Gastro-resistant coated pellet containing sodium bicarbonate, production thereof, pharmaceutical preparation and food supplement containing thereof, and their use

Abstract

The object of the invention relates to a coated pellet that is suitable for the manufacture of a pharmaceutical preparation and / or food supplement containing sodium bicarbonate, and that contains at least two coating layers. The 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. Furthermore, the invention relates to the manufacture of the coated pellet, to pharmaceutical preparations and food supplements containing such coated pellet and to the use thereof.

Description

[0001] Gastro-resistant coated pellet containing sodium bicarbonate , production thereof , pharmaceutical preparation and food supplement containing thereof , and their use

[0002] The field of the invention

[0003] 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 .

[0004] The state of the art

[0005] 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 . In addition, as the main remedy for heartburn, it is also used for neutralising the unpleasant symptoms caused by overeating, bloating, nausea, hiccoughing and acidic foods .

[0006] 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) . In other words , 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 .

[0007] Multiple solutions are known of according to the state of the art that deal with gastro-resistant coated pellets , or monolithic tablets and capsules containing sodium bicarbonate as the active ingredient .

[0008] 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 . ) . These monolithic preparations , as a result of their si ze , remain in the stomach for a long period of time , and as a result of this , but particularly in the case of the bicaNorm tablet it may happen that the sodium bicarbonate is released already in the stomach and the carbon dioxide gas formed causes unpleasant side-ef fects .

[0009] In their study referenced above , 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.

[0010] Contrary to the Breitkreutz study, 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) . According to the patent specification, 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%.

[0011] In all cases coating materials that do not dissolve in the gastric juice (gastro-resistant) 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 :

[0012] • dissolving under a pH value of 6.0 in an aqueous medium ( group 1 ) ,

[0013] • dissolving partially under a pH value of 6.0 (group 2) ,

[0014] • dissolving in an aqueous medium above a pH value of 7.0

[0015] (group 3) .

[0016] 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 .

[0017] In the case of active ingredients sensitive to acids , such as sodium bicarbonate or proton-pump inhibitor active ingredients , 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 .

[0018] On the basis of the data from the literature relating to the manufacture of gastro-resistant pellets , 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 . The use of additives that do not dissolve in water ( talc : EP3292862A1 , polydimethylsiloxane : WO9852564A1 ) , and of melts of fat-like materials (HU226580B1 ) is also described . The use of two layers (US5626875A) , and of the aforementioned intermediate insulating coating consisting of three layers in the case of sodium bicarbonate has also been described . On the basis of the data from the literature the intermediate insulating coating must be water-soluble or must disintegrate quickly in water (EP0247983B1 , W02004014345A1 ) .

[0019] In the case of gastro-resistant coated pellets 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 ) .

[0020] In the case of the manufacture of pellets with a gastro- resistant coating containing sodium bicarbonate as active ingredient , an intermediate insulating layer must also be used between the pellet containing the active ingredient and the acidic gastro-resistant coating to prevent the decomposition of the active ingredient during manufacture and storage . The methods known according to the state of the art for the manufacture of such preparations show that , in the case of sodium bicarbonate as active ingredient , the manufacture of pellets with a gastro-resistant coating is possible with the use of a very large amount ( approx . 60% - J . Breitkreutz et al . , see above ) of coating and / or a complex structure coating system ( at least four coatings , see the details disclosed in Hungarian patent no HU230560 ) .

[0021] On the basis of the above , in the case of currently marketed gastro-resistant oral pharmaceutical preparations ( tablets , soft capsules ) with a monolithic structure containing sodium bicarbonate , a general problem is the formation of gas due to the active ingredient being released in the stomach, as the occurrence of a side ef fect , while an appropriate method suitable for the industrial manufacture of pharmaceutical preparations containing (multiparticulate ) pellets with a coating making it possible to prevent this has not been elaborated to date . In other words , according to the state of the art no gastro- resistant coated pellet-based pharmaceutical preparation or food supplement containing sodium bicarbonate as the only active ingredient is known that ensures the appropriate dissolution of the sodium bicarbonate active ingredient with the use of less coating and / or a simpler coating system for economical manufacture .

[0022] However, in spite of the fact that the dissolution profile of the known gastro-resistant coated pellets containing sodium bicarbonate as active ingredient is appropriate and the pharmaceutical forms prepared from them may be suitable for treating patients , their manufacturing methods cannot be viewed as appropriate for the reasons listed above , and they are not in commercial distribution either at present .

[0023] In order to achieve the optimum si ze of pharmaceutical preparations (be they the pharmaceutical forms of tablets or capsules ) produced from pellets containing pellet cores of sodium bicarbonate , it is necessary to reduce the amount of the layers coating the pellets . Therefore , in the interest of patient compliance the manufacture of tablets and capsules with appropriate dissolution and absorption must be carried out with the use of as few coating layers as possible .

[0024] Therefore , it is necessary to elaborate a gastro-resistant coated pellet containing sodium bicarbonate as active ingredient that may be use in a tablet , capsule or on its own, and which coated pellet contains a maximum of two coating layers (not including the shell of the capsule in the case of capsule forms ) and which may be manufactured in a simpler, faster and more economical way than in the case of the current methods . Brief description of the figures

[0025] 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 .

[0026] 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 .

[0027] 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 .

[0028] Brief description of the invention

[0029] During the search for a composition of pellets with a gastro- resistant coating containing sodium bicarbonate as the only active ingredient , and that is suitable for economical industrial manufacture , it was found in a way surprising to a person skilled in the art that not only can coating materials dissolving or partially dissolving at a pH value of between 4 . 5 and 6 . 0 be used as gastro-resistant coating as used in the case of other active ingredients , but also coating materials that dissolve in a medium with a pH of over 7 . 0 , which, otherwise , are used for active ingredient release in the large intestine . On the one part , a signi ficantly lower amount of these latter coating materials is 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 .

[0030] In the case of the pellets containing sodium bicarbonate as the only active ingredient according to the present invention, we also found that in the case of gastro-resistant coating materials that dissolve in a medium with a pH of over 7 . 0 both water-soluble intermediate insulating coatings and intermediate insulating coatings that do not dissolve in water may be used .

[0031] In other words , in accordance with the above , 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 .

[0032] According to a preferable embodiment of the present invention the coated pellet has a total of two coating layers , the intermediate insulating coating and the gastro-resistant coating surrounding the intermediate insulating coating .

[0033] According to a preferable embodiment of the coated pellet according to the present invention, the diameter of the coated pellet is between 0 . 5 and 2 mm, preferably between 1 . 0 and 2 . 0 mm .

[0034] According to a preferable embodiment of the present invention, the sodium bicarbonate content of the pellet is 70 to 95 mass! of the mass of the pellet .

[0035] According to a preferable embodiment of the present invention, the sodium bicarbonate content of the coated pellet is at least 50 mass! of the mass of the coated pellet .

[0036] According to a preferable embodiment of the invention, the intermediate insulating coating of the coated pellet is between 10 and 20 mass! of the mass of the pellet .

[0037] According to a preferable embodiment of the invention, the gastro-resistant coating of the coated pellet is between 10 to 30 mass! of the mass of the pellet .

[0038] According to a preferable embodiment of the invention, 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 . According to a particularly preferable embodiment of the invention, 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 .

[0039] 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 .

[0040] According to a preferable implementation of the method according to the present invention 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 .

[0041] 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 .

[0042] 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 .

[0043] Additionally, 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 .

[0044] Furthermore , 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 .

[0045] Furthermore , 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 . Detailed description of the invention

[0046] If not mentioned to the contrary, % (percent) in the present specification is understood to mean mass percent (mass%) , and ratios are understood to mean mass ratios of the given components .

[0047] In the scope of the present specification if a numerical value is given, this is understood to mean that the last digit of the given number shows the precision of the given value according to the rounding-up rules. Therefore, for example, 8% is understood to mean all values falling within the range of 7.5% to 8.4%, and pH 7.0 is understood to mean every pH value in the range of pH 6.95 to pH 7.04.

[0048] In the scope of the present specification, if a range between two values is defined, then the concrete numerical values indicated as the limit values of the range are viewed as constituting parts of the range.

[0049] Within the context of the present invention, 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. The 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. These procedures belong to the compulsory knowledge of the person skilled in the art, descriptions of these processes may be found in specialist books and specialist articles (including: Revesz P. : Gyogyszertechnologia (Pharmaceutical Technology) , JATE Press, 2009; K. Lavanya et al. : Pelletization Technology: A Quick Review, IJPSR, 2011; Vol. 2 (6) : 1337-1355, 2011) . Within the context of the present specification, pellet is understood to mean a pellet not containing a coating. In accordance with the present invention, 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. As a consequence of this when the 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.

[0050] 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 .

[0051] In the case of the manufacture of gastro-resistant coated pellets , it is necessary to use an intermediate insulating coating between the pharmaceutical active ingredient that is sensitive to acids , such as pellets containing sodium bicarbonate and the acidic gastro-resistant coating in order to prevent decomposition of the pharmaceutical active ingredient that is sensitive to acid caused by the acidic coating layer during manufacture and storage .

[0052] The currently known methods for the manufacture of pellets with a gastro-resistant coating containing sodium bicarbonate as the only active ingredient show that the manufacture of the coated pellets is possible with the use of a very large amount of coating ( approx . 60% - J . Breitkreutz et al . ) and / or with a complicated coating system ( at least four coatings - Hungarian patent no HU230560 ) .

[0053] 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 .

[0054] 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 .

[0055] In addition, 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 .

[0056] In other words , 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 .

[0057] In other words , 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 . Although according to the primary obj ective of the present invention 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 .

[0058] For the elaboration of the present invention, initial pellets containing 80 mass! sodium bicarbonate were used, which were acquired commercially (Umang Pharmatech pvt . ltd) . It is obvious for a person skilled in the art that the higher the active ingredient content of a pellet the more ef fective it is and the smaller the preparation that may be made from it . Therefore , the scope of protection of the present invention is not limited to the 80% sodium bicarbonate content mentioned in the examples , instead coated pellets containing a lower or preferably a higher sodium bicarbonate content than this fall within the scope of protection of the present invention .

[0059] 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 . As a result of the intermediate insulating coating, the alkaline-character sodium bicarbonate in the pellet and the acidic character gastro-resistant coating are unable to chemically react with each other . With this , 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 .

[0060] 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 .

[0061] However, surprisingly there is no need for the gastro- resistant coating to dissolve for the dissolution of the sodium bicarbonate . Already in an aqueous medium with a pH of 4 . 5 the sodium bicarbonate dissolves out of the coated pellet as a result of di f fusion in spite of the fact that the dissolution of the gastro-resistant coatings used only takes place above a pH of 7 . 0 .

[0062] In addition to the two coating layers described above , the coated pellet according to the present invention may also optionally contain other layers , coatings .

[0063] In other words , the present invention provides a gastro- resistant coated pellet containing sodium bicarbonate as the only active ingredient . According to a preferable embodiment of the present invention, the coated pellet exclusively contains the two coating layers described above . According to this preferable embodiment 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 .

[0064] 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 . The reason for this is that according to our experience 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 obvious for a person skilled in the art that 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 .

[0065] According to another preferable embodiment of the present invention, 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 ) . In order to facilitate manufacture , 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 .

[0066] According to a preferable embodiment of the present invention, 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 .

[0067] According to another preferable embodiment of the present invention 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 .

[0068] According to a further preferable embodiment of the present invention, 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 ) .

[0069] 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 .

[0070] 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 .

[0071] The neutral methacrylate copolymer is actually an ethyl acrylate - methyl methacrylate copolymer . For film coating the neutral methacrylate copolymer is preferably used in aqueous dispersion . Such an 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 .

[0072] Our experience shows that among the water-soluble polymers the following are suitable for the formation of the intermediate insulating coating of the coated pellet according to the present invention: hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone .

[0073] As mentioned above, 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.

[0074] 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 Biogrund company.

[0075] Among the anionic methacrylate copolymers dissolving in an aqueous medium above pH 7.0, 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) . At the same time, 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) .

[0076] In addition, 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.

[0077] In other words, in step a) the pellet containing sodium bicarbonate as the only active ingredient is produced. As described above, the pellet may also contain excipients. To produce the pellets the components are mixed together, moistened with water and then pelleting is performed in the conventional way. Following this, in 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 . Following this , 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 .

[0078] According to a preferable form of implementation of the method for the manufacture of the coated pellet according to the present invention, 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 . According to another preferable form of implementation of the method according to the invention, 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 . According to another preferable form of implementation of the method according to the present invention 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 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 . It should be noted that these preferable forms of implementation of the method may be used separately and the j oint use of one or several is also possible . The reason for this is that our investigations have shown that in the case of anionic methacrylate copolymer dissolving in an aqueous medium over a pH of 7 . 0 , the use of a more economical water-soluble intermediate insulating coating also results in suitable dissolution ( Figure 3 ) .

[0079] 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 . I f 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 .

[0080] According to a particularly preferable embodiment of the present invention, 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 .

[0081] 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 . In the case of 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 ) . Electronic pharmacopoeia (UK) 14 October 2020 , <https : / / www . medicines . org . uk / emc / product / 12715 / smpc#gref >] . 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 .

[0082] According to the above 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 . Additionally, the 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 ) .

[0083] Examples

[0084] In the following the present invention is presented through examples . The examples serve better understanding of the invention; therefore , they should not be interpreted as representing any limitation to the claim for protection .

[0085] Example 1 : The formation of water-insoluble intermediate insulating coating in a Wurster system apparatus

[0086] 200 g of sodium bicarbonate pellets with 80% active ingredient content is filled into the material container of a Procept 4M8 fluidi zation coater apparatus with a Wurster adapter . Using an input air temperature of 65 ° C, a mixture of 120 g Surelease® Clear E-7- 19040 ( ethylcellulose ) and 80 g water are sprayed at a feed rate of 1.7 g / minute onto the pellets maintained in constant fluidization. The ethylcellulose coating of the coated pellets is approx. 15% with respect to the mass of the pellets .

[0087] Example 2: The formation of water-insoluble intermediate insulating coating in a Ventilus system apparatus

[0088] 800 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. Using an input air temperature of 50 °C, a mixture of 448.8 g Surelease® Clear E- 7-19040 (ethylcellulose) and 299.2 g water are sprayed at a feed rate of 1.8 g / minute onto the pellets maintained in constant fluidization. During the coating process a sample was taken when approximately 10% coating was achieved. At the end of the coating process the ethylcellulose coating of the coated pellets is approx. 15% with respect to the mass of the pellets .

[0089] Example 3: The formation of water-soluble intermediate insulating coating in a Ventilus system apparatus

[0090] 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. Using an input air temperature of 50 °C, 412.5 g of 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. At the end of the coating process the hydroxypropyl methylcellulose containing coating of the coated pellets is approx. 15% with respect to the mass of the pellets.

[0091] Example 4: The formation of the gastro-resistant coating with a shellac-based coating

[0092] 200 g of sodium bicarbonate pellets with 80% active ingredient content coated with 15% ethylcellulose (Surelease® Clear E-7- 19040) is filled into the material container of a Procept 4M8 fluidization coater apparatus with a Wurster adapter. Using an input air temperature of 45 °C a coating liquid made from a mixture of 80 g shellac (Bonulac® F White 912, 08E) , 5 g glycerol and 395 g water is sprayed at a feed rate of 1.5 g / minute onto the pellets provided with an intermediate insulating coating maintained in constant fluidization.

[0093] The gastro-resistant coating containing Bonulac® of the coated pellets is approx. 27% with respect to the mass of the pellets .

[0094] 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

[0095] 400 g of sodium bicarbonate pellets with 80% active ingredient content coated with 15% ethylcellulose (Surelease® Clear E-7- 19040) is filled into the material container of a Romaco

[0096] 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 .

[0097] After the coating process is completed the flow of air is reduced to the minimum and the coated pellets are treated with 30 ° C air for 30 minutes . After heat treatment 0 . 5% colloidal silicon dioxide is mixed with the product in order to prevent clumping of the particles .

[0098] The anionic methacrylate copolymer-based gastro-resistant coating of the coated pellets is approx . 15% with respect to the mass of the pellets .

[0099] 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

[0100] 575 g of sodium bicarbonate pellets with 80% active ingredient content coated with 15% hydroxypropyl methylcellulose-based coating material (Nutraf inish® 176U280028 ) is filled into the material container of a Romaco Ventilus 2 . 5 fluidi zation coater apparatus . Using an input air temperature of 26 ° C a coating liquid made from a mixture of 223 . 2 g Eudraguard® biotic 30% dispersion containing anionic methacrylate copolymer, 1 . 3 g polysorbate 80 , 3 . 3 g triethyl citrate , 3 . 3 g glycerine monostearate and 141 g water is sprayed at a feed rate of 5 g / minute onto the pellets maintained in constant fluidi zation . During the coating process a sample was taken when approximately 10% coating was achieved . After the coating process is completed the flow of air is reduced to the minimum and the coated pellets are treated with 30 ° C air for 30 minutes . After heat treatment 0 . 5% colloidal silicon dioxide is mixed with the product in order to prevent clumping of the particles . The anionic methacrylate copolymer-based gastro-resistant coating of the coated pellets is approx. 15% with respect to the mass of the pellets

[0101] The testing of the pellets

[0102] 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.

[0103] 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) .

[0104] For the tests samples of pellets containing 1 g of sodium bicarbonate or pellets provided with various coatings were used, then the pH of the solution was measured with a precision of 0.01 pH using an appropriately calibrated pH meter at specified intervals. The measurement results are presented in the appended figures.

[0105] 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. 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.

[0106] 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) . In the 0.02 N hydrochloric acid solution the pH- increasing effect of the pellets does not show in 1 hour, in the 0.01 N hydrochloric acid solution the pH-increasing effect occurs after the aforementioned 30-minute and 45-minute delay, respectively, while in the pH 4.5 phosphate buffer the increase in pH starts within 15 minutes and finishes in approx. 1 hour.

[0107] 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®) . In the 0.01 N hydrochloric acid solution 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 .

Claims

Claims1 . 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 , characterised by that the 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 .2 . Coated pellet according to claim 1 , characterised by that it has a total of two coating layers , the intermediate insulating coating and the gastro-resistant coating surrounding the intermediate insulating coating .3 . Coated pellet according to claim 1 or 2 , characterised by that the diameter of the coated pellet is between 0 . 5 and 2 mm, preferably between 1 . 0 and 2 . 0 mm .4 . Coated pellet according to any of claims 1 to 3 , characterised by that the sodium bicarbonate content of the pellet is 70 to 95 mass! of the mass of the pellet .5 . Coated pellet according to any of claims 1 to 3 , characterised by that the sodium bicarbonate content of the coated pellet is at least 50 mass! of the mass of the coated pellet .6 . Coated pellet according to any of claims 1 to 5 , characterised by that the intermediate insulating coating of the coated pellet is between 10 and 20 mass! of the mass of the pellet .7 . Coated pellet according to any of claims 1 to 6 , characterised by that the gastro-resistant coating surrounding the intermediate insulating coating of the coated pellet is between 10 and 30 mass! of the mass of the pellet .8 . Coated pellet according to any of claims 1 to 7 , characterised by that 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 .9 . Coated pellet according to any of claims 1 to 8 , characterised by that the gastro-resistant polymer of the gastro-resistant coating of the coated pellet is the anionic methacrylate copolymer dissolving in an aqueous medium at a pH of over 7 . 0 is .10 . Method for the manufacture of the coated pellet according to any of claims 1 to 9 , 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 ) coating the pellet obtained in step b ) provided with an intermediate insulating coating with 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 at a pH of over7 . 0 is used in the form of an aqueous dispersion as the gastro-resistant coating .11 . Method according the claim 10 , characterised by that 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 .12 . Pharmaceutical preparation and / or food supplement , which is provided in the form of a tablet , a capsule or a storage unit , which contains sodium bicarbonate as the only active ingredient , characterised by that it contains the coated pellet according to any of claims 1 to 9 .13 . Pharmaceutical preparation and / or food supplement according to claim 12 in the form of a tablet or capsule , characterised by that it contains between 300 mg and 1000 mg sodium bicarbonate , preferably between 300 mg and 600 mg sodium bicarbonate .14 . The use of the coated pellet according to any of claims 1 to 9 for the manufacture of tablets or capsules .15 . Coated pellet according to any of claims 1 to 9 or pharmaceutical preparation according to any of claims 12 to 13 for the use 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 .16 . Coated pellet according to any of claims 1 to 9 or food supplement according to any of claims 12 to 13 for the use in the treatment of digestion problems , heartburn, acidic digestion disorders and stomach complaints , where the food supplement is preferably a tablet or a capsule .

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