United States Patent [19] [11] Patent Number: 4,885,281

Hanstein et al. [45] Date of Patent: Dec. 5, 1989

[54] SUCRALFATE SUSPENSION [52] US. Cl. ....................................... .. 514/53; 514/54

[58] Field of Search ............................ .. 514/54, 23, 53
[75] Inventors: Ullrich Hanstein, Miihltal; Lothar
Bauer, Pfungstadst, both of Fed. [56] References Cited
Rep. of Germany FOREIGN PATENT DOCUMENTS
[73] Assignee: Merck Patent Gesellschaft mit 0055313 7/1982 European Pat. Off. .
beschriinkter Haftung, Darmstadt, 0107209 2/ 1984 European Pat. Off. .
Fed. Rep. of Germany
Primary Examiner-Amelia Burgess Yarbrough
[21] Appl. No.: 171,347 Assistant Examiner-Elli Peselev
[22] Filed: Mar.21, 1988 Attorney, Agent, or Firm-Millen, White & Zelano
[57] ABSTRACT
Related US. Application Data
The invention relates to formulations in the form of
[63] Continuation-impart of Ser. No. 878,869, Apr. 22, suspensions containing sucralfate, characterized in that
1986, abandoned. they contain, based on the sucralfate, 1-5% by weight
[30] Foreign Application Priority Data of xanthan gum and l-12.5% by weight of at least one
Aug. 22, 1984 [DE] Fed. Rep. of Germany ..... 1. 3430807
peptiser.
[51] Int. cu ............................................ .. A61K 31/70 4 Claims, No Drawings
 4,885,281
1 2 r
viscosity, such as glycerol, propanediol, sorbitol solu
SUCRALFATE SUSPENSION tion and/or liquid polyethylene glycols, and by incor
porating suspending agents and thickeners. Agents of
This application is a continuation in part of applica this type which increase the viscosity and prevent sedi
tion Ser. No. 878,869 filed Apr. 22, 1986, now aban mentation of the solid particles are usually high molecu
doned. - lar weight cellulose derivatives or polysaccharide
The invention relates to pharmaceutical formulations gums, such as, for example, carboxymethylcelluloses,
in the form of suspensions containing sucralfate as the methylcelluloses, alginates or tragacanth.
pharmaceutical active compound. Numerous attempts have been made, with only little
Sucralfate (Ulcogant( )) is a basic aluminium su or no success, to achieve the object of developing a
crose sulfate. It is known from German Offenlegungss stable sucralfate suspension which does not sediment.
chrift 1,568,346 and is used in human medicine for re For this, the essential familiar suspending agents and
lieving the symptoms of gastric and duodenal ulcers and thickeners customary in the technology of pharmaceuti
for accelerating the healing of ulcers. An advantageous cal suspensions and corresponding auxiliaries and addi
action of sucralfate in combating emesis and/or diar tives were tested. It was found that, evidently due to the
rhoea in veterinary medicine has moreover been de property of the sucralfate of releasing Al3+ ions in an
scribed in German Patent Application P 3,322,078. aqueous medium, interactions are induced with virtu
The action of sucralfate is characterised by pepsin ally all the thickening substances, and these sometimes
binding and antacid effects. Sucralfate, which is toler lead to drastic decreases or increases in viscosity and to
ated very well, displays its action in the acid medium of 20 precipitation of the thickeners. This means that the
the digestive tract, in particular at pH values below 4, sucralfate particles in such suspension formulations
where it lines the mucous membranes of the stomach sediment very rapidly, forming lumpy precipitates
and duodenum with a protective coating. As a result of which deposit and stick to the walls of the packaging
its preferential binding affinity for areas of the mucous material and can no longer be shaken up.
membrane which have been attacked, increased protec 25 It has been found that, surprisingly, stable formula
tion and accelerated healing of ulcers as well as regener tions can be obtained in the form of suspensions contain
ation of the mucous membrane and its functions occur ing sucralfate if l5% by weight of xanthan gum and
there. ll2.5% by weight of at least one peptiser, based on the
Formulations containing sucralfate have hitherto content of sucralfate, are added to these formulations.
usually been employed only in the form of solid admin The invention accordingly relates to pharmaceutical
istration forms, such as tablets, granules or powders. formulations in the form of suspensions containing su
However, liquid formulations, for example in the form cralfate, which have a content, based on the sucralfate,
of suspensions, would be advantageous for the particu of l5% by weight of xanthan gum and ll2.5% by
lar mode of action of sucralfate, especially in view of a weight of at least one peptiser.
rapid and complete lining of the mucous membranes in The invention particularly relates to such a pharma
the digestive tract. It is indeed possible to suspend the ceutical formulation in which the peptiser is at least one
commercially available solid administration forms, for salt of phosphoric acid and/or citric acid.
example in water, before use and to take them in this The invention moreover relates to a method of stabi
form. However, this proves to be inconvenient and is lising pharmaceutical formulations in the form of sus
frequently found to be unpleasant in taste for the patient 40 pensions containing sucralfate, l-5% by weight of xan
taking the medicament, and is thus not very practicable. than gum and ll2.5% by weight of at least one pep
Attempts to prepare sucralfate-containing ?nished med tiser, based on the content of sucralfate, being added to
icaments in the form of suspensions have hitherto failed, these formulations.
'since no suspensions which are stable for a prolonged Xanthan gum (Polysaccharide 1459) is a high mo
period could be obtained with the customary auxiliaries. lecular weight polysaccharide which can be obtained
In such suspensions, the solid sedimented out after a by fermentation of carbohydrates with Pseudomonas
short time and formed lumps to such an extent that in microbes, especially with Xanthomonas campestris, and
some cases it could not be shaken up again. is usually in the form of its alkali metal and/or alkaline
The invention was thus based on the object of discov earth metal salts. It is known that xanthan gum, inter
ering a method of stabilising pharmaceutical formula alia, can also be used as a suspending agent and thick
tions in the form of suspensions containing sucralfate, ener for pharmaceutical and cosmetic products (see H.
and a corresponding stable formulation as the finished P. Fiedler, Lexikon der Hilfsstoffe (Lexicon of Auxilia
medicament. ries), page 1016, 2nd edition (1981) or The United States
For the formulation of pharmaceutical suspensions, Pharmacopeia, Twentieth Revision (1980)). Thus a
attempts are made to prevent sedimentation of the sus 55 basic aluminium salt of xanthan gum is known as a phar
pended particles, or at least to keep the sedimentation as maceutical excipient, as well as the use thereof as a
low as possible, by suitable additives. This is to ensure suspending agent for barium sulfate in radiographic
that the agent remains homogeneous and can be used contrast media (compare Chemical Abstracts 79 (1973)
appropriately even after prolonged storage. If sedimen 23582m and 81 ( 1973) 964611;). On the other hand, how
tation nevertheless takes place in the course of time, it 60 ever, work is also known in which xanthan gum is used
should be ensured that the solid can readily be shaken for flocculating metal oxides, hydroxides, carbonates, in
up. Moreover, suspensions for oral use should be given, particular also of aluminium, from suspensions (Chemi
as far as possible, a pleasant or at least neutral taste. In cal Abstracts 94 (1981) 52786w, 95 (1981) 12692b and 96
particular, the solid content should be incorporated (1982) 247262). From the prior art, it could thus not be
such that this or the solid particles are not found to be 65 assumed that xanthan gum is generally suitable for stabi
troublesome when the suspension is taken. In the case of lising pharmaceutical suspensions containing sucralfate.
aqueous suspensions, the properties mentioned can usu Rather, it was found in the numerous experiments car
ally be achieved by adding liquids which increase the ried out that a satisfactory solution of the problem was
 3
4,885,281
4
hardly to be seen in xanthan gum, as in all the other secretion-inhibiting drugs. These also include those
usual thickeners, even in combination with other auxil aminoacids described in European Patent Al-0,l07,209
iaries and additives customary in the technology of which intensify the effect of sucralfate in lining the
pharmaceutical suspensions. mucous membrane or which are to retain this effect in
The result that a combination of the medicinal sub the case of adverse storage conditions of corresponding
stance sucralfate, the thickener xanthan gum and at least products.
one peptiser leads to a stable sucralfate suspension The sucralfate suspensions according to the invention
which ful?ls the requirements of galenics and of medici are prepared in a manner which is known per se, by
nal use in an outstanding manner if the amounts in the mixing the components and homogenising. They can
composition are chosen according to the invention was then be ?lled into the customary means of packaging for
all the more surprising. pharmaceutical suspensions, such as, for example, bot
The sucralfate used for the preparation of the sucral tles, drinking ampoules or portion packs for oral or
fate suspensions according to the invention is a familiar rectal administration. The active compound remains
pharmaceutical active compound and is used here pref suspended for a storage time of any desired length,
erably in the ?nely ground form with a particle size of without sedimenting irreversibly and without forming
below 50 pm. lumps or precipitating on the walls of the vessel.
The xanthan gum used, according to the invention, as The medical ?eld of application of the sucralfate
the suspending agent and thickener can be prepared on suspensions according to the invention is completely
an industrial scale by fermentation processes and is analogous to that for the known administration forms
commercially available in accordance with the quality 20 containing sucralfate as the active compound, in partic
speci?cations of the pharmacopoeias of various ular protection and healing of mucous membranes
countries. which have been attacked in the digestive tract in hu
The peptisers to be added, according to the invention, mans, in particular relief of symptoms and healing in
to the suspension are salts of inorganic or organic acids, cases of gastric and duodenal ulcers. However, the
which are intended to ensure that the high molecular 25 agent can also be advantageously used in veterinary
weight additive xanthan gum remains in the sol state, medicine for combating emesis and/or diarrhoea. For
that is to say in homogeneous distribution, in disperse corresponding treatments, the suspension is usually
systems such as the present suspensions, and does not administered orally in a dosage analogous to the known
separate out by gel formation. These peptisers can be, administration forms of sucralfate. If appropriate, how
for example, physiologically acceptable salts of phos 30 ever, such suspensions can also be administered rectally.
phoric acid, citric acid or other tribasic acids. Salts of This is a particular advantage of the sucralfate suspen
phosphoric acid and citric acid are particularly suitable sions according to the invention, since this type of use
here. Sodium dihydrogen phosphate is particularly pre was virtually impossible with the previously known
ferred. forms of administration.
According to the invention, 1-5% by weight of xan
than gum and ll2.5% by weight of at least one pep EXAMPLE 1
tiser, based on the content of sucralfate, are added to the 5 ml of an oral suspension with 20% by weight of
sucralfate suspensions for effective, permanent stabilisa sucralfate contain
tion. The content of sucralfate in these formulations can
vary within wide limits.
As a rule, such suspensions can contain 140% by sucralfate 1.118 g
weight of sucralfate, based on the total amount. Typical NaH2P04 0.03 g
xanthan gum 0.02 g
formulations of sucralfate suspensions according to the glycerol 0.50 g
invention contain, based on the total amount, l40% by sodium methyl-4-hydroxybenzoate 0.0025 g
weight, preferably l025% by weight, of sucralfate, 45 sodium propyl-4-hydroxybenzoate 0.0025 g
0.0l2% by weight, preferably 0.l-l% by weight, of aromatic substances q.s.
water to 5 ml
xanthan gum and 0.0l-5% by weight, preferably
O.l-3% by weight, of peptiser. Besides water as the
liquid medium, the suspensions according to the inven
tion can also contain liquids which increase the viscos EXAMPLE 2
ity, preferably glycerol or propanediol, in an amount of 100 ml of a rectal suspension with 10% by weight of
l-50% by weight, preferably 10-20% by weight. More sucralfate contain
over, the addition of other auxiliaries and additives
customary in the technology of pharmaceutical suspen
sions is possible. These chie?y include preservatives, sucralfate 11.18 g
55 NaHZPO4 0.40 g
such as, for example, sodium methyl-4-hydroxybenzo xanthan gum 0.19 g
ate and sodium propyl-4-hydroxybenzoate, which are glycerol 10.00 g
added together or individually in the usual concentra sodium methyl-4-hydroxybenzoate 005 g
sodium propyl-4-hydroxybenzoate 0.05 g
tions of, for example, about 0.1% by weight. Flavour water to 100 ml
improving aromas, sweeteners and ?avour correctants
can also be added. Additives of this type as a rule
scarcely exceed a content of 1% by weight, based on EXAMPLE 3
the total amount. Other active compounds can also be
added to the sucralfate suspensions according to the 5 ml of an oral suspension with 19% by weight of
invention, for example those with which it is known 65 sucralfate contain
that sucralfate can be combined, such as, for example,
antacids, spasmolytics, anti?atulents, Hz-receptor sucralfate 1.099 g
blockers, non-steroid antirheumatics and generally acid NaH1P042H2O 0.025 g
 4,885,281
5 6
_continued xanthan gum and l12.5% by weight of at least one
peptiser.
Kamila sum 0-025 3 2. Pharmaceutical formulations according to claim 1,
glyceml 1-000 5 characterised in that the peptiser is at least one salt of
sodium methyl-4-hydroxybenzoate 0.00375 g 5 phosphoric acid or citric acid
sszglifaglgiayliphydmybenzm 0%: g '3. Pharmaceutical formulations according to claim 1
aromatic Substances 00019 g or .2, characterlsed in that they contaln 140% by
water to 5 m1(=5_775 g) weight of sucralfate, based on the total amount.
4. Method of stabilising pharmaceutical formulations
_ 10 in the form of suspensions containing sucralfate, charac
We claim: terised in that 1-5% by weight of xanthan gum and
1. Pharmaceutical formulations in the form of suspen l-12.5% by weight of at least one peptiser, based on the
sions containing sucralfate, characterised in that they content of sucralfate, are added to these formulations.
contain, based on the sucralfate, 1-5% by weight of * t t * i

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 UNITED STATES PATENT ANDYTRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT N0. :4,885,28l
DATED :Deca'nber 5, 1989
INVENTUIHS) : ULLRICH HANSTEIN E1 AL
It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
corrected as shown below:

Title page, Foreign Application Priority Data:

reads "Aug. 22, 1984 [DE] Fed. Rep. of Gemany.......3430807"
should read -Aug. 22, 1984 [DE] Fed. Rep. of Gennany....Q..3430809-

Signed and Sealed this

Fifteenth Day of January, 1991

Attest:

HARRY F. MANBECK. JR.

Arresting O?icer Commissioner nfPalents and Trademarks