrolidone .
  • the high active ingredient content of the pellets is preferable , on the one hand, for economy of manufacture and, one the other hand, for increasing the active ingredient content and reducing the size of the pharmaceutical forms produced, which also contributes to establishing better patient compliance .
  • the sodium bicarbonate active ingredient content in the coated pellet is at least 50 mass! of the mass of the coated pellet .
  • the highest possible active ingredient content of the coated pellets is preferable for reasons of manufacture economy, and in the interest of increasing the active ingredient content of the pharmaceutical forms produced and reducing their si ze .
  • the mass of the intermediate insulating coating of the coated pellet is between 10 and 20 mass! of the mass of the pellet (we note that the concept of pellet within the context of the present speci fication is understood to mean the form without coating) .
  • Both water-soluble polymers and polymers that do not dissolve in water may be used as the intermediate insulating coating . The reason for this is that our experimental measurements have veri fied that the use of a 20 mass! intermediate insulating coating with respect to the mass of the pellet surprisingly does not signi ficantly slow down the dissolution of the sodium bicarbonate .
  • the mass of the gastro-resistant coating of the coated pellet is between 10 and 30 mass! of the mass of the pellet (we note that the concept of pellet within the context of the present speci fication is understood to mean the form without coating) .
  • the reason for this is that our experience shows that this amount of the coating material that dissolves above pH 7 . 0 prevents the dissolution of the sodium bicarbonate in the highly acidic medium ( gastro-resistance ) , and enables the dissolution of the active ingredient in a medium above pH 4 . 5 ( dissolution in the small intestine ) .
  • the coating materials that may be used as the intermediate insulating coating include synthetic or partially synthetic large-molecule film- forming substances that may be used for the manufacture of both pharmaceutical preparations and food supplements .
  • Our experience shows that among polymers that do not dissolve in water, the following are particularly suitable for the formation of the intermediate insulating coating of the coated pellet according to the present invention : ethylcellulose , and neutral methacrylate copolymer .
  • the ethylcellulose is partly O-ethylated cellulose .
  • Ethylcellulose may be preferably used in an aqueous dispersion for film coating .
  • Such an aqueous dispersion is the Surelease® branded preparation developed and manufactured by Colorcon Ltd, which in addition to ethylcellulose also contains oleic acid as softening agent , medium chain triglyceride and ammonium hydroxide .
  • the neutral methacrylate copolymer is actually an ethyl acrylate - methyl methacrylate copolymer .
  • the neutral methacrylate copolymer is preferably used in aqueous dispersion .
  • aqueous dispersion is the Eudraguard® control branded preparation developed by the Evonik company, which also contains polysorbate as surfactant excipient , hydroxypropyl methylcellulose as anticaking agents and talc .
  • the gastro-resistant coating of the coated pellet according to the present invention contains shellac or anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7.0.
  • Shellac is a natural polyester resin. It dissolves in an aqueous medium above pH 7.0, therefore it is generally used for active ingredient release in the large intestine. It may be used for film coating in a neutral, preferably aqueous dispersion.
  • An example of such an aqueous dispersion is the Bonulac® coating system developed by the Bioground company.
  • poly (methyl acrylate-methyl methacrylate-methacrylic acid) (in a 7:3:1 ratio) copolymer may be preferably used, the type that may be used in food supplement preparations is marketed under the brand name of Eudraguard® biotic.
  • the manufacturer, Evonik company recommends this coating material specifically for active ingredient release in the large intestine, in a medium above pH 7.0.
  • Our investigations have shown, however, that sodium bicarbonate is released from pellets coated with Eudraguard® biotic already in a medium at pH 4.5, which is verified by the elevation of the pH value of the medium. ( Figures 2 and 3) .
  • Eudragit biotic provides an effective gastro-resistant coating when applied at an amount equal to 10 to 15% of the mass of the pellet, while in the case of shellac at least a 25% coating is required in order to provide similar protection ( Figures 2 and 3) .
  • Gastro-resistant coatings do not only consist of the above film-forming substances, they also, optionally, contain excipients, such as softening agents (e.g. triacetin, triethyl citrate) , surfactants (e.g. polysorbate, sodium lauryl sulphate) , anti-caking agents (e.g. talc, glycerol monostearate) .
  • the object of the present invention also relates to a method for the manufacture of the coated pellet according the present invention and disclosed in detail above.
  • This method contains at least the following steps: a) producing the pellet containing sodium bicarbonate; b) coating the pellet containing sodium bicarbonate obtained in step a) with an intermediate insulating coating; c) coating the pellet provided with the intermediate insulating coating obtained in step b) with a gastro- resistant coating surrounding the intermediate insulating coating, where the amount of the gastro-resistant coating is 10 to 30% of the mass of the pellet, and where shellac or anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7.0 is used as the gastro-resistant coating in the form of an aqueous dispersion.
  • step a) the pellet containing sodium bicarbonate as the only active ingredient is produced.
  • the pellet may also contain excipients.
  • the components are mixed together, moistened with water and then pelleting is performed in the conventional way.
  • step b) the pellet obtained as a result of the previous step is provided with the intermediate insulating coating described in detail above.
  • the methods used for coating the pellets are known according to the state of the art and are obvious for a person skilled in the art .
  • the pellets already containing a coating layer, obtained in step b ) provided with the intermediate insulating coating, are provided with a gastro- resistant coating, in a way known of in itsel f .
  • the amount of the gastro-resistant coating applied in this step is given as a percentage ( % ) of the mass of the pellet , according to which 10 to 30 mass! gastro-resistant coating is applied to the pellet (we note that the concept of pellet within the context of the present speci fication is understood to mean the form without coatings ) .
  • the shellac or anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7 . 0 discussed in detail above is used for the gastro-resistant coating in the form of an aqueous dispersion .
  • the pellet produced in step a ) contains at least 70% sodium bicarbonate with respect to the mass of the pellet , the reason for this is that the preferable embodiment of the coated pellet according to the invention disclosed above may be produced by using such a pellet .
  • step b 10 to 20% of water-insoluble intermediate insulating coating, with respect to the mass of the pellet , is used in step b ) , and ethyl cellulose or neutral methacrylate copolymer is used as the intermediate insulating coating in the form of an aqueous dispersion, because our investigations have shown that particularly good quality pellets may be produced by using these water-insoluble filmforming substances as the intermediate insulating coating .
  • hydroxypropyl methylcellulose or polyvinyl alcohol with respect to the mass of the pellet is used as the water-soluble intermediate insulating coating in step b ) in the form of an aqueous dispersion, then anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7 . 0 is used as the gastro-resistant coating in step c ) in the form of an aqueous dispersion, the reason for this is that our investigations have shown that with the use of these filmforming substances as the gastro-resistant coating coated pellets of particularly good quality may be produced .
  • the obj ect of the present invention also relates to a pharmaceutical preparation and/or food supplement the final pharmaceutical form of which is a tablet , capsule or storage unit , and which contains sodium bicarbonate as the only active ingredient , and which pharmaceutical preparation and/or food supplement contains the coated pellet according to the present invention disclosed in detail above .
  • the pharmaceutical form is the coated pellets themselves , then this is stored in a sachet or bottle ( collectively referred to as : storage unit ) .
  • the methods for tabletting or encapsulation of the coated pellets are known in themselves and belong to the obligatory knowledge of the person skilled in the art .
  • the pharmaceutical preparation according to the present invention in the form of tablet , capsule or storage unit containing the coated pellets may be preferably used for the treatment of the illnesses selected from the following : mild metabolic acidosis , chronic kidney disease , or heartburn/ref lux .
  • the food supplement tablet , capsule or coated pellets according to the present invention may be preferably used for the treatment of digestion problems , heartburn, acidic digestion disorders and stomach complaints .
  • the pharmaceutical preparation or food supplement constitutes the coated pellets according to the present invention filled into hard capsules , or tablets made from such coated pellets , where the sodium bicarbonate content of the capsules or tablets , in the interest of swallowability of the preparation, is approximately 300 mg to 1000 mg, preferably between 300 and 600 mg .
  • the dose of such an oral pharmaceutical preparation according to the present invention depends on the illness to be treated or the health condition demanding support .
  • the active ingredient sodium bicarbonate the average daily dose is 3 to 5 g [Nephrotrans 500 mg gastro-resistant capsule , Stanningley Pharma Limited, Electronic summary of product characteristics , 4 . 2 Posology and method of administration ( internet ) .
  • the amount of active ingredient in oral dose forms containing sodium bicarbonate that may be swallowed at the same time is approximately 300 mg to 1000 mg, and within this a dose of between 300 mg and 600 mg is preferable .
  • the coated pellets according to the present invention may be used for the manufacture of tablets or capsules .
  • the reason for this is that the coated pellets are suitable for use in the generally used tabletting and encapsulating operations used in the pharmaceutical industry .
  • the pharmaceutical preparation produced with the use of the coated pellet according to the present invention is preferably an oral pharmaceutical preparation, which may primarily be a tablet or a capsule ( e . g . hard capsule ) . It should be noted that the pellets themselves may be used as an oral pharmaceutical preparation without tabletting or encapsulating them .
  • the pharmaceutical preparation according to the present invention may be used for the treatment of the illnesses selected form the following : mild metabolic acidosis , chronic kidney disease , or heartburn/ref lux .
  • coated pellets may also be used for the manufacture of a food supplement for the treatment of digestion problems , heartburn, acidic digestion disorders and stomach complaints , where the food supplement preparation is preferably a tablet or capsule ( e . g . hard capsule ) .
  • Example 1 The formation of water-insoluble intermediate insulating coating in a Wurster system apparatus
  • Example 2 The formation of water-insoluble intermediate insulating coating in a Ventilus system apparatus
  • Example 3 The formation of water-soluble intermediate insulating coating in a Ventilus system apparatus
  • 500 g of sodium bicarbonate pellets with 80% active ingredient content is filled into the material container of a Romaco Ventilus 2.5 fluidization coater apparatus.
  • a suspension made from a mixture of 75 g hydroxypropyl methylcellulose-based Nutrafinish® 176U280028 coating material and 300 g water are sprayed at a feed rate of 2 g/minute onto the pellets maintained in constant fluidization.
  • the hydroxypropyl methylcellulose containing coating of the coated pellets is approx. 15% with respect to the mass of the pellets.
  • Example 4 The formation of the gastro-resistant coating with a shellac-based coating
  • the gastro-resistant coating containing Bonulac® of the coated pellets is approx. 27% with respect to the mass of the pellets .
  • Example 5 The formation of the gastro-resistant coating with the use of anionic methacrylate copolymer in the case of a water-insoluble intermediate insulating layer
  • Ventilus 2.5 fluidization coater apparatus Using an input air temperature of 26 °C a coating liquid made from a mixture of 178.6 g Eudraguard® biotic 30% dispersion containing anionic methacrylate copolymer, 1.1 g polysorbate 80, 2.7 g triethyl citrate, 2.7 g glycerine monostearate and 112 g water is sprayed at a feed rate of 5 g/minute onto the pellets maintained in constant fluidi zation .
  • the anionic methacrylate copolymer-based gastro-resistant coating of the coated pellets is approx . 15% with respect to the mass of the pellets .
  • Example 6 The formation of the gastro-resistant coating with the use of anionic methacrylate copolymer in the case of a water-soluble intermediate insulating layer
  • the active ingredient release of the pellets was evaluated in buffers with various pH values on the basis of the change in pH caused by the active ingredient dissolution. During this the effect of the uncoated pellets, the pellets coated with the water-insoluble intermediate insulating coating, and the pellets provided with various intermediate insulation coatings and various gastro-resistant coatings causing a change in pH was measured.
  • the dissolution tests were performed using the standard method according to the European Pharmacopoeia, in 500 ml dissolving medium, in a rotating basket device, at a temperature of 37 °C, at a mixing rate of 100 rpm.
  • the following solutions were used as dissolving medium: 0.01 N hydrochloric acid solution (pH 2.0) , 0.02 N hydrochloric acid solution (pH 1.8) , 0.01 N sodium dihydrogen phosphate solution (pH 4.5) .
  • Figure 1 shows the pH-increasing effect occurring on the dissolution of uncoated pellets and of pellets with various coatings (Surelease®, Surelease® + Bonulac®, Surelease® + Eudraguard biotic®) in 0.01 N HC1 solution.
  • Uncoated The uncoated pellets ("Uncoated") and the pellets provided with only 15% Surelease® intermediate insulating coating (“Ethylcellulose”) raised the pH of the 0.01 N HC1 solution to the pH value of 6.0 within 10 minutes, while in the case of pellets containing an intermediate insulating coating (15% Surelease®) and on this a gastro-resistant coating as well (15% Surelease® + 27% Bonulac®, and 15% Surelease + 15% Eudraguard biotic®) this increase in pH took place only after 30 minutes and 45 minutes, respectively.
  • Surelease® intermediate insulating coating
  • Figure 2 shows the pH-increasing effect caused in various pH dissolution mediums of pellets containing a water-insoluble intermediate insulating coating (15% Surelease®) and gastro- resistant coatings (+ 27% Bonulac®, and +15% Eudraguard® biotic) .
  • a water-insoluble intermediate insulating coating (15% Surelease®)
  • gastro- resistant coatings (+ 27% Bonulac®, and +15% Eudraguard® biotic
  • Figure 3 shows the pH-increasing effect caused in various pH dissolution mediums of pellets containing a water-soluble intermediate insulating coating (15% Nutraf inish®) and gastro- resistant coatings (+10%, and +15% Eudraguard® biotic®) .
  • a water-soluble intermediate insulating coating (15% Nutraf inish®) and gastro- resistant coatings (+10%, and +15% Eudraguard® biotic®) .
  • the pH-increasing effect occurs after a delay of 30 minutes and 60 minutes, respectively, while in the pH 4.5 phosphate buffer the increase in pH starts after 15 minutes and finishes in 1 to 2 hours .

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Abstract

L'objet de l'invention concerne une pastille enrobée qui est appropriée pour la fabrication d'une préparation pharmaceutique et/ou d'un complément alimentaire contenant du bicarbonate de sodium, et qui contient au moins deux couches d'enrobage. La pastille enrobée contient du bicarbonate de sodium en tant que seul principe actif, la première couche d'enrobage équivalant à l'enrobage isolant intermédiaire entourant la pastille, l'autre couche d'enrobage équivalant à l'enrobage gastro-résistant entourant l'enrobage isolant intermédiaire, ledit enrobage gastro-résistant contenant de la gomme laque ou un copolymère de méthacrylate anionique se dissolvant dans un milieu aqueux sur un pH de 7,0. En outre, l'invention concerne la fabrication de la pastille enrobée, des préparations pharmaceutiques et des compléments alimentaires contenant une telle pastille enrobée, ainsi que l'utilisation associée.
PCT/HU2024/050036 2023-05-31 2024-05-17 Pastille enrobée gastro-résistante contenant du bicarbonate de sodium, production associée, préparation pharmaceutique et complément alimentaire contenant celle-ci, et leur utilisation Pending WO2024246566A1 (fr)

Applications Claiming Priority (2)

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HU2300183A HUP2300183A1 (hu) 2023-05-31 2023-05-31 Nátrium-hidrogénkarbonát tartalmú gyomornedv-ellenálló bevont pellet, ennek elõállítása, ezt tartalmazó gyógyszerkészítmény és étrendkiegészítõ készítmény, és ezek alkalmazása
HUP2300183 2023-05-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025128724A1 (fr) * 2023-12-12 2025-06-19 Arbert, Llc Sels inorganiques revêtus et leurs utilisations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013994A2 (fr) * 2010-07-30 2012-02-02 Hajnal Peter COMPOSITION PHARMACEUTIQUE À LIBÉRATION PROLONGÉE DÉPENDANTE DU pH

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013994A2 (fr) * 2010-07-30 2012-02-02 Hajnal Peter COMPOSITION PHARMACEUTIQUE À LIBÉRATION PROLONGÉE DÉPENDANTE DU pH

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BREITKREUZ J. ET AL.: "Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule?", JOURNAL OF PHARMACY AND PHARMACOLOGY : JPP, JOHN WILEY & SONS LTD, LONDON, GB, vol. 59, no. 1, 1 January 2007 (2007-01-01), pages 59 - 65, XP008135631, ISSN: 0022-3573, [retrieved on 20010218], DOI: 10.1211/JPP.59.1.0008 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025128724A1 (fr) * 2023-12-12 2025-06-19 Arbert, Llc Sels inorganiques revêtus et leurs utilisations

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