Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
20~3369
Galactomannan derivatives for coating or embedding medicinal~y
active substances
The preparation of hydrophilic polymers, for example
hydroxypropyl methylcellulose or carboxymethyl galactomannans
for the production of non-medicinal formulations containing
antimicrobial active substances is known (EP-A- 0,285,209).
Hydroxyalkyl ethers of polygalactomannans are moreover ~nown as
stabilizers for carbon-water mixtures (EP-A- 0,209,122) as well
as for the clarification of water (US patent No. 3,830,736). US
patent No. 3,740,388 relates to a process for the preparation of
carboxylalkyl ethers of polygalactomannans, it being possible to
use reaction products of this kind in the fo~m of complex
compounds with calcium as a thickening agent.
A number of galactomannan esters as well as galactomannan ethers
are also described in the literature. These galactomannan ethers
are, however, obtained using a very laborious process. What is
more, the average degree of substitution of these known products
lies between 0.1 and 1.6, that is, it is considerably lower than
the degree of substitution of the compound of the invention (see
Bartl, H., Falbe, J., Houben-Weyl Methoden der organischen
Chemie, Volume E 20/3, Thieme, Stuttgart, 1987; Carson, J.F.,
Maclay, W.D.,`J. Am. Chem. Soc., 70, 1948, 293; Heyne, E.,
Whistler, R.L., J. Am. Chem. Soc., 70, 1948, 2249).
Whilst the reference J. Am. Chem. Soc., 70, 1948, 2249 as well
as the reference Swanson, J.W., J. Am. Chem. Soc., 71, 1949,
1511 refer to methyl galactomannans with a higher degree of
substitution, the mannans prepared in this manner have a lower
molecular weight than those of the invention, i.e. although they
are methyl galactomannans, they have a substantially lower
molecular weight than the galactomannan derivatives of the
invention.
:
2~53~9
-- 2
The present invention therefore relates to new galactomannans,
the hydroxygroups of which are wholly or partially present in
the form of low molecular weight aliphatic, araliphatic and/or
aromatic ether or ester groups and in which 20 to 80~,
preferably 30 to 80% or 30 to 70%, in particular 40 to 60% or
also 45 to 55% of the mannose units present in the galactomannan
chain form connected mannose blocks of 2 to 20, preferably 5 to
20 mannose units, which are not substituted by galactose groups,
for coating and/or embedding solid and/or liquid active
substances which only release these active substances in the
colon or in the presence of glycolytic enzymes.
These galactomannans are preferably those, the ether groups of
which consist of C1-C6-alkoxy groups (in particular
C2-C4-alkoxy groups), phenyl-C1-C4-alkoxy groups or
phenoxy groups and where the ester groups consist of
C3-C22-alkanoyloxy groups, preferably C3-C16-alkanoyloxy
groups. The molecular weight of the galactomannans of the
invention lie between 104 and 1 o8 in particular 105 and
106 g
In statistical terms, the mannose/galactose ratio of the basic
galactomannan chain lies for example between 2 : 1 and 20 : 1,
preferably between 4 : 1 to 10 : 1. On average the free hydroxy
groups of the basic galactomannan in this case are 80 to 100%
etherified and/or esterified.
The straight basic chain of the galactomannans of the invention
consist of mannopyranose units in 1.4-linkage. The galactose
molecules are glycosidically linked to this chain via the
CH2-OH groups of the mannose links.
The new galactomannan derivatives of the invention can for
example be used to coat or embed medicinally active substances
or also to prepare foils.
20535~9
-- 3
The galactomannan derivatives of the invention are new. It
was surprisingly found that these galactomannan derivatives
of the invention only release active substances embedded
therein or coated by galactomannan derivatives of this kind
in the colon or only in the presence of glycolytic enzymes,
but not for example in the medium of the gastric juice or in
the medium of the small intestine.
The galactomannan derivatives of the invention are thus
particularly suitable for the preparation of medicinal
formulations where the active substances have to be or need
to be protected from the influences of gastric juice and
small intestine juice and these active substances are only
supposed to be released in the colon. Hitherto, it has
generally been necessary to administer the corresponding
active substances parenterally.
This object is not, or only inadequately, fulfilled by
hitherto known medicinal forms for the release of active
substances in the colon, in which the medicinal substances or
medicinal substance cores are coated with polymers or
embedded in polymers. The film coatings or embedding
materials used heretofore consist of conventional film
formers which are modified by cross linkage with azo groups
(Saffran et al., U.S. Pat. 4,663,308) or of mixtures thereof
(Rubinstein et al., J. Pharm. 30. 95 to 99 (1986)).
20~3-iG9
- 3a -
The working group around Saffran polymerized methacrylates
with various monomers such as styrol and an azo component
capable of polymerization, for example divinylazobenzene.
This was intended to produce cross linked polymers.
Degradation of these polymers in the colon could not be
shown, even after 8 days. Degradation within minutes or a
few hours is, however, required for the proposed purpose of
application. Moreover, primary aromatic amines as possible
degradation products constitute a possible toxicological
problem.
20~3~
The working group around Rubinstein used mixtures of various
polymethacrylates, in which the resulting film coatings change
their permeability or solubility depending on the pH value.
Active substances coated with these coatings or embedded in
these polymers can only be released in a diffusion-controlled
manner. Diffusion-controlled release is, however, too slow since
the time of release and absorption in the colon is limited. In
addition, the commencement of release is un~ortunately also
dependent on a rise in the pH value of the intestinal contents.
However, the pH value in the section of the intestine in
question is already substantially constant. This means that the
time at which release begins depends on the speed of transport
of the intestinal contents. Film coatings of this kind therefore
already begin to swell in the proximal or distal ileum and then
release the active substance in the Colon ascendens through the
~ilm coating swollen to its maximum extent. A medicinal form of
this kind leads at best to low and non-reproducible
bioavailability.
It is also extremely surprising that, it is possible in
accordance with the invention, to synthesize higher substituted,
film-forming galactomannans in one synthesis step which, on the
one hand, pass unscathed through the gastrointestinal tract and,
on the other hand, are quickly degraded in the colon. This was
also unexpected since the working group around Isogai had shown
that etherified polysaccharides with saturated aliphatic
substituents could only be obtained up to an average degree of
substitution of 2.5 (Isogai, A., J. Appl. Polym. Sci. 29, 3873 -
3882 (1984)). The film coatings made from higher substituted
ethylgalactomannans of the invention are, on the one hand, able
to survive the gastrointestinal tract unscathed. On the other
hand they are rapidly degraded in the colon. This was
particularly surprising because other working groups, for
example Wrick M.G., J. Polym. SCI. A-1, 6, 1965 (196~) refuted
the enyzymatic degradability of derivatized polysaccharides.
_ 5 _ 20~3~9
Hitherto known lower substituted galactomannans have sol~bility,
swelling and degradability properties which the galactomannans
of the invention do not have, especially in the colon.
In contrast, if the galactomannans of the invention are used to
coat or embed medicinally active substances, the medicinally
active substances reach the colon without loss of efficacy and
are only released there.
The invention also relates to a method for the preparation of
the new galactomannan derivatives in accordance with the claims.
The preparation of the galactomannan ethers of the invention is
carried out by reacting known, naturally occurring
galactomannans or synthetically prepared galactomannans with
molecular weights between 104 and 1 o8 g in an inert solvent
(for example dimethylacetamide, dimethylformamide, dimethyl
sulphoxide) with C1-C6-alkyl halides (for example
C2-C4-alkyl halides), to phenyl-C1-C4-alkyl halides or
phenyl halides at temperatures between 20 and 35C, optionally
in the presence of alkali. The halides may preferably be the
bromides. It is, however, also possible to use the chlorides or
iodides. Alkali is preferably added in the form of
alkalihydroxides, in particular NaOH.
The addition of alkali depends on the size of the batch. For
example in the case of a batch of 2.8 g to 3.2 g of
galactomannan, 110 g to 130 g alkali are used (for example in
the form of NaOH).
Less alkali is needed for larger batches (for example 1S% less),
for smaller batches, more alkali is needed (for example 5% to
10~ more~.
2053~69
It is also possible to obtain mixed ethers with the above
described process, i.e. ethers which contain alkyl radicals as
well as phenylalkyl radicals or phenyl radicals in the same
molecule, by using mixtures of the corresponding halide starting
substances as reaction components.
The esters of the invention must be prepared under anhydrous
conditions. ~he solvents that may be used are:
dimethylformamide, dimethylacetamide, dimethyl sulphoxide.
Esterification can also be carried out without solvents in the
melt. In this case, the polymer solvent can be the acylating
reagent or the reaction partner, for example alkaloyl halide or
alkaloyl anhydride.
The esterification reaction occurs for example at temperatures
between 70 and 160C, or at the boiling point of the solvent,
through reaction of the corresponding galactomannans with
molecular weights between 104 and 1 o8 g, with
C3-C22-alkanoyl halides, preferably C3-C16-alkanoyl
halides or C3-C22-alkanoyl anhydrides, preferably
C3-C16-alkanoyl anhydrides.
This acylation is expediently conducted in the presence of basic
compounds, such as pyridine.
The basic substances should be present in excess in relation to
the starting alkanoyl compound, for example in excess of 0.1 to
0.2 per Mol of the alkanoyl starting component.
The starting galactomannans used are for example naturally
occurring galactomannans, for example galactomannans of guar
seed flour, tara seed flour, locust bean gum.
The mannose-galactose ratio varies, depending on the plant of
origin, from 1 : 1 to about 7 : 1. In general it is between 2 :
1 and 4 : 1 or also 2 : 1 to 3 : 1. It is, however, also
2~53a69
-- 7 --
possible to adjust the mannose-galactose ratio of these star~ing
galactomannans at a hi~her level by treatin~ the polysaccharide
with alpha-galactosidase in the conventional manner (see for
example McCleary, B.V., Carbohyd. Res., 92, 269, (1981).
In addition to the mannose-galactose ratio it is also possible
to use the viscosity of an a~ueous solution of the
polysaccharide to characterize the starting galactomannans. The
viscosity depends on the molecular weight and hence also on the
degree of milling of the galactomannan-containing seeds. The
molecular weight of the galactomannans can be between 104 and
108 g depending on origin and method of measurement. By means
of milling it is possible to reduce the molecular weight of the
polysaccharides and to adjust to a desired range.
The desired molecular weight range is preferably 105 to 1 o6 .
In addition to the polysaccharide, commercially available
galactomannan-containing flours also contain about 5% of low
molecular weight sugar, 1% oily components, 3% cellulose and 5%
proteins. The galactomannan therefore has to be separated from
their accompanying substances. It is also necessary to purify
accompanying substances, such as proteins and lipids, as well as
to subsequently precipitate the galactomannans with subsequent
swelling of the polymers, as for example described in Example 1.
The purification method described in Example 1 is generally
applicable, it only being necessary to adjust the centrifugal
force during centrifuging. For example, if high molecular weight
or mannose-richer galactomannans are present, it is necessary to
centrifuge at a correspondingly lower speed in order also to
keep mannose-richer molecules in solution. The purified
galactomannans are tested Por nitrogen content. No nitrogen may
be determinable in a protein-free polysaccharide after
purification.
20~J~9
-- 8 --
The galactomannan derivatives of the invention preferably have
no more free hydroxyl groups or only a few free hydroxyl groups,
that is they preferably have a statistical degree of
substitution of 3. On average 80 to 100 % of the free hydroxy
gr~ups available are etherified and/or esterified, preferably 90
to 100%.
The invention relates in particular to the use of the
galactomannan derivatives of the invention to prepare film
coatings and embedding materials of pharmaceutical active
substances, in particular of orally applicable active substances
or orally applicable medicinal formulations with release of
active substance in the colon. It is achieved in that the active
substances or formulations with active substances, for example,
granulates, pellets or tablets, are coated with or embedded in
the galactomannan derivatives of the invention.
The coating of the active su~stances or of the pharmaceutical
formulations, i.e. the formulations in which the active
substances are wor~ed together with conv0ntional or necessary
pharmaceutical auxiliary substances, is carried out according to
methods known in pharmaceutical technology or the conventional
methods for coating medicinal forms. The embedding of
therapeutic active substances is also conducted according to
methods known in pharmaceutical technology. In so doing the
galactomannan derivatives of the invention are used instead of
hitherto conventional plastic or meltable embedding materials,
for example waxes, hydrated caster oil, plastics such as
cellulose ethers or esters, poly(meth)acrylic acid esters. In
addition it is also possible to use conventional pharmaceutical
auxiliary substances and additives such as softeners (especially
in the case of coatings), flavouring agents, sweeteners,
auxiliary substances such as talcum, calcium carbonate,
mannitol, cellulose powder, soluble colourants and pigments.
20~3~6~
g
If used, the auxiliary substances are for example added to the
coating mixture in amounts of 10 to 100 % by weight, preferably
from 20 to 40 % by weight, related to the weight of the
galactomannans used.
The f:Lavouring agents, sweeteners and colourants are added to
the mixtures in small amounts, for example of 0.001% to 2%.
Further information on conventional auxiliary substances and
additives are given in the technical literature, for example in
the monograph by J.H. Saunders and K.C. Frisch "High Polymers",
publishea by Interscience Publishers 1962 and 1964.
Information on the coating of medicinally active substances or
medicinal formulations with the galactomannan derivatives of the
invention.
Here it is for example also possible to use conventional
softeners (e.g. dibutylsebacate, citric and tartaric acid
esters, glycerol and glycerol esters, phthalic acid esters and
similar substances). It is also possible to add water soluble
substances such as polyethylene glycols, polyvinyl pyrrolidone,
copolymerisates of polyvinyl pyrrolidone and polyvinyl acetate,
hydroxypropyl cellulose, hydroxypropyl methylcellulose. Solids
such as talcum and/or magnesium stearate can also be added to
the coating or to the tablet mixtures.
Coating is effected by spraying solutions in organic solvents or
suspensions or dispersions of the stated substances in organic
solvents or water, it also being possible to add addltional
auxillary substances to optimize their processing
characteristics, such as surface-active substances, pigments.
The spraying is carried out for example in a coating drum or in
perforated drums or in an air suspension or fluidized air bed
process (for example Glatt fluidized air bed equipment WLSD5).
20~3~9
-- 1 o --
The coating can also be carried out in the coacervation procèss
during which so-called microcapsules or microparticles are
formed.
Coating can also be carried out by coagulation of aqueous
dispersions or suspensions of the previously mentioned
substances by mixing the active substance with the dispersion
and removing the water by drying.
Coated active substance particles and coated granulates can be
pressed into tablets; coated pellets can be filled into hard
gelatine capsules.
During coating of active substance particles or granulates which
contain the particles of active substance more coating material
is generally used than in pellets or tablets since the surface
which has to be covered is substantially larger than in the case
of pellets or tablets.
Since tablets are generally larger than pellets, the surface to
be covered is correspondingly smaller in the case of tablets.
It is possible to use 0.02 to 0.5 parts by weight of
galactomannan derivative as coating material to 1 part by weight
of active substance or medicinal formulation. A weight ratio of
one part active substance and 0.04 to 0.3 parts by weight of
coating material is preferred, 0.05 to 0.2 parts by weight of
coating material to 1 part by weight of active substance is
quite particularly preferred. Application of the coating
material in solution, suspension or dispersion occurs at
elevated temperature, preferably in a stream of air.
The temperature of the added air is for example 70 to 90C; the
temperature of the exhaust air is for example up to 40C.
Embedding the active substances or binding to the galactomannan
derivatives of the invention.
2053~9
"
In this case 1 part by wei~ht of active substance is used with
for example 0.05 to 5.0 parts by weight of galactomannan
derivative, preferably 0.08 to 3.0 parts by weight, 0.1 to 2.0
parts by weight being quite particularly preferred. ~he
preparation of these formulations occurs at temperatures between
10C and 100C.
The preparation of these forms of administration can for example
be effected:
a) by dissolving or dispersing the active substances or their
salts in the galactomannan derivatives of the invention or
mixtures thereof also with melting of the cited substances
and subsequent cooling, crushing, possibly adding other
substances such as water soluble substances or substances
that swell in water and pressing into tablets. The cooling
of the melts and crushing can also be combined in one step
by dispersing the melts in cold water or subjecting them to
spray hardening.
Swelling substances that may for example be used are: methyl
cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose (Pharmacoat, Methocel E (cellulose mixed
ethers with propoxy and methoxy substituents), alginic acid
and its salts (Na salt, Ca salt, also mixtures of sodium
alginate and calcium salts for example CaHPO4), starches,
carboxymethyl starches, carboxymethyl celluloses and their
salts (for example Na salt), gum arabic, karaya gum, ghatti
gum, agar-agar, carragheen, xanthan gum, propyleneglycol
alginate, pectin, tragacanth.
b) by mixing the active substances witb the galactomannan
derivatives of the invention and optionally swelling
substances or mixtures of these substances, also with use of
heat and for example pressing the mixtures, possibly after
2~3~
- 12 -
adding further auxiliary substances, into tablets or forming
pellets or granulates.
c) by mixing the active substances with solutions of the
galactomannan derivatives of the invention in organic
solvents such as for example ethanol, ethyl acetate, acetone
or isopropanol, possibly mixing with carrier materials such
as celluloses, as well as subsequent evaporation of the
solvents and mixing the embedded active substances with
additional auxiliary substances and processing into shaped
bodies, such as tablets, granulates or pellets.
d) by moistening a mixture of the active substances and of the
galactomannans of the invention and optionally the swelling
substances mentioned with organic sol~ents such as ethanol,
ethyl acetate, acetone or isopropanol, possibly with ..
addition of binding agents such as polyvinyl pyrrolidone or
copolymers of polyvinyl pyrrolidone and polyvinyl acetate,
granulating the mixture obtained, subsequent drying,
addition of possible additional auxiliary substances and for
example pressing the mixture into tablets.
d) by mixing the active substances with a solution of the
galactomannan derivatives of the invention in polyethylene
glycol of molecular weight 200 to 1500, possibly with
addition of other auxiliary substances such as stearates or
swelling agents and for example encapsulating the mass
obtained into soft or hard gelatine capsules.
Quite generally, the preparation of these medicinal formulations
is carried out in manner known per se, it also being possible to
use the known and conventional pharmaceutical auxiliary
substances as well as other conventional carrier and diluting
agents in addition to the galactomannan derivatives of the
invention. Carrier and diluting agents of this kind wh~ch may
for example be used are those which are mentioned or recommended
2053~9
- 13 -
in the following literature references as auxiliary substancès
for pharmacy, cosmetics and related fields: Ullmanns
Ency~clopadie der technischen Chemie, Volume 4 (1953), page 1 to
39; Journal of Pharmaceutical Sciences, Volume 52 ~1963), page
918 et seg. H.V.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie
und angrenzende Gebiete; Pharm. Ind., Issue 2, 1961, page 72 et
seq.; ~r. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie,
Kosmetik und angrenzende Gebiete, 2nd edition, Editio Cantor,
Aulendorf in Wurttemberg 1981.
Examp~es of conventional auxiliary substances, carrier
substances and diluting agents are gelatines, natural sugars
such as raw sugar or lactose, lecithin, pectin, starches (e.g.
corn starch) as well as starch derivatives, cyclodextrins and
cyclodextrin derivatives, polyvinyl pyrrolidone, gelatines, gum
arabic, alginic acid, tylose, talcum, silicic acid (for example
colloidal) or highly disperse SiO2, levulose, tragacanth,
sodium chloride, stearates, magnesium and calcium salts of fatty
acids with 12 to 22 carbon atoms, in particular saturated (for
example stearates), polyethylene glycol with a mean molecular
weight between 200 and 20,000, preferably between 200 and 5,000,
in particular between 200 and 1,000, or their mixtures and/or
polymerisates of vinyl pyrrolidone and/or mixed polymerisates of
vinyl pyrrolidone and vinyl acetate, esters of aliphatic
saturated or unsaturated fatty acids (2 to 22 carbon atoms, in
particular 10 to 18 carbon atoms) with monovalent aliphatic
alcohols (1 to 20 carbon atoms) or multivalent alcohols such as
slycols, glycerol, diethylene glycol, pentaerythritol, sorbitol,
mannitol, etc. which may optionally also be etherified,
benzylbenzoate, dioxolanes, glycerin formals, tetrahydrof~-rfuryl
alcohol, polyglycol ethers with C1 to C12 alcohols, dimethyl
acetamide, lactamides, lactates, ethyl carbonates, silicones (in
particular medium-viscous polydimethyl siloxanes), calcium
carbonate, sodium carbonate, calcium phosphate, sodium
phosphate, magnesium carbonate, gum arabic, alginic acid,
stearates, fats and similarly acting substances.
20a~ 9
- 14 -
In addition, the forms of administration can also contain
substances active at the interface. Examples of these are:
alkali soaps such as alkali salts of higher fatty acids (for
example Na palmitate, Na stearate) or their derivatives (for
example Na ricinolacetate sulfate esters); sulfurated compounds
or sulfonated compounds formed by reacting higher fatty alcohols
with sulphuric acid or chlorosulfonic acid and used for example
as sodium salts (for example sodium lauryl sulphate, sodium
cetyl sulphate, sodium stearyl sulphate, sodium cetyl
sulphonate); salts of the gallic acids, saponines; quaternary
ammonium compounds; partial fatty acid esters of sorbitane;
partial fatty acid esters and fatty acid esters of
polyoxyethylene sorbitane; sorbitol ethers of polyoxyethylene;
fatty acid esters of polyoxyethylene; fatty alcohol ethers of
polyoxyethylene; fatty acid esters of saccharose; fatty acid
esters of polyglycerol; proteins, lecithins.
The forms of administration may also contain celluloses, in
particular if coprimates are to be produced. Those which may be
considered are: purified cellulose (sold for example as
Elcem ~ or microcrystalline cellulose as sold for example
under the trade mark Avice ~. It is, however, also possible to
use other fillinq agents such as calcium hydrogen phosphate,
lactose, starches (for example potato starch, corn starch),
glucose, mannitol and saccharose as well as filling agents with
a binding agent function such as microcrystalline cellulose,
hydrolysed or partially degraded starches and
microcrystallizates of cellulose powder and lactose.
In addition the forms of administration may contain
sedimentation retardants such as highly disperse silicic acids
which have a surface of 50 to 500 m2/g, in particular 100 to
400 m~/g (determined usinq the BET method). These are for
example commercially available under the trade mark Aerosi ~.
~ ~ ~ 3 ~ ~ ~
It may also be appropriate to use mould lubricants in the form
of administration. Those that can be cited are:
talcum or siliconized talcum, calcium and magnesium stearate,
stearic acid, paraffin, hydrated fats and oils, silicone oil
~mulsion.
Other auxiliary substances which may be considered are
substances which encourage disintegration (so-called
disintegrants), such as:
cross-linked polyvinyl pyrrolidone, sodiumcarboxymethyl starch,
sodiumcarboxymethyl cellulose, formaldehyde gelatine,
formaldehyde casein, polyacrylic acid, ultraamylopectin.
It is also possible to add stabilizers, colourants, antioxidants
and complex formers (for example ethylene diamine tetraacetic
acid) and the like as well as to add acids such as citric acid,
tartaric acid, maleic acid, fumaric acid.
Antioxidant~ that may for example be used are sodium
metabisulphite, cysteine, ascorbic acids and their esters (for
example -palmitate), flavonoids, gallic acid alkyl ester,
butylhydroxyanisol, nordihydroguaiaretic acid, tocopherols as
well as tocopherols + synergists (substances that bind heavy
metals through complex formation, for example lecithin, ascorbic
acid, citric àcid, phosphoric acid).
Preservatives that may for example be used are sorbic acid,
p-hydroxybenzoic acid esters (for example low alkyl esters),
benzoic acid, sodium benzoate, trichloroisobutyl alcohol,
phenol, creosol, benzethonium chloride and formalin derivatives.
Plasticizing agents for the galactomannan derivatives of the
invention that may be considered are:
20S33~9
- 16 -
citric and tartaric acid esters (acetyltriethyl-,
acetyltributyl-, tributyl-, triethyl-citrate); glycerol and
glycerol esters IglYcerol diacetate, -triacetate, acetylated
mono~lycerides, caster oil); phthalic acid esters (dibutyl-,
diamyl-, diethyl-, dimethyl-, dipropyl-, D-(2-methoxy- or
etho~cyethyl)-phthalate, ethylphthalyl- and butylphthalylethyl-
and butylglycolate); alcohols (propylene glycol, polyethylene
glycol of various chain lengths), adipates (diethyl-,
di(2-methoxy- or ethoxyethyl adipate); benzophenone; diethyl-
and dibutylsebacate, -succinate, -tartrate; diethyleneglycol
dipropionate; ethyleneglycol diacetate, -dibutyrate,
-dipropionate; tributyl phosphate, tributyrin;
polyethyleneglycol sorbitane monooleate; sorbitane monooleate.
To apply the galactomannan derivatives of the invention it is
possible to use solvents from the group of aqueous sol~ents,
alcohols, ketones, esters, ethers, aliphatic carbons,
halogenated solvents, cycloaliphaticl heterocyclic solvents and
mixtures thereof. Typical solvents are, inter alia, acetone,
diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl
alcohol, methyl acetate, ethyl acetate, isopropyl acetate,
n-butyl acetate, methylisobutyl ketone, methylpropyl ketone,
n-hexane, n-heptane, ethylglycol monoethyl ether, ethyleneglycol
monoethylacetate, methylene dichloride, ethylene dichloride,
propylene dichloride, carbon tetrachloride, nitroethane,
nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,
cyclohexane, cyclo octane, benzene, toluene, naphtha,
1,4-dioxan, tetrahydrofuran, diethylene glycol dimethyl ether,
water and mixtures thereof, such as acetone and water, acetone
and methanol, acetone and ethyl alcohol, methylene dichloride
and methanol and ethylene dichloride and methanol as well as
mixtures thereof. These solvents are removed again during the
coating process.
2~3~
- 17 -
Active substances that can ad~antageously be formulated with the
galactomannan derivatives of the invention are for example in
parti,cular medicinally active substances which are digested in
the small intestine and can consequently not be given orally,
prefe:rably peptide medicaments. Examples are: peptides,
cardiovascular remedies, antirheumatic/analgesic agents, agents
for treating diseases of the colon (Morbus Chron, Colitis
ulcerosa), antiasthmatic agents, antifibrolytic agents,
antihaemorrhagic agents, antitumour agents, enzyme preparations,
antibiotics, antimycotics, substances acting on the CNS (central
nervous system).
Examples of peptide active substances are in particular ACTH
(adrenocorticotropic hormone), corticostatin, calcitonin,
insulin, oxytocin, somatostatin and analogs, LHRH analogs,
bombesin analogs, cholecystokinin and derivatives, endothelin
and analogs, thrombin inhibitors, peptide growth factors (for
example IGF , EGF , NGF ) magainine ( PGS peptides), gastrin
analogs, bradykinin analogs, parathormon analogs, neurokinin and
analogs, VIP and analogs, ANP (atrial natriuretic peptide) and
analogs, neokyotrophin and analogs, angiotensin analogs,
encephalins, dynorphins, dermorphins, deltorphins,
renin-inhibiting peptides, tumour qrowth factor peptides, MSH
(melanocyte stimulating hormone~ analogs, mitotoxins,
tyrphostines, chromogranin A, thymopentin, TRH and analogs,
substance P, tuftsin, fibronectin and peptidic immunomodulators
such as cyclosporin A, FK 506, neuropeptide Y and NPK.
Medicinal forms which release the active substance in the
presence of qlycolytic enzymes advantageously include coated
solid medicinal formulations which are coated with the
galactomannan derivatives of the invention, such as coated
tablets, capsules, film-coated tablets, pellets or
microparticles. The medicinally active substances are released
in the colon after oral administration by glycolytic degradation
of the polymer.
20~3~9
- 18 -
Glycolytic enzymes that may be considered here are: mannases,
mannosidases, galactosidases such as beta-D-mannase,
beta--D-mannosidase, alpha-D-mannosidase, beta-D-galactanase,
beta--D-galactosidase, alpha-D-galactosidase, beta-D-glucosidase
and alpha-D-glucosidase, beta-D-glucuronidase,
alpha-L-arabinosidase, beta-D-fucosidase, beta-D-xylanase,
beta-D-xylosidase, pectinase.
It is optionally also possible to add glycolytic enzymes of this
kind separately to the medicinal formulations of the invention,
it then being necessary to select a formulation that releases
these glycolytic enzymes at the site of action. This can for
example be effected in the following manner:
Two-compartment formulations for insertion into the bladder or
other body cavities contain the active substance, for example an
antibiotic, in one compartment coated with the galactomannans of
the invention whereas glycolytic enzymes are inserted into the
2nd compartment. By coating the 2nd compartment with acid- or
alkali soluble films, for example of the polyacrylate type (for
example eudragits), the activation of the enzymes and then the
release of the active substance can be directed in dependence of
the pH value of the environment in such a way that the
polyacrylate film only becomes permeable for the water needed to
activate the enzyme within a specific pH range.
2~3~69
1 9
Example 1
Galactomannan methyl ether (degree of substitution 3.0)
Purified, protein-free galactomannan is used obtained from
locust bean ~um with degree of qrinding 175.
50 g locust bean gum (Vidogum L 175, Unipectin AG,
Eschenz/Switzerland) are moistened with 70 g methanol in a 5
litre Erlenmeyer flask to produce a lump-free solution with
water. The mixture is made up to 5 litres with boiled distilled
water and stirred over night.
The suspension is then centrifuged at 6500 g for about 20
minutes. The supernatant solution is decanted off from the
proteins. 2.5 litres in each case of this solution are mixed
with the same volume of methanol and shaken. The pure white
precipitating g~lactomannan is filtered off and washed out
several times with methanol.The purified polymer is suspended in
methanol and stored closed in a refrigerator. The polymer is
filtered off from methanol and 100 g weighed into a 1 litre
pear-shaped~flask.
Another sample of 5 g is dried in a drying cabinet at 120C and
weighed in order to calculate the dry mass of galactomannan used
in the synthesis. This should be between 2.8 g and 3.2 g.
After addition of 215 ml dimethyl sulphoxide, the suspension is
gassed with nitrogen in a rotation evaporator and the methanol
is rotated off at 45C under a water jet vacuum. The polymer
pulp so obtained is transferred under nitrogen gassing into a 2
litre brown glass three-necked flask with KPG stirrer * and
intensive cooler (temperature 5C).
* A stirrer driven by an electric motor and introduced into
the stirring vessel through a ground closure.
20~3~
- 20 -
After 15 minutes 120 g sodium hydroxide are added with stirring.
Immediately thereafter the remaining 200 ml dimethyl sulphoxide
are added. This batch is stirred for one hour. The polymer pump
is then mixed with 626 ml iodine methane. The temporarily
generated slight heat (30C) is not taken off. A reaction
temperature of 20C to 25C is maintained for the remainder of
the reaction time.
After 48 hours the reaction mixture is allowed to stand and the
supernatant is decanted into a 1 litre brown glass pear-shaped
flask.
The contents of this flask are ventilated with nitrogen in a
rotation evaporator and drawn off in a ~ater jet vacuum at 65C
until no more solvent is transferred. The remaining dimethyl
sulphoxide is then drawn off in an oil rotary slide valve vacuum
at 65C over a cooling trap (liquid nitrogen).
The residue rotated off is collected and mixed with 1 to 2
litres peroxide-free diethyl ether. The suspension is added to a
2 litre three-necked flask and stirred over night under reflux
at room temperature.
The ether extract is then suction filtered and the filtration
residue washed out several times with diethyl ether. The
accumulated filtrates are drawn off in a rotation evaporator
under a water jet vacuum at 40C until phase separation occurs
and the polymer separates out in almost pure form. The remaining
yellow dimethyl sulphoxide phase is decanted off from the
polymer.
The polymer is pressed out on filter paper and dissolved in
methanol. The concentrated, highly viscous methanol solution
(ca. 100 ml) is added to 5 litres hot water (60C) with
stirring. The precipitated polymer is heated on a petri dish in
a drying cabinet at 60C until the polymer has separated from
the water.
~0~3569
- 21 -
The polymer is then pressed out on filter paper and dried in a
drying cabinet at 120C. After being weighed, the polymer is
dissolved in chloroform and cast into petri dishes. These are
left to dry at room temperature with exclusion of dust until a
film is formed. Very high-tensile, resilient films are obtained
that are clear and colourless.
If the synthesis is carried out on a larger scale (for example
using more than 12 g galactomannan), it becomes increasingly
important to remove the heat of reaction at the beginning of the
reaction. It is undesirable to heat the reaction mixture over
35C since yellow by-products would otherwise be formed. These
by-products greatly discolour the ethyl galactomannan and are
very difficult to remove. For this reason, in the case of larger
batches, the reaction mixture should be cooled tv 20C using a
water bath and stirred vigorously.
To achieve an over 80% yield the entire reaction mixture must be
constantly intermixed. In the case of smaller scale syntheses a
KPG stirrer at medium revolution count is sufficient. For larger
batches there is, however, a risk that either the educts will be
insufficiently mixed or that the suspended galactomannan
filaments will wind themselves around the stirrer shaft and will
not react. It is therefore necessary to use more elaborate
stirrers. If only a large-paddled stirrer is used, the pitch
line velocity at the stirrer paddle and the shearing force are
too great.
,
20:~3..6~
- 22 -
Example 2
Galactomannan ethyl ether (degree of substitution 3.0)
Purified, protein-free galactomannan is used obtained from
locust bean gum with degree of grinding 175.
50 g locust bean gum (Vidogum L 175, Vnipectin AG,
Eschenz/Switzerland) are moistened with 70 g methanol in a 5
litre Erlenmeyer flask to produce a lump-free solution with
water. The mixture is made up to 5 litres with boiled distilled
water and stirred over night.
The suspension is then centrifuged at 6500 g for about 20
min~tes. The supernatant solution is decanted off from the
proteins. 2.5 litres in each case of this solution are mixed
with the same volume of methanol and shaken. The pure white
precipitating galactomannan is filtered off and washed out
several times with methanol. The purified polymer is suspended
in methanol and stored closed in a refrigerator. The polymer is
filtered off from methanol and 100 g weighed into a 1 litre
pear-shaped flask.
Another sample of 5 g is dried in a drying cabinet at 120C and
weighed in order to calculate the dry mass of galactomannan
used. This should be between 2.8 g and 3.2 g.
After addition of 215 ml dimethyl sulphoxide, the suspension is
gassed with nitrogen in a rotation evaporator and the methanol
is rotated off at 45C under a water jet vacuum. The polymer
pulp so obtained is transferred under nitrogen gassing with KPG
stirrer * and intensive cooler (temperature 5C).
* A stirrer driven by an electric motor and introduced into
the stirring vessel through a ground closure.
2.Q.~3 i63
- 23 -
After 15 minutes 120 g sodium hydroxide are added with stirring.
Immediately thereafter the remaining 200 ml dimethyl sulphoxid~
are added. This batch is stirred for one hour. The polymer pump
is th,en mixed with 745 ml bromomethane. The temporarily
generated slight heat (30C) is not taken off. A reaction
temperature of 20QC to 25C is maintained for the remainder of
the reaction time.
After 48 hours the reaction mixture is allowed to stand and the
supernatant is decanted into a 1 litre brown glass pear-shaped
flask.
The contents of this flask are ventilated with nitrogen in a
rotation evaporator and drawn off in a water jet vacuum at 65C
until no more solvent is transferred. The remaining dimethyl
sulphoxide is then drawn off in an oil rotary slide valve vacuum
at 65C over a cooling trap (liquid nitroyen).
The residue rotated off is collected and mixed with 1 to 2
litres peroxide-free diethyl ether. The suspension is added to a
2 litre three-necked flask and stirred over night under reflux
at room temperature.
The ether extract is then suction filtered and the filtration
residue washed out several times with diethyl ether. The
accumulated filtrates are drawn off in a rotation evaporator
under a water jet vacuum at 40C until phase separation occurs
and the polymer separates out in almost pure form. The remaining
yellow dimethyl sulphoxide phase is decanted off from the
polymer.
The polymer is pressed out on filter paper and dissolved in
methanol. The zoncentrated, highly viscous methanol solution
(ca. 100 ml) is added to 5 litres hot water (60C) with
stirring. The precipitated polymer is heated on a petri dish in
a drying cabinet at 60C until the polymer has separated from
the water.
2t)!~3569
- 24 -
The polymer is then pressed out on filter paper and dried in a
drying cabinet at 120C. After being weighed, the polymer is
dissolved in chloroform and cast into petri dishes. These are
left to dry at room temperature with exclusion of dust until a
film is formed. Very high-tensile, resilient films are obtained
that are clear and colourless.
If the synthesis is carxied out on a larger scale (for example
using more than 12 g galactomannan), it becomes increasingly
important to remove the heat of reaction at the beginning of the
reaction. It is undesirable to heat the reaction mixture over
35C since yellow by-products would otherwise be formed. These
by-products greatly discolour the ethyl galactomannan and are
very difficult to remove. For this reason, in the case of larger
batches, the reaction mixture should be cooled to 20C using a
water bath and stirred vigorously.
To achieve an over 80% yield the entire reaction mixture must be
constantly intermixed. In the case of smaller scale syntheses a
KPG stirrer at medium revolution count is sufficient. For larger
batches there is/ however, a risk that either the educts will be
insufficiently mixed or that the suspended galactomannan
filaments will wind themselves around the stirrer shaft and will
not react. It is therefore necessary to use more elaborate
stirrers. If only a large-paddled stirrer is used, the pitch
line velocity at the stirrer paddle and the shearing force are
too great.
20~3~6 ~
- 25 -
Example 3
Acetylgalactomannan ethyl ether (mixed substitution)
Purified, protein-free galactomannan is used obtained from
locust bean gum with degree of grinding 175.
50 g locust bean gum (Vidogum L 175, Unipectin AG,
Eschenz/Switzerland) are moistened with 70 g methanol in a 5
litre Erlenmeyer flask to produce a lump-free solution with
water. The mixture is made up to 5 litres with boiled distilled
water and stirred over night.
The suspension is then centrifuged at 6500 g for about 20
minutes. The supernatant solution is decanted off from the
proteins. 2.5 litres in each case of this solution are mixed
with the same volume of methanol and shaken. The pure white
precipitating galactomannan is filtered off and washed out
several times with methanol. The purified polymer is suspended
in methanol and stored closed in a refrigerator. The polymer is
filtered off from methanol and 100 g weighed into a 1 litre
pear-shaped flask.
Another sample of 5 g is dried in a drying cabinet at 120C and
weighed in order to calculate the dry mass of galactomannan
used. This should be between 2.8 g and 3.2 g.
After addition of 215 ml dimethyl sulphoxide, the suspension is
gassed with nitrogen in a rotation evaporator and the methanol
is rotated off at 45C under a water jet vacuum. The polymer
pulp so obtained is transferred under nitrogen gassing with KPG
stirrer * and intensive cooler (temperature 5C).
* A stirrer driven by an electric motor and introduced into
the stirring vessel throuyh a ground closure.
~0~3~9
- 26 -
After 15 minutes 120 g sodium hydroxide are added with stirring.
Immediately thereafter the remaining 200 ml dimethyl sulphoxide
are added. This batch is stirred for one hour. The polymer pump
is then mixed with 745 ml bromomethane. The temporarily
generated sliqht heat (30C) is not taken off. A reaction
temperature of 20C to 25C is maintained for the remainder of
the reaction time.
After 2 hours the reaction mixture is allowed to stand and the
supernatant is decanted into a 1 litre brown glass pear-shaped
flask.
The contents of this flask are ventilated with nitrogen in a
rotation evaporator and drawn off in a water jet vacuum at 65C
until no more solvent is transferred. The remaining dimethyl
sulphoxide is then drawn off in an oil rotary slide valve vacuum
at 65C over a cooling trap (liquid nitrogen).
The residue rotated off is collected and mixed with 1 to 2
litres peroxide-free diethyl ether. The suspension is adde~ to a
2 litre three-neck~d flask and stirred over night under reflux
at room temperature.
The ether extract is then suction filtered and the filtration
residue washed out several times with diethyl ether. The
accumulated filtrates are drawn off in a rotation evaporator
under a water jet vacuum at 40C until phase separation occurs
and the polymer separates out in almost pure form. The remaining
yellow dimethyl sulphoxide phase is decanted off from the
polymer.
The polymer is pressed out on filter paper and dissolved in
methanol. The concentrated, highly viscous methanol solution
(ca. 100 ml) is added to 5 litres hot water (60C) with
stirring. The precipitated polymer is heated on a petri dish in
a drying cabinet at 60C until the polymer has separated from
the water.
- 27 - 20 ~ 3 ~ 6 ~
The polymer is then pressed out on filter paper and dried in a
drying cabinet at 120C.
The polymer is dissolved in 250 ml acetanhydride and transferred
to a 1 litre round-bottom flask with reflux condenser and
magnetic stirrer. After addition of 300 to 350 ml pyridine the
mixture is heated to boiling point for 5 hours with stirring.
The hot reaction solution is then added to 8 to 10 l water and
the precipitated polymer washed in methanol. The pressed out
polymer is then dissolved in a little chloroform and
precipitated again in 5 l methanol.
The polymer is then dried in a drying cabinet at 80C. After
being weighed, the polymer is dissolved in chloroform and cast
into petri dishes. These are left to dry at room temperature
with exclusion of dust until a film is formed. Very
high-tensile, resilient films are obtained that are clear and
colourless.
