WO1995023594A1 - Produit ou comprime granulaire contenant un systeme effervescent et un principe actif pharmaceutique, et son procede de preparation - Google Patents

Produit ou comprime granulaire contenant un systeme effervescent et un principe actif pharmaceutique, et son procede de preparation Download PDF

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Publication number
WO1995023594A1
WO1995023594A1 PCT/EP1995/000650 EP9500650W WO9523594A1 WO 1995023594 A1 WO1995023594 A1 WO 1995023594A1 EP 9500650 W EP9500650 W EP 9500650W WO 9523594 A1 WO9523594 A1 WO 9523594A1
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WIPO (PCT)
Prior art keywords
weight
acid
effervescent
parts
organic acid
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PCT/EP1995/000650
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English (en)
Inventor
Gerhard Gergely
Thomas Gergely
Irmgard Gergely
Stefan Gergely
Original Assignee
Gerhard Gergely
Thomas Gergely
Irmgard Gergely
Stefan Gergely
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Priority claimed from EP94203112A external-priority patent/EP0670160B1/fr
Application filed by Gerhard Gergely, Thomas Gergely, Irmgard Gergely, Stefan Gergely filed Critical Gerhard Gergely
Priority to HU9602380A priority Critical patent/HU228147B1/hu
Priority to BR9506964A priority patent/BR9506964A/pt
Priority to AU18114/95A priority patent/AU681256B2/en
Priority to JP7522671A priority patent/JPH09509669A/ja
Priority to CA002183952A priority patent/CA2183952C/fr
Publication of WO1995023594A1 publication Critical patent/WO1995023594A1/fr
Priority to PL95316113A priority patent/PL181714B1/pl
Priority to NO19963588A priority patent/NO315308B1/no
Priority to FI963385A priority patent/FI118033B/fi

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Classifications

    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • Granular product or tablet containing an effervescent system and an active pharmaceutical substance as well as a method for its preparation Field of the Tnv ⁇ ⁇ t:i on
  • This invention relates to a granular pharmaceutical preparation or more particulary a tablet containing an effervescent system and a - preferably acid-sensitive - pharmaceutical substance, such as cisapride, beta-carotene, an H2 blocker such as cimetidine or ranitidine, and/or a substance which is to be administered in an effervescent pharmaceutical preparation with comparatively small amounts of effervescent components or a comparatively low acid- binding capacity.
  • a granular pharmaceutical preparation or more particulary a tablet containing an effervescent system and a - preferably acid-sensitive - pharmaceutical substance, such as cisapride, beta-carotene, an H2 blocker such as cimetidine or ranitidine such as cimetidine or ranitidine
  • an object of this invention is to provide an effervescent system which will avoid the aforesaid disadvantages and offer the possibility of administering to a patient pharmaceutical substances, inclusive of acid- sensitive substances which have hydrophobic properties or properties influencing the surface tension of water, in pleasant-to-drink effervescent solutions. It is a further object of this invention to create an effervescent tablet or an instant effervescent granular product with an acid binding capacity of less than 5 meq, in order to avoid undesired antacid effects. This is especially advantageous for all H2 blockers. Lastly, it is desired that the tablet or granular product is to dissolve rapidly in water at a temperature of about 15-20°C in less than about 2 minutes.
  • Neutral substances within the meaning of this invention include polymers soluble in water and/or alcohol, such as e.g. polyvinylpyrrolidone, carbohydrates, such as saccharose, pentaerythritol, glucose, and fructose (although the latter two, under the influence of the only slightly alkaline effervescent-grain surface due to the bicarbonate coating, are subject to a Maillard reaction tending to make them yellow and therefore they are not particulary preferred herein) , hydrocolloids, such as maltodextrin, dextrin and the like; especially preferred are higher alcohols, such as xylitol, mannitol and sorbitol.
  • alcohol such as e.g. polyvinylpyrrolidone
  • carbohydrates such as saccharose, pentaerythritol, glucose, and fructose (although the latter two, under the influence of the only slightly alkaline effervescent-grain surface due to the bicarbonate coating, are subject to
  • 093/00886 discloses that a foreign acid, possibly gluconic acid delta-lactone, which hydrolyzes to gluconic acid, can be incorporated at the surface of acid vehicle crystals, with the result that the crystal lattice is disturbed and a melting point depression is achieved.
  • a foreign acid possibly gluconic acid delta-lactone, which hydrolyzes to gluconic acid
  • gluconic acid delta-lactone which hydrolyzes to gluconic acid
  • An effervescent tablet is generally defined as being particularly rapid when the dissolution (or complete suspending) of the tablet components takes less than 120 sec, preferably 90 sec or less.
  • alkali and/or earth alkaline carbonate and/or bicarbonate particles are anchored on the grain surface in order to prohibit an interaction between the acid and the active substance.
  • EP-A1-415 326 for coating acid vehicle crystals with several times the amount of sugar in order, in combination with bicarbonate, to achieve a slightly prickling effect, for a chewable tablet or lozenge has not been able to solve the combination of the problems or tasks: such a system would not be sufficiently reactive to dissolve an effervescent tablet in water within a reasonable time. It was the aim of the said EP-A1 to slow down the reaction between acid and carbonate in order not to produce an undesired high effervescent effect in the mouth.
  • a tablet having a core of acid, bicarbonate and calcium were coated with a neutral substance, for example with sorbitol in an aqueous, alcoholic or in a water/alcohol-solution, such a tablet would not provide reliable protection for acid- sensitive active substances contained in the core.
  • a neutral substance e.g.
  • the structure of the effervescent system according to this invention not only prevents direct contact of an acid-sensitive drug with the acid crystals thereby providing an effervescent tablet or granular product with substantially more shelf-stability, but it also permits the preparation of substantially smaller tablets, i.e., those with smaller amounts of effervescent components which, when dissolved, result in a buffer system.
  • the present tablets according to the invention in contrast to buffer systems of antacid effervescent preparations, can remain at far less than 5 meq of acid binding capacity. Also, in terms of product preparation, a retarded reaction and better compressibility into tablets is obtained.
  • an effervescent tablet can be prepared which for the first time contains an acid-sensitive drug, such as cisapride, or an H2 blocker such as cimetidine, and which has an acid-binding capacity of less than 5 meq for a tablet (or granular product) weight of only 1.6 to 2.3 g.
  • an acid-sensitive drug such as cisapride
  • an H2 blocker such as cimetidine
  • At least a portion of the carbonate and/or bicarbonate particles intended for a full dose can be applied to this coating, so that effervescent grains are formed from acid crystals on which a first coating of neutral substance has formed, and thereon a second coating of carbonate and/or bicarbonate, which has partially reacted with the acid in some cases.
  • the invention can be particularly expediently used for products or processes as described, for example, in EP-B1- 76 340, US-A-4 867 942 and WO93/00886, and whose description and claims are herein regarded as having been disclosed.
  • the application of the neutral substance causes a depression of the melting point on the surface of the citric acid crystals.
  • the adhesive force for the next coating containing alkali or alkaline earth carbonates and/or bicarbonates increases, and at the same time this signifies a slower and therefore more uniform reaction of the citric acid crystal surface and better passivation, so that the acid-sensitive drugs are less attacked by the effervescent grains.
  • the melting point depression protracts the recrystallization time of the citric acid or of the citrates that have formed, which signifies better compressibility of the effervescent granules over a longer period of time.
  • the amount of neutral substance applied to the acid vehicle crystals depends on the amount of solvent with which the acid can be wet, since a maximum of 50 - 70 % by weight can be dissolved in an aqueous solution. It is therefore preferably added in an amount of 0.05 bis 1.0, in particular 0.07 bis 0.8, % by weight, based on the acid. Additions of less than 0.07 have only a weak effect and those of less than 0.05 have no effect which is relevant according to the invention: the shelf-stability of acid-sensitive active substances is reduced. Additions of over 0.8 generally begin to have an interfering effect, and at above 1.0 the reactivity of citric acid and of the effervecent system is consierably slowed down.
  • the amounts of neutral substance which can be applied to, for example, citric acid are determined by the amount of solution with which the citric acid can be wet, since the neutral substances are in fact applied in solution, and a 50 to max. 70% solution can be prepared.
  • the citric acid crystals cannot be wet with an infinitely large amount of water and hence solvent.
  • the neutral coating can also contain small amounts of a solid, edible organic acid, and in some cases an acid different from the one of which the vehicle crystals consist - as disclosed per se in another context - but here also in order to intensify the melting point depression and/or to control the effervescent reaction and rate of dissolution.
  • a solid, edible organic acid and in some cases an acid different from the one of which the vehicle crystals consist - as disclosed per se in another context - but here also in order to intensify the melting point depression and/or to control the effervescent reaction and rate of dissolution.
  • Each such effervescent grain is, taken by itself, actually a small effervescent "tablet", and effervesces by itself. Therefore, if desired, a short dissolving time, small quantity and low acid-binding capacity can be achieved.
  • a very thin monosodium citrate coating in accordance with this invention acts advantageously because 1 mol of monosodium citrate binds 1 mol of water of crystallization and thus contributes to the drying or to maintenance of dryness.
  • uncovered citric acid surfaces can be covered again or more completely with bicarbonate.
  • Alcohol may disrupt the bonding of water of crystallization, because during drying the residual moisture is removed along with the alcohol by evaporation.
  • Small amounts of an antifoaming agent can also be added to the alcohol in order to accelerate the dissolution of the final tablet.
  • the antifoaming agent is preferably added in an amount of 0.005 bis 0.5% by weight, based on the total amount including any fillers, flavors, etc., or 0.05 - 2.0% by weight, based on active substance. Additions of less than 0.005 have no effect relevant according to the invention; additions of more than 0.5 give rise to troublesome or unacceptable side effects.
  • the cisapride as a slightly soluble, hydrophobic active substance, requires a larger amount of antifoaming agent for suppressing the foam, but the required fillers and the effervescent base result in a substantially smaller amount of simethicone being used per tablet, so that the ratios are inverted.
  • the simethicone is required in smaller amounts, in order to suppress the smaller tendency to foaming in the local reaction on dissolution of the effervescent tablet, whereas in the case of cisapride - as already mentioned - the tendency to foam is substantially greater and the principle is therefore also slightly different.
  • simethicone occurs at the surface after dissolution of the effervescent tablet, by virtue of the fact that - especially in the case of insoluble active substances - particles of the active substance collect and remain hanging and thus result in unattractive dissolution behavior, this film then additionally having the tendency to form a ring on the glass wall.
  • a tenside for example, docusate sodium
  • docusate sodium Due to their wettable nature, such drug particles dissolve more quickly and no longer adhere to the foam bubbles. The proportion of such substances must be determined very precisely to achieve the desired dissolving characteristics.
  • the antifoaming agent can be applied to the effervescent system and/or to the drug, this is not preferred according to the invention. In the first case, it might cause undesirable slowing of the dissolution and reaction of the effervescent components unless very slight amounts of antifoaming agent sufficient for the achievement of the desired effect are used.
  • the moisture released in the preparation of the effervescent system by the neutralization reaction, and not entirely removed by heating and/or vacuum treatment, as well as moisture picked up from the air during storage, can best be bound by the addition of a moisture-binding agent, especially anhydrous sodium carbonate (which can absorb 10 mols of water per mol) or sodium sulfate.
  • a moisture-binding agent especially anhydrous sodium carbonate (which can absorb 10 mols of water per mol) or sodium sulfate.
  • the agent can be bound either by applying it to one or more of the coatings applied to the vehicle crystals, or by adding it to the total mixture. This improves shelf life because the reaction of the acid-sensitive active agent with the acid is further suppressed or completely prevented by the reduction of moisture.
  • excessive amounts of such moisture- binding agent, for example sodium carbonate are not desirable as it may retard the effervescent reaction.
  • Sodium carbonate as a drying agent therefore, should not be used for completely covering the effervescent grains, since it is preferable to operate with only small quantities effective to merely dry the residual moisture, or to retard the reaction during manufacture, and to avoid undesirably lengthening the dissolving time of the tablet. Therefore, the final addition of sodium carbonate should not be used for complete coverage (or a tablet coating) , due to both the quantity and the grain size (approx. 0.1 - 0.05 mm), and it is therefore not suitable for producing a continuous coating on the bicarbonate already present. However, it can be partially hooked onto the effervescent grains. It is also possible, however, not to add the sodium carbonate until after the drying operation.
  • the percentage amount of sodium carbonate per tablet depends on several factors, such as, for example, the amount of effervescent base used, the amount and type of the fillers used, the presence of other carbonates, such as, for example, calcium carbonate, etc.
  • the moisture-binding agent in particular sodium carbonate
  • the moisture-binding agent is preferably added in an amount of between 1 and 10, in particular 4 - 6, % by weight (based on the total amount, including any fillers, flavors, etc.).
  • Additions of less than 4 have only a weak effect, and with those of less than 1 , the drying effect and increase in stability is too small, they have no effect relevant according to the invention.
  • Additions of over 6 generally begin to have a troublesome effect because sodium carbonate dissolves more slowly and reacts more poorly; above 10% the dissolution time is already significantly lengthened, since sodium carbonate first absorbs water (up to 10 molecules of water of crystallization) on dissolution of the effervescent tablet, i.e. is calcined and only then reacted with the citric acid.
  • effervescent tablets can be produced, even with the difficult substances referred to, which at a tablet weight of, e.g., 1.6 g,will attain a dissolving time of less than 100 seconds. It is also to be noted that especially cimetidine, due to its hydrophobic character, further lengthens the dissolving time in comparison with other drugs, under otherwise equal conditions.
  • Granulation with sorbitol solution permits rapid dissolution without the incorporation of an extraneous acid that is otherwise necessary, for example, according to WO93/00886.
  • the steps taken according to the invention will enable the control of reactions which take place at the surface of individual crystals or granules, which thus constitutes a local mechanism, while also during dissolution the above-described desired advantages will be achieved throughout.
  • the system is also extraordinarily well suited for the processing of substances which are both acid-sensitive and sparingly soluble in water.
  • substances which are both acid-sensitive and sparingly soluble in water.
  • Such substances such as cisapride for example, exhibit very unpleasant behavior in suspension, since, as mentioned above, they tend to froth together with the effervescent system, adhere to a glass wall, form unpleasant rings and tend to agglomerate on the surface of the drink.
  • a vehicle which can consist of an Aerosil and/or a neutral substance, on which the drug is applied preferably with the surface of its grains partially dissolved, and/or with binding agents and/or tensides if desired, and dried, or is bound to the vehicle surface by means of binders.
  • the amount of the suspended substance is limited to at most 8, preferably at most 4.5, % by weight (based on the total mixture) , for example for cisapride, since larger amounts would result in increased sinking of the granule particles after dissolution of the tablet.
  • the amount of binder used is likewise limited to 1% by weight, since it otherwise leads to undesirable agglomerated granules of active substance, suspended substance and binder, which dissolve only with difficulty and then sink to the bottom, i.e. prevent the desired suspension.
  • the drug can also be dissolved in the methyl ethyl ketone or in acetone and coated onto mannitol, Aerosil (R) and sodium bicarbonate.
  • Example 1 Preparation of effervescent tablets containing 200 mg of cimetidine
  • effervescent system 102 parts by weight of coarse citric acid and 25 parts by weight of finely powdered citric acid (the latter is preferable for improving build-up to effervescent grains on the vehicle crystal as the powder particles provide a rough surface on which up to about 30% of bicarbonate can be anchored) or tartaric acid are aspirated into a preheated vacuum tank and heated to approx. 60°C with stirring.
  • a solution 1 which has been formed from 36 parts by weight each of water and sorbitol, 21 parts by weight of citric acid and 7 parts by weight of sodium bicarbonate, is aspirated and distributed on the citric acid by mixing.
  • the product is removed through a sieve.
  • a mixer 20 parts by weight of cimetidine, with 21.1 parts by weight of sorbitol powder if desired, are mixed for 10 minutes at 6 rpm with 178.4 parts by weight of the effervescent system prepared in a) . Then 7 parts by weight of the antifoaming agent granules prepared in b) and screened through a 0.6 mm sieve, and 4.5 parts by weight of lemon flavoring, are added, mixed for another 5 minutes at 6 rpm. The final mixture is pressed into tablets which weigh 2.3 g, contain 200 mg of cimetidine, and have a hardness of 6-8 kp.
  • Example 2 Preparation of effervescent tablets containing 200 mg of cimetidine, and citric and malic acid in the effervescent grains:
  • Example 3 Effervescent tablets containing 400 mg of cimetidine, and mannitol as a neutral substance
  • citric acid 49 parts by weight of citric acid are aspirated into a preheated vacuum tank and heated with stirring to 60°C. Then, 0.45 parts by weight of a solution 1 , which has been prepared from 0.25 parts by weight of water and 0.20 parts by weight of mannitol, is aspirated in and distributed on the citric acid by mixing, whereupon 14.7 parts by weight of sodium bicarbonate and 3.2 parts by weight of aspartame are then added. Reaction is started with stirring and then drying is performed with a vacuum up to 200 mbar. 0.5 parts by weight of sodium carbonate are next aspirated and distributed in the mixture by stirring, and then drying is performed with a vacuum to 15 mbar.
  • a solution 2 which has been prepared from solution 1 by the addition of 0.16 parts by weight of monosodium citrate, is aspirated into the mixture and distributed by mixing.
  • the effervescent grains obtained therefrom are then dried by vacuum and stirring to 20 mbar, and finally 2.8 parts by weight of sodium carbonate are added.
  • To this mixture is then added 17.3 parts by weight of cimetidine, 4.3 parts by weight of mannitol, 8 parts by weight of sorbitol, 0.9 parts by weight of flavoring, and 4 parts by weight of antifoaming agent granules prepared according to Example 1 b) , until distribution is uniform.
  • Example 4 Effervescent tablets containing 300 mg of cimetidine, as well as maltodextrin as a neutral substance.
  • Example 3 for a 300 mg cimetidine effervescent tablet, a 50% solution of maltodextrin is selected, which is then used in the same amount as in the case of the 400 milligram form.
  • the tablet weight can be 2.3 g.
  • the tablets have a dissolving time of preferably 60 to 150 seconds and a buffering capacity below 5 meq, measured according to USP XXII, by back-titration (with 0.5 N NaOH) of an effervescent tablet dissolved in 70 ml of water and with 30 ml of 1.0 N HCl added.
  • Cimetidine 2 - 30% corresponds to an effervescent tablet containing 50 to 600 mg of cimetidine
  • Insoluble and hydrophobic cisapride is attached to a suspending substance by means of a binder and a small amount of a tenside as follows: A solution of 10 parts by weight of cisapride, 2 parts by weight of polyvinylpyrrolidone and 0.8 part by weight of docusate sodium in 1 part by weight of ethanol and 40 parts by weight of acetone is applied to 10 parts by weight of Aerosil _R_ , uniformly distributed and then dried while stirring. The granules are sieved to 0.1 - 0.3 mm.
  • effervescent grains To 1152 parts by weight of effervescent grains are added 50 parts by weight of maltodextrin, 100 parts by weight of lactose, 184 parts by weight of mannitol, 40 parts by weight of flavoring, 50.2 parts by weight of anti-foaming granules (0.2 parts by weight of simethicone coated onto 50 parts by weight of mannitol) , as well as the granulated drug prepared in b) , mixing is carried out for 15 minutes for uniform distribution and the mixture is then pressed to form tablets of 1.6 g, which have an acid-binding capacity of only 2 meq. Cisapride effervescent tablets having such a low acid- binding capacity are unknown to date.
  • 840 parts by weight of crystalline citric acid, 210 parts by weight of citric acid powder, 45 parts by weight of sodium cyclamate, and 4 parts by weight of sodium saccharin are heated in a vacuum mixing tank at 60°C. Then a solution consisting of 6 parts by weight of water, 1 part by weight of sodium citrate, and 3 parts by weight of sorbitol is aspirated in and distributed by stirring. 500 parts by weight of sodium bicarbonate are next added and allowed to react, and thereafter 370 parts by weight of monosodium citrate are added, which are also allowed to react. Lastly, 100 parts by weight of sodium carbonate are added and the granules are dried with slow stirring up to 15 mbar.
  • ranitidine hydrochloride 125 parts by weight of mannitol plus 100.4 parts by weight of a granulated antifoaming agent (consisting of 100 parts by weight of mannitol and 0.4 parts by weight of simethicone) and the flavoring agent are added.
  • a granulated antifoaming agent consisting of 100 parts by weight of mannitol and 0.4 parts by weight of simethicone
  • the tablets have a dissolving time of 60 to 80 seconds and an acid-binding capacity of about 2 meq and contain (in percent by weight) 6.8 ranitidine hydrochloride, 42.0 citric acid, 14.8 monosodium citrate, 20.0 sodium bicarbonate, 4.0 sodium carbonate, 2.0 sweeteners, 5.0 mannitol, 0.1 sorbitol, 4.0 granulated antifoaming agent (containing 0.016 diemthylpolysiloxane) and 1.2 flavoring.
  • Example 8 Example 8 :
  • the granules are screened to 1.5 m , and then mixed for 10 minutes at 10 rpm with 167 parts by weight of ranitidine hydrochloride, 100 parts by weight of anti-foaming granules (containing 0.4 parts by weight of simethicone and 100 parts by weight of lactose) , plus 54 parts by weight of sweetener and 40 parts by weight of flavoring, until uniform distribution is obtained.
  • the mixture is then pressed to tablets weighing 1.43 g and having a dissolving time of 65-70 sec, a hardness of 8, and an acid-binding capacity of about 1.5 meq.
  • the product contains no monosodium citrate.
  • Ranitidine effervescent tablets having such a low acid-binding capacity have not been disclosed to date.
  • citric acid 38.2% is heated with 0.26% of sodium saccharin to 60°C, then two-thirds of a solution which consists of, with respect to the final mixture, 0.6% water, 0.18% sorbitol, and 0.12% sodium citrate is applied. The solution is distributed for 5 minutes by mixing at 10 rpm. Then 16.2% of sodium bicarbonate and 2.9% of aspartame are added and anchored on the surface of the citric acid by reaction on the neutral substance coating. Then follows a second wetting with the third one-third of the solution; then 12.9% monosodium citrate and, finally, 5.2% sodium carbonate are added.
  • the effervescent grains are dried while mixing them slowly by applying a vacuum, at a temperature of at least 50°C, to 15 mbar.
  • the basic effervescent granular product is screened to 1.5 mm and mixed with 11.0% of ranitidine hydrochloride, 6.5% of mannitol, 6.5% of anti ⁇ foaming granules plus 0.2% of flavoring, and pressed to tablets of 1.55 g, which have a dissolving time of 50 sec at a hardness of 7.3 and an acid-binding capacity of less than 2 meq.
  • Example 10 Vehicle crystal grains coated only with a neutral substance
  • cisapride for example, in comparison to ranitidine, is not as highly sensitive to acid, it is nevertheless also possible by the procedure to be described below to achieve protection against the acid, all the more so since the drug is embedded in granules.
  • 160 parts by weight of mannitol, 10 parts by weight of cisapride, 5 parts by weight of aerosil and 10 parts by weight of sodium bicarbonate are heated with mixing to 60°C.
  • half of a solution of 27 parts by weight of methyl ethyl ketone (or 45 parts by weight of acetone) , 2 parts by weight of alcohol, 2 parts by weight of poly(vinyl pyrrolidone) K30, 1 part by weight of propylene glycol and 0.8 parts by weight of docusate sodium are added and distributed for 5 minutes for the purpose of uniform wetting.
  • the mixture is dried to 0.8 bar, the second part of this solution is aspirated, and again distributed by stirring for 5-10 minutes, and finally vacuum dried.
  • the active agent granules are then screened to 0.3 mm and already have an enhanced protection against acid attack simply due to the sodium bicarbonate they contain. They can then be mixed with the acid crystals coated with neutral substance, the remaining carbonates and bicarbonates, as well as the other tablet ingredients, and pressed to give tablets.
  • citric acid dried and coated according to a) is then mixed with the drug granules prepared according to b) , 50 parts by weight of sweetener, 80 parts by weight of sodium carbonate, 430 parts by weight of sodium bicarbonate, and 50 parts by weight of maltodextrin, 100 parts by weight of lactose, 150 parts by weight of mannitol, 50 parts by weight of an antifoaming granulate, and 20 parts by weight of flavoring, and then pressed to tablets of about 1.6 g, which have a dissolving time of 60 to 70 seconds at a hardness of 7.
  • Example 11 Cisapride effervescent tablets
  • Citric acid consisting of an amount of 300 parts by weight of granules, 80 parts by weight of fine granules and 40 parts by weight of powder, together with 5 parts by weight of saccharin sodium, is uniformly wet at 60°C with 2.2 parts by weight of a solution which contains 0.4 part by weight of sorbitol, 0.15 part by weight of sodium bicarbonate, 0.45 part by weight of citric acid and 1.2 parts by weight of water. 12 parts by weight of malic acid are then aspirated in and uniformly anchored on the sorbitol layer formed on the citric acid crystals.
  • the final mixture is prepared analogously to Example 5.

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Abstract

L'invention concerne un produit granulaire à système effervescent comprenant des principes actifs pharmaceutiques sensibles à l'acide tels que, par exemple, le bêta-carotène, la cimétidine, la ranitidine ou le cisapride. Ce produit est particulièrement utile pour prévenir l'action antiacide, présentant une capacité de fixation de l'acide inférieure à 5 meq, à un poids d'environ 1,6 à 2,3 grammes. Les grains effervescents sont constitués de cristaux véhiculeurs comprenant au moins un acide organique solide comestible, de préférence de l'acide citrique, se présentent sous forme de produit granulaire, séparés du principe actif pharmaceutique, et sont enrobés d'au moins une couche de substance neutre soluble dans l'eau et/ou d'alcool capable de provoquer une chute du point de fusion des grains d'acide à leur surface, comme, par exemple, un polymère soluble dans l'eau, un alcool supérieur, un hydrate de carbone et/ou un hydrocolloïde. Une seconde couche contient au moins une partie de l'alcali et/ou du carbonate alcalino-terreux prévu pour le dosage total.
PCT/EP1995/000650 1994-03-01 1995-02-23 Produit ou comprime granulaire contenant un systeme effervescent et un principe actif pharmaceutique, et son procede de preparation WO1995023594A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
HU9602380A HU228147B1 (en) 1994-03-01 1995-02-23 Granular product or tablet containing an effer vescent system and an active pharmaceutical substance, as well as a method for its preparation
BR9506964A BR9506964A (pt) 1994-03-01 1995-02-23 Produto granulado ou comprimido contendo um sistema efervecente e uma substancia farmacéutica ativa bem como um processo para a sua preparaçao
AU18114/95A AU681256B2 (en) 1994-03-01 1995-02-23 Granular product or tablet containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation
JP7522671A JPH09509669A (ja) 1994-03-01 1995-02-23 発泡系及び製剤学的活性物質を含む顆粒状生成物又は錠剤並びにその調整方法
CA002183952A CA2183952C (fr) 1994-03-01 1995-02-23 Produit ou comprime granulaire contenant un systeme effervescent et un principe actif pharmaceutique, et son procede de preparation
PL95316113A PL181714B1 (en) 1994-03-01 1996-08-22 Granulated product or tablet containing an effervescent system and a pharmaceutically active substance as well as method of obtaining them
NO19963588A NO315308B1 (no) 1994-03-01 1996-08-28 Granulert produkt eller tablett inneholdende et brusende system og en aktivfarmasoytisk substans, samt fremgangsmater til fremstilling derav
FI963385A FI118033B (fi) 1994-03-01 1996-08-30 Poresysteemin ja aktiivisen farmaseuttisen aineen sisältävä raetuote tai tabletti sekä menetelmä sen valmistamiseksi

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE4406641 1994-03-01
DEP4406641.4 1994-03-01
CH873/94-6 1994-03-23
CH87394 1994-03-23
EP94203112A EP0670160B1 (fr) 1994-03-01 1994-10-26 Produit granulaire ou comprimé contenant un système effervescent et un agent actif pharmaceutique, et son procédé de préparation
EP94203112.1 1994-10-26

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WO1995023594A1 true WO1995023594A1 (fr) 1995-09-08

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JP (1) JPH09509669A (fr)
CN (1) CN1213739C (fr)
AU (1) AU681256B2 (fr)
BR (1) BR9506964A (fr)
CA (1) CA2183952C (fr)
CZ (1) CZ291710B6 (fr)
DE (1) DE670160T1 (fr)
FI (1) FI118033B (fr)
HU (1) HU228147B1 (fr)
NO (1) NO315308B1 (fr)
NZ (1) NZ281228A (fr)
PL (1) PL181714B1 (fr)
RU (1) RU2153331C2 (fr)
TW (1) TW403658B (fr)
WO (1) WO1995023594A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004050058A2 (fr) * 2002-11-29 2004-06-17 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant un compose medicamenteux basique, respectivement, acide, un agent tensio-actif et un acide, respectivement, une base, hydrosobluble, physiologiquement acceptable
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US7785650B2 (en) 2001-05-15 2010-08-31 Mcneil-Ppc, Inc. Method for dip coating dosage forms
US8309118B2 (en) 2001-09-28 2012-11-13 Mcneil-Ppc, Inc. Film forming compositions containing sucralose
US8658208B2 (en) 2010-02-26 2014-02-25 Toray Industries, Inc. Coated solid preparation
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US10543170B2 (en) 2012-12-19 2020-01-28 Bayer Animal Health Gmbh Tablets with improved acceptance and good storage stability
WO2021076506A1 (fr) * 2019-10-17 2021-04-22 Isp Investments Llc Composition d'excipient co-traité effervescent stable et son procédé de préparation

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10224607B4 (de) * 2002-06-04 2008-03-13 Lts Lohmann Therapie-Systeme Ag Filmförmige, zerfallsfähige Zubereitungen zur Wirkstofffreisetzung und Verfahren zu deren Herstellung
WO2006059716A1 (fr) * 2004-12-03 2006-06-08 Takeda Pharmaceutical Company Limited Preparation solide
PT2788289T (pt) * 2011-12-09 2019-10-25 Merck Patent Gmbh Carbonato de sódio anidro de baixa porosidade.
US20150289554A1 (en) * 2012-10-25 2015-10-15 Otc Nutrition Llc Fast Dissolving Solid Calcium Mineral Supplement Compositions and Processing Making
CN105670003A (zh) * 2014-11-21 2016-06-15 常州坤宇环保科技有限公司 高吸水树脂防结块剂
EP3318135A1 (fr) * 2016-11-03 2018-05-09 Perfetti Van Melle S.p.A. Matériau de bonbon effervescent, son procédé de préparation et produits fabriqués à partir de celui-ci

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1270781A (en) * 1969-02-24 1972-04-12 Abbott Lab Tableting medium
US4704269A (en) * 1985-06-11 1987-11-03 Hudson Pharmaceutical Corporation Effervescent antacid and analgesic compositions
EP0415326A1 (fr) * 1989-08-31 1991-03-06 Ss Pharmaceutical Co., Ltd. Composition pour une préparation moussante
WO1993000886A1 (fr) * 1991-07-01 1993-01-21 Gerhard Gergely Systemes effervescents dopes avec des reactifs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1270781A (en) * 1969-02-24 1972-04-12 Abbott Lab Tableting medium
US4704269A (en) * 1985-06-11 1987-11-03 Hudson Pharmaceutical Corporation Effervescent antacid and analgesic compositions
EP0415326A1 (fr) * 1989-08-31 1991-03-06 Ss Pharmaceutical Co., Ltd. Composition pour une préparation moussante
WO1993000886A1 (fr) * 1991-07-01 1993-01-21 Gerhard Gergely Systemes effervescents dopes avec des reactifs

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US7785650B2 (en) 2001-05-15 2010-08-31 Mcneil-Ppc, Inc. Method for dip coating dosage forms
US8309118B2 (en) 2001-09-28 2012-11-13 Mcneil-Ppc, Inc. Film forming compositions containing sucralose
WO2004050058A2 (fr) * 2002-11-29 2004-06-17 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant un compose medicamenteux basique, respectivement, acide, un agent tensio-actif et un acide, respectivement, une base, hydrosobluble, physiologiquement acceptable
WO2004050068A1 (fr) * 2002-11-29 2004-06-17 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant un compose medicamenteux respectivement basique, tensioactif et base respectivement acide hydrosoluble et tolerable physiologiquement
WO2004050058A3 (fr) * 2002-11-29 2004-09-30 Janssen Pharmaceutica Nv Compositions pharmaceutiques comprenant un compose medicamenteux basique, respectivement, acide, un agent tensio-actif et un acide, respectivement, une base, hydrosobluble, physiologiquement acceptable
US9192577B2 (en) 2002-11-29 2015-11-24 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a basic drug compound, a surfactant, and a physiologically tolerable water soluble acid
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8658208B2 (en) 2010-02-26 2014-02-25 Toray Industries, Inc. Coated solid preparation
US10543170B2 (en) 2012-12-19 2020-01-28 Bayer Animal Health Gmbh Tablets with improved acceptance and good storage stability
US11147764B2 (en) 2012-12-19 2021-10-19 ELANCO US, Inc. Tablets with improved acceptance and good storage stability
WO2021076506A1 (fr) * 2019-10-17 2021-04-22 Isp Investments Llc Composition d'excipient co-traité effervescent stable et son procédé de préparation

Also Published As

Publication number Publication date
CZ251996A3 (en) 1997-01-15
NO315308B1 (no) 2003-08-18
FI963385A (fi) 1996-10-30
CA2183952C (fr) 2007-01-16
RU2153331C2 (ru) 2000-07-27
AU681256B2 (en) 1997-08-21
NO963588D0 (no) 1996-08-28
NZ281228A (en) 1997-06-24
DE670160T1 (de) 1996-03-14
NO963588L (no) 1996-10-31
TW403658B (en) 2000-09-01
CN1213739C (zh) 2005-08-10
HUT75677A (en) 1997-05-28
JPH09509669A (ja) 1997-09-30
HU9602380D0 (en) 1996-10-28
FI118033B (fi) 2007-06-15
PL181714B1 (en) 2001-09-28
PL316113A1 (en) 1996-12-23
CZ291710B6 (cs) 2003-05-14
AU1811495A (en) 1995-09-18
CA2183952A1 (fr) 1995-09-08
CN1142182A (zh) 1997-02-05
BR9506964A (pt) 1997-09-09
FI963385A0 (fi) 1996-08-30
HU228147B1 (en) 2012-12-28

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