CA1113393A - Solid oral pharmaceutical product with increased efficacy and predetermined steady state of solubility - Google Patents

Abstract

Abstract The present invention relates to a solid oral pharma-ceutical preparation with protracted release of the active ingredient consisting of discrete solid granules containing the active ingredient soluble in the stomach and auxiliary agents and of an equally solid external phase surrounding the said granules, whereby the granules forming the internal phase consist of granules prepared from a powder mixture which contains as active ingredient, or in addition to it a pharmaceutically acceptable basic bismuth salt, particularly bismuth subnitrate /basic bismuth nitrate/ or bismuth subcarbonate and auxiliary materials prepared with an aqueous emulsion containing a hydrophobic component and hydrophylic emulsifiers, and the external phase contains a solid, dry, amphoteric gel forming substance preferably tragacanth in an amount of 1-50 per cent w/w related to the total weight of the preparation in admixture with auxiliary agents.
The preparation is produced by the wetting of the powder mixture containing the basic bismuth salt, auxiliary material and in given case additional active ingredient with the aqueous emulsion of the hydrophobic component prepared by applying the hydrophylic emulsifiers then by granulation and admixing the dried granules with the amphoteric gel forming substance, and pressing it into tablets, or filling into capsules.

Description

3~ ;3 The present invention is directed to a solid oral pharmaceutical pre-paration with protracted action consisting of discrete solid granules containing the active ingredient and an equally solid external phase surrounding the said granules whereby the granules forming the internal phase consist of granules pre-pared from a powder mixt~e ~hich contains as active ingredient, or in addition to it a basic bismuth salt, preferably bismuth subnitrate or bismuth subc~rbon-ate and usual pharmaceutical auxiliary materials prepared with an aqueous emul-sion containing a hydrophobic organic substance, particularly stearic, or palmitic acid, and a hydrophylic e~ulsifier; and the external phase containing an amphoteric gel forming substance, particularly tragacanth in admixture with usual pharmaceuti~al auxiliary agents, particularly carriers and/or lubricating agents.
me invention gives a solution of a very important problem in the field of antacid therapy. m ou~h it is well known that hyperacidity does not ; cause such ulcers, it can be a conditian of its formation; ulcer forms only on surfaces exposed to the effect of hydrochloric acid. me presence of excess hydrochloric acid prevents the curing of ulcer already formed, so the therapy requires a proper die-t and in given case, besides observing o~er instructions, the neutralization of the excess acid to a proper ~egree. m us the acid binding medicine for the given purpose must satisfy the following requirements:
- the initial neutralizing effect must be quick and must keep its efficacy dur-ing the normal digestion time of the stomach;
- it must bind the required amDunt of acid;
- it must raise the pH value of the gastric ad d to a level at which the pepsin acti~ity is of reduced value but not fully i ~ibited;
- it may not cause a higher rise in the pH value of the gastric acid than de-sired;

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- it should not cause a systematic alkalosis even when applied repeatedly and for a long time.
The findings of a great number of tests con~ucted at a clinic in cases of hyperacidity show that the best acid binding effect can be expected frcm pre-parations whose on-time dose at a pH of 3 in a simulated gastric acid of 3 p~
/measured by constant pH method/ keep their acid bind mg effect through the re-tarded release of the active ingredient for at least an ho~r and during this time it continuously reacts with 7-10 ml of hydrochloric acid while maintaining constant pH of 3O
Accord mg to the state of art pharmaceutical preparations on the market applied in case of hyperacidity show a divergent picture as to their acid binding ability~ /Steiberg et al: J. Pharm. Sci. 54, 625. 1965. Matts S.G., et al., Brit. Med. J. 1.5437: 753-756/1965/. E.g. the research of Mr. Beckm~nn is alread~v directed to the introduction of a preparation which has an effect pro-longed in time. However, the dried alllminiumhydroxide~magnesiumcarbonate gel was not able even in vitro conditions to keep the chemical reaction of the gastric acld at the required level during the total period of normal biological digestion.
In a compliance with the findings of the above authors and similarly to our results most of the antacid preparations lose their acid binding ability in 8-10 minutes, i.e. they are not capable of further neutralizing the hydro-chloric acid forming continuously during the norm~1 digestion time.
This efficiency can be diminished only partly in the case of antacid -preparations by changing the composition of the acid binding ingredients. It is well known that in preparaticns containing carbonates, these carbonates mostly react in a moment with gastric acid thus they not only fail to exert a retarded effect but also release C02 which irritates the wall of the stomach and con-~, . ;;. . .. i " .

sequently stimulates the oe lls of mucous membrane to produce even morP hydro-chloric acid.
By the application of acid binding agents exerting their effect more slowly and without releasing CO2 such as magnesi~noxides or aluminiumhydroxide, these disadvantages can be overccme to a yreat extent, but none of th~ prepara-tions oontaining the most favourable combination of acid binding agents prepared by the known method can bring about an effect lasting for more than 8-10 minutes mentioned above, consequently none o~ the agents prepared by the known methods is c~pable of at least partly satisfying the requirements summed up in the fore-going.
Our invention relates to co.ntrolled release twc-phase solid oral pharmaceutical cc~positions /tablets, coated pills, capsules/ with protracted action and comprises the granulation of a powder mixture which contains the active ingredient, a solid carrier, and optionally pharmaceutical auxiliary agents with a liquid consisting of an aqueous emulsion which contains hydro-phobic and hydrophylic cDmponents, said granules are surrounded by an equally solid external phase which owing to its specific physico-che~ical properties further increases the release time of the active ingredient to a significant extent thereby au~m~nting the protracted biological utilization of the active ingredient to a level app~oaching the theoretical optimum and pressing tlle granules thus ob-tained into tablets or filling the same into capsules. me special granulating emulsion contains as hydrophobic componen-t stearic, or : palmitic acid, while as hydrophyli.c components two types of non-ionic . . .

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3~g surface active agents, namely *Tween~type emulsifiers, and optionally a mucus forming substance e.g. sodium carboxi-methyl-cellulose, by appropriate selection of the components of the emulsion and changing their quantitative ratio and rate of release of the active ingredient could be modified.
In one aspect the invent.ion provides a solid oral pharmaceutical preparation with protracted action, in the form of a tablet or capsule which preparation comprises an internal phase of discrete solid granules, which contain a solid external phase sur- ;
rounding the said granules, wherein the granules are prepared from a powder mixture which contains a pharmaceutically active ingredient or an acid-binding non-toxic metal compound selected:~om:-the group ~ consisting of basic bismuth carbonate basic ~ismuth, nitrate, mag-; nesium oxide, magnesium hydroxide, magnesium trisilicate and aluminium hydroxide and auxiliary agents with an aqueous emulsion containing a hydrophobic component and hydrophilic emulsifiers; and the external phase contains a solid amphoteric gel-forming substance in an amount of-1-50 per cent w/w related to the total weight of ~.
the preparation, including auxiliary agents.
In a preferred aspect the invention provides a solid ~ :~
oral pharmaceut;cal composition ~ith protracted action in the form : of tablets or capsules, havi.ng an internal phase consisting of solid granules and a solid external phase surrounding t~le said granules, wherein the granules are prepared from a powdered mixture of the . ~:
active in~redients and of auxiliary agents granulated with an aqueous emulsion containing 2 to 10~ w/w of stearic or palmitïc :
acid, 0.5 to 5% w/w of sodium carboxymethyl cellulose and 1 to 7 ~; of w/w two different non-toxic emulsifiers imparting a HLB-value . * Trade Mark ;. -4-. . ;..... . . . . . .. . .

of 8 to 12, and the said granules contain lO to 90% w/w of one or more pharmaceutically active compound including at least 56 w/w of a basic bismuth salt insoluble in water in neutral medium, 5 to 2Q% ~/w of a non-toxic gel-forming arganic substance selected from the group cons;sting of sodium carboxymethyl cellulose, sodium alginate and tragacanth and 5 to 7% of solid residue o~ the said granulating emulsion, and the said solid external phase contains an amphoteric gel-formi.ng substance selected from -the group con-sistï.ng of tragacanth, pectin and sodium carboxymethyl cellulose, in an amount o~ 1 to 50% of the total weight of the composition, and usual pharmaceutical excipients.
In another aspect the invention provides a process for the production of a solid oral pharmaceutical preparation with protracted action as claimed in claim l wherein a powder mixture which contains a powdered acid-binding, solid non-toxic metal compound which is insoluble or only slightly solu~le in water in neutral medium, and is selected from the group consisting of basic bismuth carbonate, basic bismuth. nitrate, magnesium o~ide, magne---sium hydroxide, magnesium trisilicate and aluminium hydroxide auxiliary agents, is granulated by wetting with an aqueous .~emulsion which contains a hydrophobic component, and a hydrophylic component which. is a non-iOnic emulsifier; admixing the dried granules with 1-50 per cent w/w o~ a dry powder amphoteric gel-forming substance related to total auxiliary ayents, and pressing the dry powder mixture thus obtained into tablets, or filling into capsules.
..In a preferred aspect the invention provides a process : for preparing a solid oral ph.armaceutical composition having ~_ -4a-.~.,1 ~ ~J~ ~ 3.~v'~

protracted action, characterized in that a powder mixkure containing 30 to 80~ w/w of pharmaceutically active ingredients including at l~ast 5% w/w of a basic bismuth salt capable of binding acid and substantially insoluble in water in neutral medium and auxil-iary agents including 5 to 20% w/w of a non-toxic organic gel-forming agent ls granulated by wetting it with an aqueous emulsion containing 2 to 10~ w/w of stearic or palmitic acid, 0.5 to 5% w/w of sodium carboxymethyl cellulose and 1 to 7% w/w of two different non-toxic emulsifiers imparting a HLB-value of 8 to 12, the dried granules are admixed with 1 to 50% by weight, calculated on the total weight of the composition, of a dry powder amphoteric gel-forming substance selected from the group consisting of tragacanth, pectin and sodium carboxymethyl cellulose and ~ith usual pharmaceu-tical excipients and the mixture is pressed into tablets or filled into capsules.
The present invention is based on the recognition that basic bismuth.salts of amphoteric character used as active ingredient in antacidic preparations particularly bismuth - subnitrate or bismuth subcarbonate enter into molecular interaction at an approximately neutral pH interval with gel-forming substances of vegetable or animal origin particularly tragacanth, further :
also albumin, casein, pectin, etc. and form a sti.cky homogeneous ~ mass of gel-like structure and strongly increased viscosity from the basic bismuth compound is released extremely slowly and uniform-ly even in acidic medium. Thus in the case of the antacid prepara-~; tion containing the basic bismuth compound itself as active ingredient the acid bind;ng capacity of the composltion in the stomach is maintained at a uniform level for a long period of time, . -4b-~ . .. . . . . . . .

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while if composition is used which contains in addition to the slow releasing basic bismuth compound also other active ingredients, :~
the latter is also released from the mass formed in the stomach from the composition at a similarly slow, uniform rate.
This surprising ph.enomenon can be illustrated experimen-tally in the following simple manner:
~ In 1 per cent aqueoùs tragacanth mucus 10, 15 or 20 percent w/w of finely powdered basic bismuth nitrate is suspended.
The homogeneous suspensions are divided into equal portions and the pH value of the samples is adjusted to 2, 3, 4, 5, 6, 7, 8 and 9, respectively ~y adding a few drops of di.luted '~ , .

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hydrochlo~ic ac~d or diluted aqueous sodium hydroxide solution (the own p~I
value of the suspension is to about 4,5), Thereafter the viscosity of the samples kept at a temperature of 23C is measured by a Hoppler~type rheovis-cosimeter at certain intervals, Since tragacanth binds alkali to a certain extent, the pH value of the samples is checked and if necessary corrected several times in the course of the experiment.
Some resul~s are presented graphically in the accompanying draw-ings.
Thus, Figure 1 is a graph of ~ e equilibrium viscosity values measured at 23C and pH;
Figure 2 is a graph of the change of ~ e viscosity of a 20 per cent basic bismuth nitrate suspension measured at pH 4.5 and 23C with time;
Figure 3 is a graph of gelation velocity and time.
In Table I are compared the viscosity values of the sample series containing basic bismuth nitrate (bismuth subnitratej in varying concentra-tions at various pH values with those of tragacanth mucus having the same con-centration ~1%~ and pH value but not containing basic bismuth ni~rate. The said viscosity values were measured 40 minutes, 3 hvurs and 16 hours respec-tively after the preparation of the suspension. The ~ e equilibrium viscosity values measured at ~3C are shown in the function of the pH. (Figure 1) ~The obtained viscosity values clearly show that between pH 4 and 7 ; the samples containing the bismuth compound behave in quite a different manner than in a more strongly acidic or alkaline interval. Between the above pH
values the viscosity extremely increases and reaches several fold the initial value, then the maximal value remains practically the same for a longer period of time. The macroscopic picture of suspensions having different pH values reveal a similarly conspicuous difference; the following table shows the changes observed ~uring 48 hours in a 10 per cent suspension.

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6a -~, i 33~3 At the interpretation of the reaction between basic bismuth nitrate and tragacanth it must be taken into eonsideration that the reaction occurs only with solvated tragacanth. me solvation of tragacanth, which proceeds only slcwly, requires a considerable amount of time. From this it follows that al-though in solid antacid preparations such eomposition in the beginning the tragacanth is in excess related to the basic bismuth nitrate, at first it is the basic bismuth nitrate which is in significant exeess, because the solvation of tragacanth is protracted, taking plaoe only gradually. In this case, however, as it ean be seen from Figure 2, where the ehanges of ne viscosity of a 20 per cent basic bismuth nitrate suspension measured at pH 4t5 and 23& in the f~nc-tion of time are shown, the reaction proeeeds rapidly and the equilibrium viscosity can increase to manifold of the initial value already within 30 minutes.
The velocity of gelation strongly depends on the concentration of the i~ basic bismuth nitrate and other basic bismuth ccmpounds suspended in the tragacanth mucus as well.
Figure 3 presents this correlation in the case of 10-30 per cent of basic bi~nuth nitrate susp nded in 1 per cent tragaeanth mucus at an approxi-mately neutral p~ value, a-t 23C /the shaded area between the two curves shows the standard deviation of ~easurements, while the solid perpendicular lines at 10, 20, and 30 per eent show the scattering at these concentrations. The high increase of the viscosity of the suspensions with nearly neutral weakly acidic pH, and the further fact that while in acidic or a:lkaline ~suspensions the sus-pended bismuth c~npound does not undergo physical changes and with time pre-eipi~ates frcm the tragaeanth ~ucus, in nearly neutral suspensions the origin-ally sllspended metal compound itselfjellifies, and after a certain time the whole suspension beoomes a hom~genous jelly-like gel, both elearly show that the : : : . ,.. :. ~ : ,: : ~

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suspended originally insoluble basic bismuth compounds enter into m~lecular reaction with the amphoteric gel forming substance, the tragacanth, and a hamogenous, sticky jelly-like mass is fo~medwhich contains the metal ccmpound bound in gel form.
The above experim~nts ~ere repeated in a similar manner except that basic bismuth nitrate was replaced by another basic bismuth salt being insoluble or but slightly soluble in water /e.g. alum m iumhydro~ide or magnesium hydroxide/;
similar results were achieved. In our experience tragacanth gave the best re~
sults, but satisfactory results were given by other hydrocolloids as amphoteric gel forming substances/ too, e.g. pectin or albumin. These experimental results ~how that the above discussed behaviour can be regarded as a general property of basic bismuth salts insoluble in water in neutral medium and of amphoteric gel formm g substances.
~It has been found that this property of the above mentioned bismuth - compounds can be advantageously m~de use of in pharmacy, first of all for the production of antacid pharmaceutical preparations which exert their action Ln the stomach uniformly for a longer period due to the controlled, strongly pro-`~tracted, uniform release of the acid binding active ingredient. If namely the said bismuth compounds are surrounded with such amphoteric gel forming substance , when getting into contact with gastric acid in the stomach, then the described gel forming process starts in the stanach itself undex the effect of the nearly neutral or weakly acidic pH value formed "in situ" as a result of the beginning diffusion of the basic bismuth salt. The formed strongly viscous, sticky jelly-like mass including the basic bismuth salt, adheres to the stomach wall and exerts its action uniformly for a longer period of time, in an optimal manner, corresponding to the physiological re ~irem~nts. m is optimal mcde of action, complying with theoretical considerations was substantiated by clinical tests : - : , ~ , carried out with telem~tric Heidelberg capsule, and ooloured pictures taken in situ in the stomach with a glass filter optics.
Although the primary field of application of the present invention is the production of antacid preparations - namely in this case ~le antacid active ingredient itself serves as basic bismuth-compound req~lired to obtain the de-sired effect, - the present inven-tion may b2 advantageously used for the produc-tion of any pharmaceutical preparation from which the active ingredient is uni-formly and protractedly released within the desired lGng period of time /e.g.
compositions having spasmolytic, hypno-tic or antihistaminic effect/ if this active ingredient is combined with a non-toxic basic bisrnuth salt, providing for the protracted release of this active ingredient in the above described manner.
In solid pharmaceutical ccmposition for oral use the optimal level of ` protracted release of the active ingredient following the interaction of the acid binding metal compound and the amphoteric gel forming substance in the stomach can be ensured by preparing granules from the powder mL~ture of a non-.. . .
toxic basic bismuth salt and the powdered form of pharmaceutical carrier sub-stan oes, and optionally a pharmaceutical auxiliary agent and/or a further ac-tive ingredient with an aqueous ernulsion containing a hydrophobic cc~,ponent, prefer-ably stearic acid, or palmitic acid, and hydrophylic emulsifier; the granules thus obtained are mixed prior to tabletting or filling into capsules with a dry powder mixture, which - in addition to the c æriers or other auxiliary sub-stan oes, e.g. lubricant - contains a gel forming substance of amphoteric charactar, preferably tragacanth in a sufficient quantity to ensure the mucus concentration reguired for the above described gel formation when reaching the stomach. This means tha-t to the dried granules, beside the usual lubricants and/or other auxiliary materials an amphoteric gel formlng substan oe most expediently tragacanth is admixed in a quantity corresponding to 80-800 per cent _ g _ ~b ~

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w/w of the included metal ccmpound~ and this inhGmogeneous mixture consisting of solid granules and the pcwder mLxtu~e constituting the external phase is cam-pressea to tablets or filled into capsules by the m~thod used in pharmaceutical ;~
practi oe.
According to an advantageous method of preparation of -the granules forming the internal phase the granulation of the pow~er mixture containing as `~ active ingredient a non-toxic basic bismuth salt, the carrier and optionally ~ other a ~iliary agent is carried out by using an aqueous emulsion which conta ms ; as hydrophGbic component stearic acid or palmitic acid mentioned above and as hydrophylic ccmponent two different non-ionic emulsifiers, whereby the two different surface active agents and their quantitative ratio are preferably selected so that the so called HLB /hydrophyl-lipophyl-balan oe/ or the emulsify-ing system - being characteristic of the emulsifying capacity - should be between 8 and 12, preferably abo~t 10.
~; Namely each emulsifying system can be characterized by the necessary HLB value /see Griffin W.C., J. SGC. Cosmetic. Chem. 5, 249 /1954/; Racz I., A~ta Pharm. Hung. 34, 25. /1964/ /, ensuring optimal stability in a given system . ., fm ~ the aspect of emulsifying.
e necessary HIB values of a given emulsifying system /~B z/ are as follcws:
WA . HIBA ~ WB HIBBB ~ Wc . C

WA B WC
wherein WA and WB are the weights of both emwlsifiers /A and B/ in g in an emul-sion resulting in ideal physical stability, Wc etc. are the weight of the optional further emulsifier in g /C etc. such as sodium carboxymethyl cellulose/
HIBA~ EDL3B etc. are the own HLB values of the substances in caption from litera-ture or can be measured by the method of I. Racz and E. Orban tJ. CollO Sci. 20 99. /1965/ /.

. ~ , 3~3 Theoretical calculation based on the HLB value of the oomponents of the granulating emulsion enables the selection of the oomposition ratio being op-timal from the point of view of the retardation of the active ingredient re-lease whichever emulsifier is used. On the basis of calculations o the HIB
values of non-ionic emulsifiers to be considered prim~rily applicable /Poly-ox ethylene-sorbitan-monooleates, polyoxyethylene-sorbitan-monolaurates, poly-o~yethylene-sorbitan-monostearates and monopalmitates, sorbitan fatty acid esters/ it may be stated as practical rule that generally satisfactory results ma~ be obtained i the amount of the hydrophobic ccmponent /e.g. stearic acid/
emulsified in the granulating liquid is taken 25 parts by weight, the two different non-ionic emulsifiers are used in a ratio 1-7, preferably 1-3 parts by weight. It is particularly preferable to add beside the -two non-ionic emulsi-fiers a mucus forming substanoe, preferable 5-7 parts by weight of sodium carboxymethyl oe llulose/ to the granulating emulsion. Such granulat:Lng emu~sions are expediently prepared by dissolving the hydrophobic component in double amount of alcohol under warming, adding the emulsifyer to the solution thus ob-tained, and emulsifyLng the still warm alcoholic solution in an approximately ~ .
five fold amount of water or advantageously in a sodium carboxy-methyl-cellulose ; solution having a oono~ntrat~on of about 2 per cent.
me granulating emulsion thus abtained is then used for the granula-tion of the powder mixture containing the basic bismuth salt, possibly an active ingredient, carrier and optionally other auxiliary agents. Two parts by weight of the powder mixture are admixed and kneaded preferably with 1 part by weight of granulating emulsion and the wet mass granulated by known methods e.g by pressin~ through a sieve. To the dried granules the amphoteric gel forming sub-stance is added in an amount of 1-50 per oent w/w - related to the total weight of the f mished preparation - optionally in the presence of an auxiliary agent , i , ;33~

such as a carrier and/or lubricating agent, expediently magnesium stearate, whereafter the mixture obtained is pressed into tablets or filled in-to capsules.
Accord mg to a further preferred embodiment of the present invention in addition to or instead of the already mentioned mucus formlng substance an amphoteric gel forming agent /e.g. tragacanth/ may also be added to the powder mixture, preferably in the same amount as the basic bismuth compound present in the powder mixture~ Thus~ a composition is prepared in which the amphoteric gel forming substance is not only present in the external phase surrounding the granules, but also inside the granules which form the inbernal phase; this further promDtes the rapid interaction between the basic bis~luth co~pound and the amphoteric gel forming substance discussed above.
Thus, the present invention relates to a solid oral pharmaceutical preparation with protracted action - mainly tablets or capsules - consisting of discrete solid granules which contain the active ingredient soluble in the stcmach and auxiliary agents, and of an equally solid exte~nal phase surrounding the said granuLes whereby the granules forming the internal phase consist of ; granules prepared from a pcw~Pr mixture which contains as active ingredient or in addition to it a basic bismuth salt, particularly bismuth subnitrate /basic bismuth nitrate, Bi/N03/. ~ O/ or bismuth subcarbonate and auxiliary agents with an aqueous emulsion containing a hydrophobic ccmponent and hydrophyl emulsifiers;
and the external phase contains a solid amphoteric gel forming substance in an amount of 1-50 per cent w/w related to the total weight of the composition, and auxiliary agent.
q~e active ingredient content of the granules forming the internal phase is preferably 10-80 per cent w/w. In the case of antacid ccmposition the active ingredient is the basic bismuth salt itself preferably basic bismuth carbonate, basic bismuth nitrate, alone or in ccmbination with at least one ~ 3 ~4~

other non-toxic acid bind m g agent, preferably aluminium hydroxlde or magnesium hydroxide while if the ~omposition contains active ingredients having other effects, /e.g. spasmolytics/, the granules contain beside 1-60 per cent w/w of such an active ingredient, preferably 40-80 per cent w/w of acid binding metal compound being insoluble, or but slightly soluble in water in neutral medium, expediently aluminium hydroxide.
e granules forming the internal phase contain as h~drophobic ccmpon-ent derived from the granulating em~lsion, preferably 2-10 per cent w/w of stearic acid or palmitic acid; as hydrophylic component preferably two dif~erent non-ionic emulsifiers, particularly polyoxyethylene-sorbitan-monooleate, poly-oxyethylene-sorbitan-monolaurate, - monostearate, and/or monopalmitate, or sorbitan-fatty acid esters in a total amount of 0.5-5 per cent w/w are used, optionally in ccmbination with 2 to 20 per cent w/w of a mucus forming substance, preferably sodium carboxymethylcellulose, sodium alginate, and/or an a~photeric gel forming substance, particularly tra~acanth.
Further details o the present invention are to be found in the examples without limiting the scope of the claims to the examples.

For the production of a tabletted preparation the following quantities of substances are used per tablet:
Magnesium trisilicate 0.28 y magnesium oxide 0.12 g Bismuth subnitrate 0~05 g Tragacanth 0.05 g Sodium carboxymethylcellulose 0.035 g The above listed substances, complying in quality with the require-ments of the Pharmacopoeia and milled to co~ply in pcwder fineness with the ~.

requirement for "fine powder" /sieve No. V/ of the Pharmacopoeia, mixed to form a homogenous mixture, then kneaded with a granulating liquid prepared as follows:
m ree hundred /300/ g of stearic acid is dissolved in 300 g of 96 per cent alcohol under heating, then 70 g of "Tween 85" and 20 g of "Tween 20"
~mulsifiers /non-ionic emulsifier of polyoxyethylene-sorbitan-m~nooleate base/
are admixed and the alcoholic mixture is emulsified still warm in 3500 g of an aqueous, 4 per cent carboxymethylcellulose sodium mucilage. This em~sion is used, for the preparation of the tablets, according to the usual method; the powder mixture of the above specified composition is mixed in 2:1 weight propor-tion with the granulating e~ulsion and kneaded, then the obtained wet mass is passed through a sieve, dried, the usual finishing and lubricating substances /e.g. magnesium stearate, Aerosil* R 972/, as well as 0,02 g tragacanth per tablet are ad~xed and the mixture is pressed into tablets of 0.76 g eac~l.
The tablets thus prepared remain in the stomach adhering to the gastric wall for longer period than the usual preparations. In simulated gastric fluid in which the pH is m~intained constantly at 3, measured ~y the so-called "constant pH = 3 method", each tablet consumed 5,3 to 6,2 milliequiva-lent of hydrochloric acid per hour, at a constant rate.
Example 2 Proceeding also as described in Example 1, for completing the tablet mass, the follcwing materials are used for 1 tablet - also in quality campl~ing with the requirements of the Pharmacopoeia:
Magnesium trisilicate 0.25 g Sodium alginate 0.12 g r~agnesium oxide 0.10 g Calcium lactate 0.06 g Tragacanth 0.06 g *Trademark - 14 -. : . : ~ . , . . :

Bisnuth subnitrate 0.05 g Scdium carboxymethylcellulose 0.04 g The granulating liquid is applied in a composition and quantitative .~ ratio as given in Example 1, and proceeding as described above a tabletted pre-paration is produced the properties of which are essentially identical with ~-: those indicated in Ex~n?le 1. Similarly gosd results may be obtained b~ the appl;cation of any emulsifying system of different HLB value.
: In the following we present so~e advantageously applicable emulsifying ~ ccmbinations and the calcul~tion of the ~LB values of the emulsifying systems :.~ 10 ccnsisting of the ccmponents cited above~
1. Compon~nts Quanti.ty HIE-value Stearic acid 50 g CMC-Na 60 g 15 Tween 85 60 g 11 Tw2en 20 20 g 16,7 Resulting HIB,value:
50 . 1 + 60 . 15 + 60 . 11 ~ 20 . 16,7 - - = 10,2 50 + 60 ~ 60 + 20

2. Components Quantity HIB-val~le S~earic acid 50 g CMC-Na 60 g 15 Tween 80 60 g 15 Glycerol monostearate 20 g 3,8 .
Resulting HLB-value:
50 . 1 + 60 . 15 + 60 . 15 + 20 . 3,8 10, 1 50 + 60 + 60 + ~0 .';~.

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3. Components Quantity HLB-value Ste æic acid 50 g CMC-Na 60 g 15 Span* 60 20 g 4,7 Pol~oxy-ethylene-ste æ ate 60 g 16,9 Resulting HLB-value:

50 . 1 + 60 15 + 20 . ~,7 + 60 . 16,9 = 10,8 50 + 60 + 20 + 60 m e pow~er mixture granulated with -the chosen granulating fluid is mixed with the usual lubricating and finishing additives and ar'ter addition of 0.02 g of tragacanth, the granules are tabletted. The rate constant of acid neutralization reaction of the tablets thus prepared will vary in accordance with the HLB value of the granulating liquid. :
E~m~e 3 Production of a preparation filled .into gelatin capsules. The process ls as described in the previous examples, but the powder mixture containing the active ingredient is prepared from the ingredients listed below, corresponding ~: -in quality to the requirements of the Pharmacopoeia, calculated for 1 capsule:
Mag.nesium trisilicate 0.20 g Magnesium oxi.de 0.085 g Bismuth subnitrate 0.035 g Sodium carboxymethylcellulose 0.023 g The powder mixture is granulated subsequently according to the usual method with the gran~lating liquid specified in Example 1, then the usual lubricating and finishing materials, and for each capsule 0.07 g of tragacanth is admixed and filled into gelatin capsules of proper siæe in quan~;ties corres-ponding to 1 dose for each c~psule *Tradem3rk - 16 -3~ :
After ingestion the content of the medicated capsules thus prepared, getting into the stomach adhers to the gastric wall and remains in the stomach for a more prolonged time than usual and in the meantime the slcwly released active ingredient gradually reacts with the h~drochloric acid present in the stomach. Measured by the previously mentioned "constant pH = 3" method, each capsule consumes 4.4 to 5.2 milliequivalent of hydrochloric acid per hour at a uniform rate.
Exa~ple 4 For the production of a preparation filled into gelatin capsules we prooeed as described above, but the powder mixture containing the active ingred-ient is prepared from the ~ollowing materials, corresponding in quality to the rec~lirements of the Pharmacopoeia, calculated for 1 capsule:
Magnesium trisilicate 0.20 g Sodium alginate 0.10 g Magnesium oxide 0.075 g Calci~n lactate 0.04 g Basic bismuth nitrate 0.035 g ~bismuth subnitrate/
Sodium carboxymethylcellulose 0.023 g S~bsec~uently the pawder mixture is granulated with any of the indicated granulating fluids according to the usual method, then the usual lubricating and finishing substances are acbmixed in quantities correspanding to 1 dose for each capsule and after the acldition of 0.02 g of tragacanth per capsule, t~le muxture is filled into capsules of adequate size. The properties of the so obtained medicated capsules are identical to those specified in the previous Example.
Example 5 For the production of a preparation filled into gelatin capsules we - :. .

proceed as described above, but the powder mixture containing the active ingred~
ients is prepared fram the following materials, corresponding in quality to the requirements of the Pharmacopoeia, calculated for l capsule:
~agnesium trisilicate 0.20 g Magnesium oxide 0.07 g ~luminium hydroxide 0.08 g Basic bismuth car~onate 0.04 g /bismuth subcarbonate/
Sodium carboxymethylcellulose 0.023 ~
Subsequently the powder mixture is granulated with any of the granulat-ing fluids specified in Example l according to the usual method, then followingaddition of the adequate quantities of the usual l~ricating and finishing mate-rials 0.06 g of pectin is admixed to the granulated mass and filled into gelatin capsules of adequate size. m e properties of the medicated capsules thus ob-tained are identical to those specified in the previous Example.
Example 6 Fbr the production of a preparation filled into gelatin capsules, we proceed as described in the previous Examples, but the powder mixture containing ~he active ingredients are prepared from the substances listed below, correspand-ing in quality to the requirements of ~he Pharmacopoeia, calculated for 1 capsule:
Magnesium trisilicate 0.20 g Bismuth subnitrate 0.10 g Sodium carboxym~thylcellulose 0.023 g Subsequently the powder mixture is granulated with one of the granulat-ing fluids specified in Example l according to the usual method, and following addition of the usual lubricating and finishing materials and 0.10 g of acacia per capsule, the mixture is filled into gelatin capsules of adequate size. me ~.

properties of the medicated capsules thus obtained are identic~l to those speci-fied in the previous Example.
Example 7 The process to be follcwed is as described in Ex~mple 1, but for the preparation of tablets containing a spasmolytic as active ingredient, the follow-ing substances are used, calculated for 1 tablet:
3'4,6,7-Tetraethoxy-l-benzal-3,4-dihydro-isoquiline hydrochloride /Drotaverine hydrochloride/ 0.15 g Tragacanth 0.20 g Sodium alginate 0.12 g Bismuth subnitrate 0.05 g Sodium carboxymethylcellulose 0.04 g l'he granulating fluid is applied in the same co~position and quantita-tive ratio as described in Example 1 and thus, proceeding further as specified in Example l, tablets will be produced, the properties of which will be essentially identical to those specified in Example l.
F~r the practical illustration of the advantages of the preparations prepared according to the present invention, comparative clinical experiments were performed in human subjects by measuring the duration of action and acid neutralizing effect of the individual preparations~
The experiments were performed in groups of 6 hyperacid volunteers /fasting gastric pH between 0.5 and 2.0/, but free of any other gastro-intestinal disease; simultaneously with antacid capsules prepared according to the methDd specified in Example 3 /A/ parallel experiments were performed under identical conditions /B/ with tablets without external phase of an amphoteric gel formong substan oe and /C/ with a kncwn antacid preparation in clinical use oontaining 400 ~ of dried Mg/OH/2 ~ Al/OH/3 gel in the form of tablets of pro--- 19 ~

~,~

longed action, produced under the Trade Name MaaloxR Tablets. Each of the threetablets was a~inistered to the experimental subjects in doses corresponding to 7.00 /+ 0.5/ mEq acid binding agent and the pH value of the gastric juioe as well as its changes in the function of time were measured by the aid of Heidelberg capsules /cf.: Conell, A.~., Waters, T.E.: "Assessment of Gastric Function by pH Telemetering Capsule". Lan oe t 2, 227 /1964/; Steinberg, W.H., Mina, E`.A., Pick, P.G., Frey, H.G.: "Heidelberg Capsule I. In Vitro Evaluation of a New Instrument for Measuring Intragastric pH". J. PharmO Sci. 54, 772.

/1965/ /.
In the case of each of the three preparations four parameters were registered after measuring the initial pH values:
1. the time re~uired to reach pH = 3, 2. the highest pH value, 3. the duration of the effect at about p~ = 3,

4. the ~lration of the effect at abou~. p~ = 4.
me obtained results /average values obtained for the 6 subjects/ have been summarized in the following table:

. ~
Preparation /A/ /B/ /C/

Initial pH 1.2 1.1 1.0 TLme for attaining pH = 3,0 8.5 6.2 5.4 /~inutes/

Duration of the effect at30.0 19.0 16.6 pH = 3.0 /munutes/

Duration of the effect above 25.9 16.3 8.6 pH = 3.5 /minutes/

Peak pH value 6.6 5.0 4.9 _ :
; - 20 -:, - , . . ~ ' I ' ,, , . ,, : ." ., : : , , .- . , ,::

~ ~33~3 It can ke seen from the tabulated data that the duration of the effect of th~ two-phase preparation exceeds considerably both the preparation prepared without extcrnal phase and the known preparation. ~

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Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A solid oral pharmaceutical preparation with protracted action, in the form of a tablet or capsule which preparation comprises an internal phase of discrete solid granules which contain a solid external phase surrounding the said granules, wherein the granules are prepared from a powder mixture which contains a pharmaceutically active ingredient or an acid-binding non-toxic metal compound selected from the group consisting of basic bismuth carbonate basic bismuth nitrate, magnesium oxide, magnesium hydroxide, magnesium trisilicate and aluminium hydroxide and auxiliary agents with an aqueous emulsion containing a hydrophobic component and hydrophilic emulsifiers; and the external phase contains a solid amphoteric gel-forming substance in an amount of 1-50 per cent w/w related to the total weight of the preparation, including auxiliary agents.

2. A preparation according to claim 1 which contains an acid-binding, non-toxic metal compound insoluble in water and in neutral medium, in an amount of 30-80 per cent w/w.

3. A preparation according to claim 1 which contains as active ingredient of the granules of the internal phase a spasmolytic, hypnotic, antihistaminic, or other therapeutically active compound which is soluble in the stomach in an amount of 1-60 per cent w/w and further containing an acid-binding, non-toxic metal compound in an amount of 40-80 per cent w/w which is insoluble in water and in neutral medium.

4. A preparation according to claim 1 wherein the granules forming the internal phase contain as acid-binding non-toxic metal compound basic bismuth nitrate, basic bismuth carbonate, aluminium hydroxide, or magnesium hydroxide.

5. A preparation according to claim 1 wherein the granules forming the internal phase contain as hydrophobic component derived from the granulating emulsion stearic acid or palmitic acid in an amount of 2-10 per cent w/w.

6. A preparation according to claim 1 wherein the granules forming the internal phase contain as hydrophylic component derived from the granulating emulsion non-ionic emulsifiers in 0, 5-5 per cent w/w.

7. A preparation according to claim 1 wherein the granules forming the internal phase contain as an auxiliary substance a mucus-forming orgel-forming agent, selected from the group consisting of sodium carboxymethylcellulose, sodium aliginate and tragacanth in an amount of 2-20 per cent w/w.

8. A preparation according to claim 1 wherein the external phase surrounding the granules contains 1-50 per cent w/w of an amphoteric gel forming substance selected from the group consisting of tragacanth, albumin casein and pectin.

9. A preparation according to claim 1 wherein the internal phase also contains a therapeutically active ingredient soluble in the stomach.

10. A process for the production of a solid oral pharmaceutical preparation with protracted action as claimed in claim 1 wherein a powder mixture which contains a powdered acid-binding, solid non-toxic metal compound which is insoluble or only slightly soluble in water in neutral medium, and is selected from the group consisting of basic bismuth carbonate, basic bismuth nitrate, magnesium oxide, magnesium hydroxide, magnesium trisilicate and aluminium hydroxide auxiliary agents, is granulated by wetting with an aqueous emulsion which contains a hydrophobic component, and a hydrophylic component which is a non-ionic emulsifier; admixing the dried granules with 1-50 per cent w/w of a dry powdered amphoteric gel-forming substance related to total auxiliary agents, and pressing the dry powder mixture thus obtained into tablets, or filling into capsules.

11. A process according to claim 10 wherein the internal phase also contains a therapeutically active ingredient soluble in the stomach.

12. A process according to claim 10 wherein the hydrophobic component of the emulsion is stearic or palmitic acid.

13. A process according to claim 10 wherein there is added to the powder mixture as an auxiliary agent a mucus-forming or gel-forming substance selected from the group consisting of sodium carboxy methyl cellulose, sodium alignate and tragacanth and an amount of 2 to 20 per cent w/w.

14. A solid oral pharmaceutical composition with protracted action in the form of tablets or capsules, having an internal phase consisting of solid granules and a solid external phase surrounding the said granules, wherein the granules are prepared from a powdered mixture of the active ingredients and of auxiliary agents granulated with an aqueous emulsion containing 2 to 10% w/w of stearic or palmitic acid, 0.5 to 5% w/w of sodium carboxymethyl cellulose and 1 to 7% w/w of two different non-toxic emulsifiers imparting a HLB-value of 8 to 12, and the said granules contain 10 to 90% w/w of one or more pharmaceutically active compound including at least 5% w/w of a basic bismuth salt insoluble in water in neutral medium, 5 to 20% w/w of a non-toxic gel-forming organic substance selected from the group consisting of sodium carboxymethyl cellulose, sodium alginate and tragacanth and 5 to 7% of solid residue of the said granulating emulsion, and the said solid external phase contains an amphoteric gel-forming substance selected from the group consisting of tragacanth, pectin and sodium carboxymethyl cellulose, in an amount of 1 to 50%
of the total weight of the composition, and usual pharmaceutical excipients.

15. A pharmaceutical composition as claimed in claim 14, wherein the granules contain 30 to 80% w/w of at least one basic metal compound capable of binding gastric acid selected from the group consisting of magnesium oxide, magnesium trisilicate, aluminium oxide and aluminium hydroxide, including at least 5% of basic bismuth nitrate or carbonate, 5 to 20% w/w of a non-toxic gel-forming organic substance selected from the group consisting of sodium carboxymethyl cellulose, sodium alginate and tragacanth and 5 to 7% of solid residue of the said granulating emulsion.

16. A process for preparing a solid oral pharmaceutical composition having protracted action, characterized in that a powder mixture containing 30 to 80% w/w of pharmaceutically active ingredients including at least 5% w/w of a basic bismuth salt capable of binding acid and substantially insoluble in water in neutral medium and auxiliary agents including 5 to 20% w/w of a non-toxic organic gel-forming agent is granulated by wetting it with an aqueous emulsion containing 2 to 10% w/w of stearic or palmitic acid, 0.5 to 5% w/w of sodium carboxymethyl cellulose and 1 to 7% w/w of two different non-toxic emulsifiers imparting a HLB-value of 8 to 12, the dried granules are admixed with 1 to 50% by weight, calculated on the total weight of the composition, of a dry powdered amphoteric gel-forming substance selected from the group consisting of tragacanth, pectin and sodium carboxy-methyl cellulose and with usual pharmaceutical excipients and the mixture is pressed into tablets or filled into capsules.