CA2158437A1

CA2158437A1 - Aluminium containing pharmaceutical preparation with controlled release

Info

Publication number: CA2158437A1
Application number: CA002158437A
Authority: CA
Inventors: Istvan Racz; Janos Plachy; Istvan Antal
Original assignee: Individual
Current assignee: Synepos AG
Priority date: 1993-03-16
Filing date: 1994-03-16
Publication date: 1994-09-29
Also published as: WO1994021268A1; PL310821A1; FI954348A; JPH08507775A; EP0689445A1; FI954348A0; AU6426994A

Abstract

A pharmaceutical preparation containing at least one aluminum compound for antacid and/or abstringent and adsorbent actions is manufactured by treating 2-300 parts by weight of a water-swellable compound of limited swelling ability with 2-50 parts by weight of water and thereafter admixing it with a powder comprising at least one of the group consisting of 100 parts by weight of said at least one aluminum compound, 2-150 parts by weight of at least one phosphate compound and at least one auxiliary material. The mixture may be granulated and dried, and thereafter either pressed to tablets or filled into capsules; it may also be transformed into a suspension.

Description

W05U~ 8 1 ~ 15~437 PCT~p9~

Aluminium contA~n~n~ rh~r~ce1~tical preparation with controlled release FIELD OF THE lNv~NllON

The invention relates to an antacid and/or adstringent and a~au Le.~t pharmaceutical preparation contA;n;~ at least one aluminium ~u~d, as well as a process for the production of such preparations.

BA~K~uN~ OF THE INVENTION

The (diseq~ h1num between protective and aggressive fac-tors, such as hydrorhloric acid, r~r~n, bile acid, lyso-lecithin, nicotine, A1coho1, stress, Helicobacter pylori etc. leads to different pathogenic events, such as ulcer, in the gastl~3~ 1 area. Most antacid preparations used for the treatment of nlcer and pre-ulcer hyperAci~ity contain al1~m~nium com~u~s. Ho~eveL, when aluminium is taken into the orqanism and aLao,Lb~, this may cause osteomA1Ac~A, oste~dya~rophia, ~ athy, ~17h~mer disease etc. These ~-C?~vantages are described by C.Gitzinger, Fortschritte der Me~ n, 105, 3/Suppl.19/,1987; and by W.Kurtz, ibid. 105, 5/Suppl.19/,1987.

According to EP-A1-220,849, the proh~h~l1ty of aluminium absorption and h~nc~ of unwanted side effects is increased with decreasing the final pH in the aluminium-based (e.g.
aluminium hydroxide, magnesium-aluminium-hydrate, m-~1drate etc.) liquid preparation ~oral suspension) to pH=2.20-3.25 assuming cytoprotective effects.

According to US-A-4,704,278, the same consequence occurs when the system contains a significant amount of citrate, which is ~Ae~ partly from a colloidal point of view, partly to ensure a quick start of the action. All factors increas-WO94n~us PCT~4J~ ~

2 21~3~

ing the solubillty of all~m~nium ~v...~uu~s, such as thecitrate ion, increase the risk of aluminium absorption.

The process according to US-A-4,639,362 ~lo~es combined molecules of r-gn~s~um and aluminium ~ ents such as mag-aldrate), in which the aluminium content is lower than in the,usual antacid formulae. On the other hand, the higher n~c~l~m content may result in an undesired laxative effect.
1t) ' It has therefore been one object of the invention to provide an antacid and/or adstringent and absorbent rhAr~-ceutical preparation which avoids the drawbacks related to the ab-sorption of aluminium in the hody of a patient. Another ob-~ect of the invention relates to the provision of a phAr~-ceutical preparation with sustA~ne~ release of the antacid and/or adstringent and ~b~ t compounds.

~UMMARY OF THE lN v~ N
These objects are achieved by the inventive measures based on the surprising novel reco~n~tion that the dissolution of ~t~o~t~hl~ aluminium in aqueous media can -s;gn;ficantly be decreased or completely ~nh~h,ited by applying certain types of macromolecular hydroco~ and water-soluble and/or water-insoluble ~o~ ate compounds in the presence of each ''other. ~

This pheno~enon was observe,d in every case, i.e. in a tablet as well as in a suspension preparation, when the aluminium compound was ~rrl~ed and treated in mixture with at least one hydrocolloid of limited swelling ability and at least one water-soluble and/or water-insoluble phosphate compound, resulting in a limited or ;nh~b;~ted aluminium release due to the contact with gastric fluids by swel~;ng of the hydro-colloid. The limited swel1~ ng ability is influenced by the pH and the presence of A13+ and can be characterized for the WO 51'2l't6B 21 3 8 4 3 7 ~,00829 various hydlo~ollo~ds by viscosimetry. ~sually, about 10% of the hydrocolloids - given as ~Y~mr1es hereinafter - are in-deed swelled.

The pr~nc;r1e of the invention is a phosphate delivery system controlled by the swe11;ng ~orh~n;sm of the hydro-colloid.
BRIEF DESCRIPTION O~ THE DRA~INGS

In Fig.1, the top left rectangle symbolizes the magaldrate example. FYC~CS acid (AC) in the gastric fluid is neutr~;7-eA ~N) by the OH--flux. The resulting Al3l-flux is bound by the rho~rhAte P and the swelled (arrow B) l.~h~o11o~A HY to the phosphate/hydro-col1o~A/aluminium system tPHAS). The phosphate/
hydroco~ A system (P+HY) controls the ~icso1ution and h;nA;ng of the aluminium as shown in Fig.2 (left of the dotted line: stomach ST; right of the dotted line: intestlnes IN) partly through an oscil-lating reaction mech~n~-~ inf~ nce~ by the change of the intragastric pH-value, partly by h;nA;n~ the aluminium to the ~dLo~o11o~, advantageously to a crQs-s1~nked polymer.
Fig.3 shows the pr;nc~rle of the aluminium capture based partly on the c~;ficant difference in the sol~bility of aluminium hydroxide and aluminium phosphate; partly, it is also based on the function of the hydrocolloid-phosphate system, which binds the aluminium and is activated by the swelling of the hydrocolloid. ~he described aluminium capturing system does not decrease the acid neutralization ca-pacity of the aluminium ~o,u~ d at the acidic pH of the stomach (ST) but ;nh~h' ts the absorption of alu-minium from the stomach (ST~ and the duodenum (inte-stines (IN), see Fig.2) of higher pH.

W094~ 2 1 5 ~ ~ 3 7 PcTn~

Fig.4 demonstrates the function of the control me~h~n;~m by exyerimental observations obt~;n~ from the pH-potentiometric titration. When titrating 500 ml o~ a 0.01 M HCl solution (p~=2) with 1.0 M NaOH in the presence of several ~-0 ~L~'~nts (AlCl3, Nymcel ZSB10(R) as hydrocolloid of limited swel1~ng abil-ity, NaH2P04.2aq), the pote~tiometric curves differ.
Curve 1 ~s~gn~tes S00 ml 0.01 N ~Cl solution con-t~in~n~ 0.01 mol AlCl3; Curve 2 designates 500 ml 0.01 N HCl solution cont~ g 0.01 mol AlCl3 and 0.001 mol NaH2P04; Curve 3 deci~n~tes 500 ml 0_01 N
ECl solution cont~n~n~ 0.01 mol AlCl3 and 1 g Nymcel ZSB-10(R); Curve 4 ~nS~ qn~tes 500 ml 0.01 N
~Cl solution cont~n~ng 0.01 mol AlCl3, 1 g ~ymcel 2SB-10(R) and 0.001 mol NaH2P04.The inflexion point of the potentiometric curve is at much lower alkali consumption in the case of the AlCl3-hydrocolloid-~ oxyllate com~nn~nts.
In vivo experimental data of human male volunteers demon-strate the decrease in the.aluminium aLa~ly~ion (Table 1~:
The mixture according to the invention may be prepared by first swell~ng the water-sw~ h1e compound of limited swel-ling ability in water and thereafter admixing thereto or em-_ . he~in~ in it a powder comprising at least one of the yLo~cons;-cting of 100 parts ~y weight of aluminium ~v~ d~ 2-150 parts by weight of at least one phosphate ~ d, and at least one al~Yi ry material. The ~l~eL combination of the hydrocolloid with the phosphate e~ ~u~d results in the desired sust~ine~ release effect.

On the other hand, a tablet preparation may also be produced wherein the ~ ~u"ents are mixed under dry conditions whereby the sw~ q and sust~ine~ release occurs in the digestive system. On the other hand, the final mixture may be transformed into a suspension or filled into capsules.

WO 5~ ?C~ 5 . 2 1 ~ 7 /E~/00829 Table I. - rh~ngQ of the al-~m~nium amount excreted by the urine of S pat~ents o~er 24 hours after administration of 750 mg mag-l~rate compared to the control ~alue of the pre-~ious day:
yg Al/24 h e1ir1n~ted by urine Subject magaldratemagaldrate with the phosphate-hy~lo~olloid . system acc. eYAmrle 3 #1 + 13.8 + 8.6 ~2 ~ 19.2 + 9.0 #3 + 4.0 - 7.1 #4 1 13.0 - 22.2 #5 ~ 18.0 ~ 14.0 Average: ~ t3.6 + 0.~6 Sx (S.E.M) 2.677 ~g 6.683 yg t-value e~Limental 5.081 0 0688 prnhA~ ty <o o5 ~0.05 Difference siqnlficantnot si~nificant Sx (S.E.M.) is the st~n~Ard deviation of the mean value;
the t-value is the Student-t at 5% significance level.

The aluminium compound may be selected from a wide range of inorganic and org~n~c salts or complex compounds, such as all~minium l,yJL~lde, aluminium glycinate (dihydroxyaluminium 2S a~ino~c~tate hydrate, USP XXII p. 445), alumini-lmso~;um trisilicate, aluminium l~yJlo~ye~rhQnAte-(dihydroxyaluminium sodium cArh~n~te, USP XXII p.447~, basic aluminium carbonate gel (USP XXII p.50), aluminium phosphate (USP XXII p.53), aluminium ~gnec~um silicate (B.P.), natural or synthetic aluminium- and magnesium-~ontA;n;n~ co..~ ds, preferably aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminium~gn~ium hydlo~ysulphate (magaldrate).

The water-swell~hle ~ ~.ds may be selected from the group comprising cellulose glycolic acid, starch glycolic acid, polyacrylic acid, copolymers of acrylic acid-methacrylic acid, alginic acid (poly~-nn11ronic acid, USNF XVII), poly-wog4n~ PCTn3~l~829 6. 2158437 vinylpyrr~ one, calcium alginate (~PC), sodium a1ginate(USNF XVII), r~rhsr~l(R) 934P (carbomer, USNF XVII), carb-oxymethylcellulose calcium ~USNF XVII), cA-~o~ymethylcellu-lose sodium (carmellose, USP XXII), carrageenan (USNF XVII), croscarmellose sodium (USNF XVII,Ac-Di-Sol(R)), cross-linked polyvinylpyrro1t~on~ (USNF XVII, Polyplasdone XL(R)j, hydrox~ ylmethylcellulose (USP XXII), c~o~ymethylcellu-lose sodium of low substitution grade (Nymcel ZSB-10(R)~, sodium starch glycolate (USNF XVII, Primojel(R)), tragacanth (USNF XVII), xanthan gum (USNF XVII).

The rho~rhate compound may be selected from the group com-prising mono-, di- and tribasic calcium phocrhAte; m-ono-, di- and trthA~tC m7gnectum phosphate; mono- a.nd ~;b~-c;c sodium ~llo~Late; mono- and ~;h~s~c potassium phosphate;
mono- and ~;c~lct um glycerophosphate.

Al~Y;1;Ary materials may be disintegrants such as starch, mlcrocellulose, cross-1~n~e~ polyvinylpyrro1 t ~Qne etc.;
tableting aids, such as lubricants, e.g. talc, magnec;um stearate etc.; sweeteners such as c~crh~rose~ glucose, sac-charin-sodium, sodium cyclamate, aspartame etc.; flavouring agents such as lemon, orange and c~ssic aroma; fillers such as lactose.
DETAI~ED D~CRIPTTON OF q~ lN v~Nll0N

The invention is further exp1~eA by way of the following ~Y~r1es.
Example 1 500g hydrotalcite and 70g tribasic calcium phosphate powder (c-~ ~n,-.ents of the ~nner phase) are ho,--oye~lized. 90g of cross-linked polyvinylpyrrolidone are swelled with 60-75 ml water (required for wet granulation) during 2 hours and then ~;Ye~ with the powder mixture and kneaded. The wet mass is granu~ated ~y passing it through a sieve with openings of wo g4n~s ?~ 15 g 4 3 ~ ~JE~/0082g ~. .
1.4 mm. The granules are dried to a moisture content of 2.~%
and then regr~n~ ted through a sieve with openings of 0.8 mm. 10g of cross-llnked polyvinylpyrr~ one~ 20g talc and 10g mAg~esium stearate ~powder .~ ents of the outer phase) are passed through a sieve with or~n~ngs of 0.32 mm and m~Yed with the dry granules. The mixture is compressed to give 1000 tablets each of 0.7 g average weight.

Example 2 The same y ~ e is followed as i-n Example 1 with the following compounds (for 1000 tablets o~ 0.75 g average weight eachJ:
Inner phase: All~m1njum hyd~y~rho~Ate 600 g tr~b~g~ magnesium ~ Ate 34 g ~rh~Yymethylcellulose sodium of low substitution grade 10 g cross-l ~ nke~ ymethyl-cellulose sodium (Ac-Di-Sol(R)) 10 g water 80-100 ml 20 outer phase: potato starch (disintegrant) 50 g talc 24 g m~n~sium stearate 12 g Nymcel ZSB 10(R) 10 g Example 3 The same ~L~ C~ e is followed as in FY~rle 1 with the following ~o~ds (for 1000 tablets of 1.3 g average weight each): - J
Inner phase: magaldrate 750 g dibasic calcium phosphate 450 g Nymcel ZSB 10(R) 273 g water 80-100 ml outer phase: magnesium stearate 25 g Nymcel ZSB 10~R) 200 g water 80-100 ml O 94m268 2 15 ~ 4 ~ 7 J~/En4/00829 - 8.

~Y~m~le 4:
The same ~Locedule is followed as in ~Y~rle 1 with the following ~ o~lds (for 1000 tablets for 1.5 g average weight each):
5 Inner phase: aluminium hyJLu~ide 375 g tribasic calcium phosphate100 g Nymcel ZS8 10(~) 200 g water 80-100 ml outer phase: mi~ w.y~L~ ne c~ l~ce Avicel PH 102(R) 825 g Example 5 The same y~ e is ~ollowed as in Example 4 with the following compounds (for 1000 tablets of 1.5 ~ average weight each), with the e~e6~Lion that double-layered tablets are formed. The antacid active ingredient is pressed as the first layer, onto which the second layer cont~;n~n~ the other ~J ,L~nts and the miclo~y~t~ ne cellulose is pressed:
First layer: aluminium hydroxide 375 g ml~ Lys~Alltne cellulose (Avicel PH 102(R)) 400 g second layer:Ny~cel ZSB 10~R) 200 g tribasic calcium phosphate100 g water 80-100 ml micsG~ly~t~ e cellulose (Avicel PH 102(R)) 425 g Example 6 The same procedure is followed as in ~Y~mrle 4 - with the exception that three-layered tablets are formed - with the following compounds (for 1000 tablets of 1.5 g average weight each~: ~

og4n~ 2 1$ 8 4 31 9.

First layer: Aluminium hy~roxide 375 g micL~,y~tA11~ne cellulose (Avicel PH 102(R)) 400 g second layer:Ny~cel ZSB 10(R) 200 g mi~.o~ly~t~11ine cellulose (Avicel PH 102(R)~ 250 g water 80-100 ml third layer: tribasic calcium phosphate 100 g mi~ o~Ly~t~All~ne cellulose (Avicel PH 102(R)) 175 g Example 7 The same proc~3~e is fo11o~1od as in ~Y~mr1e 4 - with the ion that the part~c1~s of the rhoc~hAte.~G.~ d are coated by ~ ying on them (and afterwards drying) an i~o~Lo~.An~1~c solution of Eudragit L100-55 - with the following compounds (for 1000 tablets of 1.5 g average weight each):
Inner phase (aluminium):
aluminium hydroxide 375 g inner phase (phosphate):
tr~b~s~c calcium phosphate 100 g coating:
Eudragit ~ 100-556 7.5 g i~v~or~o1 60 g Nymcel ZSB 10(R) 200 g water 80-100 ml outer phase: mic~u~ysta11~ne cellulose (A~icel PH 102(~)) 82S g Example 8 The same ~L v~edUre iS followed and composition used as in ~x~rle 7 with the exception that the tribasic calcium phosphate is coated with a solution of 4.5 g celluloseacetatephtalate in 30 ml of acetone.

WO94~LU~ 2 1~ 8437 PCT~4/Oo~s 1~ '.
Example 9 1000 ml of an antacid suspension are prepared, having the following composition:
magaldrate . 200 g 5 cross-linked caL~o~ymethylcellulose sodi~m (Ac-Di-Sol(R)) 50 g tribas~c calcium phosphate 75 g tribasic magnesium phosphate 75 g hydroxy-~o~lmethylcellulose 4000 12 g 10 methylparaben 10 g alcohol 10 g water, ~e~0~17-ed to 1000 ml AC-D~-soltR) is swelled in a 2% solution of the viscosity incr~tn~ agent HPMC 4000 (vis~oc~ty 4000 cP); then, the 1~ hom~ywlo~ mixture of the various powder components is su~u~ed ln it. Finally, the alcnholic solution of the microbiological preservative (methylparaben) is ~d~ed.

Example 10 Example 9 is repeated ~ that the composition differs as follows:
aluminium hydr~ide 100 g n~c acid 140 g r~nnb~i c sodium ~huayl~ate 140 g 25 hydroxy-~ upylmethylcellulose 4000 12 g ~-o~ylparaben 2.5 g methylparaben 2.5 g alcohol 10 g water, deionized to 1000 ml The alginic acid is first swelled in the acidic hydroxy-propylmethylcellulose solution cont~;ning monobasic sodium phosphate to ~Lv~uce the limited swell;ng form o the hydrocollo~d.

Example 11 The following powder components for 1000 capsules:

wo g4m268 1 1 21 S ~i 4 3 7 PCT/EP94100829 . r aluminium hydroxide250 g mo~ob~sic sodium phosphate 100 g alginic acid 100 g are mixed and granulated in the dry state or by adding water and drying; then, 0.5 g Aerosll R972(R) lubricant is mixed with the dry granules. A 0.40-0.45 g portion of the mixture is filled into a hard gelatine capsule.

Example 12 A tablet preparation with antacid and adstringent effect is formulated with the following composition for 1000 tablets:
aluminium ~ko~i~P 500 g aluminium glycinate 500 g cellulose glycolic ac~d 250 g 15 C~rhsro~ g34p(R) 25 g trtb~s~c magnesium phosphate 100 g magnesium stearate 23 g Aerosil ~972(R) 2 g The ~ ~e~s is completed in the usual way: the cellulose glycolic acid is swelled in the ~r~crol 934p(R) solution.
This liquid is used for the wet granulation of the powder - mi~ule. The tablet preparation is formed as described in Example 1.

Claims

C L A I M S

1. Process for the manufacture of a pharmaceutical preparation containing at least one aluminum compound for antacid and/or adstringent and absorbent action, at least one water swellable compound, and at least one phosphate compound, characterized in that 2-300 parts by weight, preferably 20-150 parts by weight, of the water-swellable compound(s) are swelled with 2-50 parts by weight of water, preferably for about two hours, whereafter a mixture comprising 100 parts by weight of said at least one aluminium compound and 2-150, preferably 20-75, parts by weight of said at least one phosphate compound is added and mixed with the swelled compound(s).

2. Process according to claim 1, characterised in that at least one of said water-swellable compound(s) is of limited swelling ability, preferably selected from the group consisting of cellulose glycolic acid, starch glycolic acid, alginic acid, calcium alginate, carboxy-methylcellulose calcium, croscarmellose sodium, cross-linked polyvinylpyrrolidone, carboxymethylcellulose sodium of low substitution grade, and sodium starch glycolate.

3. Process according to claim 1 or 2 with at least two water swellable compounds, characterised in that at least one water-swellable compound is selected from the group consisting of polyacrylic acid, copolymers of acrylic acid-methacrylic acid, polyvinylpyrrolidone, sodium algi-nate, carbomer, carboxymethylcellulose sodium (carmellose), carrageenan, hydroxypropylmethylcellulose, tragacanth and xanthan gum.

4. Process according to any one of the preceding claims, characterised in that said aluminium compound is selected from the group consisting of aluminium hydroxide, aluminium glycinate (dihydroxyaluminium aminoacetate hydrate), aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate), basic aluminium carbonate gel, aluminium phosphate, alu-ium magnesium silicate, natural or synthetic aluminium- and magnesium-containing compounds, such as aluminiummagnesium hydroxycarbonate (hydrotalcite) and alumlniummagnesium hydroxysulphate (magaldrate).

5. Process according to any one of the preceding claims, characterized in that said phosphate is selected from the group consisting of mono-, di- and tribasic calcium phosphate; mono-, di- and tribasic magnesium phosphate;
mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono- and dicalcium gly-cerophosphate

6 Process according to any one of the preceding claims, characterized in that the particles of said phosphate compound(s) are coated - per 100 parts by weight of said phosphate compound(s) - with 2.5 to 15 parts by weight of a sustained release coating material.

7. Process according to any one of the preceding claims, characterized in that at least one auxiliary material selected from the group consisting of tableting vehicles, diluents, sweeteners and flavouring agents is further added to the mixture.

8. Process according to any one of the preceding claims, characterized in that the mixture is granulated and dried and thereafter preferably pressed to tablets or filled into capsules.

9. Process according to any one of claims 1 to 7, characterized in that the mixture is transformed into an aqueous suspension.

10. Pharmaceutical preparation containing at least one aluminium compound for antacid and/or adstringent and absorbent action, at least one water swellable compound, and at least one physiologically acceptable phosphate compound, said preparation preferably being obtained by the process of claim 1, characterized in that 100 parts by weight of said at least one aluminium compound and 2-150 parts by weight, preferably 20-75 parts by weight, of said at least one phosphate compound are embedded in 2-300 parts by weight, preferably 20-150 parts by weight, of a water-swelled portion of said at least one water-swellable compound, for sustained release of the antacid and/or adstringent and absorbent compound(s) to the stomach and inhibited absorption of aluminium ions by the gastro intestinal tract.

11. Pharmaceutical preparation according to claim 10, characterized in that the water swellable compound is se-lected from the group consisting of hydrocolloids, syn-thetic polymers and natural polymers.

12. Pharmaceutical preparation according to claim 10 or 11, characterized in that at least one water swellable compound is of limited swelling ability, preferably being selected from the group consisting of cellulose glycolic acid, starch glycolic acid, alginic acid, calcium algi-nate, carboxymethylcellulose calcium, croscarmellose sodium, cross-linked polyvinylpyrrolidone, carboxymethylcellulose sodium of low substitution grade, and sodium starch glycolate.

13. Pharmaceutical preparation according to any one of claims 10 to 12 with at least two water swellable compounds, characterised in that at least one water-swellable compound is selected from the group consisting of polyacryllc acid, copolymers of acrylic acid-methacrylic acid, polyvinylpyrrolidone, sodium alginate, carbomer, carboxymethylcellulose sodium (carmellose), carrageenan, hydroxypropylmethylcellulose, tragacanth and xanthan gum.

14. Pharmaceutical preparation according to any one of claims 10 to 13, characterised in that said aluminium salt is selected from the group consisting of aluminium hydroxide, aluminium glycinate (dihydroxyaluminium amino-acetate hydrate), aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate), basic aluminium carbonate gel, aluminium phosphate, alu-minium magnesium silicate, natural or synthetic aluminium- and magnesium-containing compounds, such as aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminiummagnesium hydroxysulphate (magaldrate).

15. Pharmaceutical preparation according to any one of claims 10 to 14, characterised in that said phosphate compound is selected from the group consisting of mono-, di- and tribasic calcium phosphate; mono-, di- and tribasic magnesium phosphate; mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono-and dicalcium glycerophosphate.

16. Pharmaceutical preparation according to any one of claims 10 to 15, characterised in that the particles of said phosphate compound(s) are coated - per 100 parts by weight of said phosphate compound(s) - with 2.5 to 15 parts by weight of a sustained release coating material.

17. Pharmaceutical preparation according to any one of claims 10 to 16, characterized in that it further comprises at least one auxiliary compound selected from the group consisting of tableting vehicles, diluents, sweeteners and flavouring agents.

18. Pharmaceutical preparation according to any one of claims 11 to 17, characterized in that it is in the form of a tablet, a suspension or contained in a capsule.

19. Pharamceutical preparation manufactured according to any one of claims 1 to 9.