Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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.
