Title: Use of water-soluble or water-dispersible polyurethanes as coatings or binders for pharmaceutical presentations
United States Patent: 6,123,963
Inventors: Kim; Son Nguyen (Hemsbach, DE); Sanner; Axel (Frankenthal, DE); Kolter; Karl (Limburgerhof, DE)
Assignee: BASF Aktiengesellschaft (Ludwigshafen, DE)Appl. No.: 168098
Filed: October 8, 1998The use of water-soluble or water-dispersible polyurethanes which consists of a) 0.1-30% by weight of at least one polyol, b) 20-45% by weight of at least one polyetherpolyol, c) 10-45% by weight of at least one diamine comprising an ionic group, d) 30-50% by weight of at least one polyisocyanate with or without e) further additives as coatings or binders for pharmaceutical presentations.
Description of the Invention
The present invention relates to the use of water-soluble
or water-dispersible polyurethanes as coatings or binders for
pharmaceutical presentations.
Solid pharmaceutical presentations such as tablets, capsules, pellets,
granules, crystals etc. are coated, ie. provided with a film coating, for
a wide variety of reasons. Thus, for example, an unpleasant odor or taste
can be masked, and the swallowability can be improved. The stability of
the active ingredients may be increased by the coating since less water
vapor and oxygen reach the interior of the tablet. The presentations have
a better appearance and can be distinguished better by incorporating dyes.
Furthermore, in particular, the rate of release of the active ingredient
can be adjusted by the film coating.
A distinction is generally made between instant release forms and slow
release forms.
In the case of instant release forms, the disintegration of the tablet and
the release of the active ingredient from the presentation should, where
possible, not be influenced by the coating, for which reason the film
coating must dissolve rapidly in gastric fluid. In addition, it must have
good film properties. The tensile strength and the ultimate elongation
should be high, so that the film coating withstands mechanical effects
occurring during pharmaceutical processing--especially packaging--and
during transport and storage.
A product which is frequently employed for coating instant release tablets
is hydroxypropylmethylcellulose (HPMC). Hydroxypropylmethylcellulose shows
a steep increase in viscosity as the concentration increases in aqueous
solution.
Since the solution of film former must be finely atomized for coating
tablets, and the droplets which are formed must thoroughly wet the surface
of the tablets, as well as spread well, the viscosity must not exceed a
certain limit (from 150 to 250 mpas) which depends on the type of spray
nozzle and of apparatus. It is therefore possible in the case of HPMC to
employ only relatively low concentrations of film former.
The recommended concentration for Pharmacoat.RTM. 606 (supplied by Shin-etsu)
in the literature is 5-7% by weight (Pharmaceutical Coating Technology,
edited by Graham Cole, Taylor and Francis Ltd. 1995 and, manufacturers'
technical data sheets). These low spray concentrations result in
relatively long processing times and thus high costs.
In addition, hydroxypropylmethylcellulose has further disadvantages, inter
alia in the wetting characteristics, in the adhesiveness to the tablet
surface, in the pigment-binding capacity, in the mechanical properties of
the films, in the hygroscopicity, and in the permeability to water vapor
and oxygen and in the difference in disintegration times between
film-coated tablets and core.
It is an object of the present invention to provide water-soluble or
water-dispersible polyurethanes as coatings or binders for pharmaceutical
presentations which do not have the abovementioned disadvantages.
We have found that this object is achieved by the use of water-soluble or
water-dispersible polyurethanes consisting of
a) 0.1-30% by weight of at least one polyol,
b) 20-45% by weight of at least one polyetherpolyol,
c) 10-45% by weight of at least one diamine comprising an ionic group,
d) 30-50% by weight of at least one polyisocyanate with or without
e) further additives.
Polyurethanes, and polyesters as well as poly(ester-urethanes) have
already been disclosed as auxiliaries in pharmaceutical formulations.
Thus, DE-A-42 25 045 describes the use of water-soluble or
water-dispersible polyurethanes consisting of at least one compound which
comprises two or more active hydrogen atoms per molecule, of one
diisocyanate and of a diol comprising acidic or salt groups. The diols
comprising carboxylate groups have the disadvantage that they make the
polymer insoluble in gastric fluid.
The polyurethanes described in DE-A-42 41 118 and consisting of
polyesterdiols/diols/tert-amine-containing diols or diamines/diisocyanates
are labile to hydrolysis in the acidic pH range and tend to form tacky
films.
DE-A-43 33 238 claims pyrrolidone group-containing polyesters and
polyamides as constituent of film coatings in pharmaceutical formulations.
The polyesters described herein are likewise too labile to hydrolysis
under gastric acid conditions. Said polyamides have the disadvantage that
they are too viscous and too tacky and therefore do not have the
properties required of film formers.
DE-A-31 51 923 describes crosslinked polyetherurethanes which can be
employed as tabletting auxiliaries. However, in order to achieve the
required solubility in water of the crosslinked polyetherurethanes, the
polyether content must be chosen to be so high that the polymer is too
tacky.
U.S. Pat. Nos. 4,743,673; 3,388,159 and 4,789,720 describe polyurethanes
which either are insoluble in water or form undesirably tacky films.
The polyurethanes according to the invention and their structural
components a) to d) can be described in detail as follows.
The polyols used as component a) are low molecular weight polyols, in
particular diols comprising 2 to 10 carbon atoms and having an
MW.ltoreq.500 g/mol. Suitable and preferred representatives of this class
are ethylene glycol, 1,2-propylene glycol and 1,3-propylene glycol,
1,4-butanediol, 1,3-butanediol, 1,4-butenediol, 1,4-butynediol,
1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol,
cyclohexanedimethanol (1,4-bishydroxymethylcyclohexane),
2-methyl-1,3-propanediol, also diethylene glycol, triethylene glycol,
tetraethylene glycol, dipropylene glycol and dibutylene glycol. Triols
such as glycerol are also suitable.
Particularly preferred diols are 1,6-hexanediol and
1,4-bishydroxymethylcyclohexane.
The amounts of component a) in the polyurethane according to the invention
are in the range from 0.1 to 30% by weight, preferably in the range from
0.3 to 20% by weight, particularly preferably in the range from 0.5 to 15%
by weight.
Components b) are polyetherpolyols, in particular polyetherdiols, having a
molecular weight of from 300 to 6000 g/mol, preferably 500 to 4000 g/mol,
particularly preferably 500 to 2000 g/mol.
The polyetherdiols which can be employed can be obtained in particular by
polymerizing ethylene oxide, propylene oxide, butylene oxide,
tetrahydrofuran, styrene oxide or epichlorohydrin with itself, e.g., in
the presence of BF3, or by addition of these compounds, as
mixture or successively, onto starter components with reactive hydrogen
atoms, such as alcohols or amines, e.g. water, ethylene glycol,
1,3-propylene glycol or 1,2-propylene glycol,
4,4'-dihydroxydiphenylpropane or aniline.
Preferred polyetherdiols are polytetrahydrofuran with a molecular weight
of from 500 to 2000 g/mol, and polyethylene glycol and polypropylene
glycol with a molecular weight of from 500 to 2000 g/mol.
It is also possible to replace up to 30 mol % of component b) by a
polylactatediol. These polylactatediols have the advantage that on
hydrolysis, for example in gastric fluid, they form toxicologically
acceptable monomers.
The amounts of component b) in the polyurethane according to the invention
are in the range from 20 to 45% by weight, preferably in the range from 22
to 40% by weight, particularly preferably in the range from 23 to 35% by
weight.
The other component c) comprises compounds which have at least two amino
groups able to react with isocyanate groups and, in addition, ionic groups
or potentially ionic groups which can be converted by a simple
neutralization or quaternization reaction into ionic groups. Introduction
of monomers c) makes the polyurethanes self-dispersible, ie. in this case
no dispersing auxiliaries such as protective colloids or emulsifiers are
required on dispersion in water.
The introduction of cationic or anionic groups can take place by also
using diamines having (potentially) cationic or (potentially) anionic
groups.
However, the ionic groups are preferably introduced by also using
comparatively low molecular weight compounds, in particular diamines with
a molecular weight below 500 g/mol, having (potentially) ionic groups.
Preferred (potentially) ionic components c) are N-alkyldialkanolamines
such as N-methyldiethanolamine, N-ethyldiethanolamine, diamino sulfonates
such as the Na salts of N-(2-aminoethyl)-2-aminoethanesulfonic acid,
diamino carboxylic acids or carboxylates such as lysine or the Na salt of
N-(2-aminoethyl)-2-aminoethanecarboxylic acid and diamines having at least
one additiional tertiary amine nitrogen, e.g.
N-methyl-bis(3-aminopropyl)amine.
Particular preference is given to sulfo-containing diamines and their
salts such as N-(2-aminoethyl)-2-aminoethanesulfonic acid and its Na, K or
ammonium salts.
Conversion of the potentially ionic groups, which may initially be
incorporated into the polyadduct, into at least partially ionic groups
takes place in a conventional way by neutralization of the potentially
anionic or cationic groups or by quaternization of tertiary amine nitrogen
atoms.
Employed for the neutralization of potentially anionic groups, e.g.
carboxyl groups or, preferably, sulfonate groups, are inorganic and/or
organic bases such as alkali metal hydroxides, carbonates or bicarbonates,
ammonia or primary, secondary and, with particular preference, tertiary
amines such as triethylamine or dimethylaminopropanol.
Suitable for converting the potentially cationic groups, e.g. the tertiary
amine groups, into the corresponding cations, e.g. ammonium groups, are,
as neutralizing agents, inorganic or organic acids, e.g. hydrochloric,
phosphoric, formic, acetic, fumaric, maleic, lactic, tartaric or oxalic
acid or, as quaternizing agents, for example methyl chloride, methyl
bromide, methyl iodide, dimethyl sulfate, benzyl chloride, chloroacetates
or bromoacetamide. Further neutralizing or quaternizing agents are
described, for example, in U.S. Pat. No. 3,479,310 (Column 6).
This neutralization or quaternization of the potential ionic groups can
take place before, during or, preferably, after the isocyanate
polyaddition reaction.
The amounts of component c) in the polyurethane according to the invention
are in the range from 10 to 45% by weight, preferably in the range from 15
to 43% by weight, particularly preferably in the range from 20 to 43% by
weight.
Polyisocyanates (component d) which should be particularly mentioned are
diisocyanates X(NCO)2, where X is an aliphatic hydrocarbon
radical having 4 to 12 carbon atoms, a cycloaliphatic or aromatic
hydrocarbon radical having 6 to 15 carbon atoms or an araliphatic
hydrocarbon radical having 7 to 15 carbon atoms. Examples of diisocyanates
of these types are tetramethylene diisocyanate, hexamethylene diisocyanate,
dodecamethylene diisocyanate, 1,4-diisocyanatocyclohexane,
1-isocyanato3,5,5-trimethyl-3-isocyanatomethylcyclohexane(isophorone
diisocyanate), 2,2-di(4-isocyanatocyclohexyl)propane, trimethylhexane
diisocyanate, 1,4-diisocyanatobenzene, 2,4-diisocyanatotoluene,
2,6-diisocyanatotoluene, di(4-isocyanatophenyl)methane, p-xylylene
diisocyanate, m- or p-tetramethylxylylene diisocyanate, and mixtures
consisting of these compounds. It is also possible to use small amounts of
compounds with one or more than two isocyanate functionalities.
The diisocyanates which are preferably used are isophorone diisocyanate
and hexamethylene diisocyanate.
It is also possible to replace up to 10 mol % of the abovementioned
diisocyanate by polyisocyanates such as Basocyanat.RTM. HI 100 (supplied
by BASF).
The amounts of component d) in the polyurethane according to the invention
are in the range from 30 to 50% by weight, preferably in the range from 32
to 48% by weight, particularly preferably in the range from 32 to 45% by
weight.
Further additives (component e) which may also be used are emulsifiers or
protective colloids.
Examples of emulsifiers and protective colloids to be mentioned are alkali
metal salts of long-chain fatty acids, alkyl sulfates and alkylsulfonates,
alkylated arylsulfonates or alkylated oxydiphenylsulfonates.
Further suitable emulsifiers are products of the reaction of alkylene
oxides, especially ethylene or propylene oxide, with fatty alcohols, fatty
acids, phenol or alkylphenols.
Examples of protective colloids which can be used are polyvinyl alcohol,
polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, gelatin,
casein and the like.
The K values of the polymers should be in the range from 20 to 150,
preferably 25 to 120, particularly preferably in the range from 30 to 80.
The K value required in each case can be adjusted in a conventional way
through the composition of the starting materials. The K values are
measured by the method of Fikentscher, Cellulosechemie, 13 (1932) 58-64
and 71-74, at 25oC. in 0.1% by weight solution in N-methylpyrrolidone.
The acid number (or the corresponding salt number) of the polyurethane
according to the invention is determined by the composition and the
concentration of the compounds of component c). The acid number is from 30
to 120, in particular from 40 to 90.
The water-soluble or water-dispersible polyurethanes according to the
invention are expediently prepared by reacting monomers a, b and d in the
presence of an inert, water-miscible solvent to give polyurethane
prepolymers.
Suitable organic solvents are in principle all aprotic organic solvents,
especially those with a boiling point of from 40 to 90oC. under
atmospheric pressure. Examples which may be mentioned here are
tetrahydrofuran, ethyl acetate and, especially, methyl ethyl ketone and
acetone.
The structural components of the polyurethanes are generally reacted in
the abovementioned solvents at from 20 to 160oC., in particular
from 40 to 90oC.
The reaction of the diisocyanates can be speeded up by also using
conventional catalysts, e.g. dibutyltin dilaurate, tin(II) octoate or
diazabicyclo[2.2.2]octane.
The solids content of the resulting organic solution before dispersion in
water is normally from 20 to 90% by weight, in particular 50 to 80% by
weight.
The organic solution of polyurethane prepolymers, ie. polyurethanes which
still contain free isocyanate groups, is reacted with the amino-functional
components c), in the presence or absence of water, to give the final
product.
Conversion of potential salt groups, e.g. sulfo groups or tertiary amino
groups, which have been introduced into the polyurethane via monomers c),
into the corresponding ions takes place by neutralization with bases or
acids or by quaternization of the tertiary amino groups before or during
the dispersion of the polyurethanes in water.
The solids content of the resulting aqueous polyurethane dispersions or
solutions is, as a rule, from 10 to 70% by weight, in particular 15 to 50%
by weight.
The polyurethane dispersions or solutions can be converted by various
drying processes such as spray drying, fluidized spray drying, drum drying
or freeze drying into powder form, from which an aqueous dispersion or
solution can be prepared again by redispersion in water.
The water-soluble or water-dispersible polyurethanes according to the
invention are outstandingly suitable as film formers and/or binders which
are soluble or dispersible in gastric fluid for pharmaceutical
presentations.
The invention therefore also relates to solid pharmaceutical presentations
having a coating or binder consisting of
a) 0.1-30% by weight of at least one polyol,
b) 20-45% by weight of at least one polyetherpolyol,
c) 10-45% by weight of at least one diamine comprising an ionic group,
d) 30-50% by weight of at least one polyisocyanate with or without
e) further additives,
where components a) to e) may have the meanings mentioned above.
The coated presentations are preferably inter alia film-coated tablets,
film-coated microtablets, sugar-coated tablets, coated pastilles,
capsules, crystals, granules or pellets.
The binder-containing presentations are preferably inter alia tablets,
microtablets, cores, granules or pellets.
As shown in Table 1, the aqueous solutions of the polyurethanes according
to the invention have a distinctly lower viscosity than corresponding
solutions of hydroxypropylmethylcellulose.
TABLE 1
______________________________________
Viscosity Viscosity
(30% by weight aq.
(20% by weight aq.
solution) [mPas]
solution) [mPas]
______________________________________
Polyurethane A 1)
8 --
Polyurethane B 2)
40 --
Polyurethane C 3)
21 --
Pharmacoat .RTM. 606
-- >2000
______________________________________
Composition (% by weight):
1) 31.35% poly THF (MW 650), 0.71% 1,6hexanediol,
40.21% isophorone diisocyanate,
27.73% sodium N(2-aminoethyl)-2-aminoethanesulfonate
2) 23.15% poly THF (MW 650), 0.95% 1,6hexanediol,
33.60% isophorone diisocyanate,
42.30% sodium N(2-aminoethyl)-2-aminoethanesulfonate
3) 29.46% poly THF (MW 650),
1.48% 1,4cyclohexanedimethanol,
41.56% isophorone diisocyanate, 27.5% sodium
N(2-aminoethyl)-2-aminoethanesulfonate
It is thus possible to employ more concentrated polymer formulations when coating tablets with the polyurethane dispersions as well as for binder applications, which means that the processes can be made considerably less costly and less time-consuming.
Redispersion of the powdered or granular polyurethanes to give aqueous dispersions or solutions takes place considerably faster than with other film formers or binders, because the polyurethanes are thoroughly wetted with water, form few aggregates and dissolve very rapidly. Aqueous dispersions of the polyurethanes according to the invention are extremely resistant to shearing and far exceed commercially available pharmaceutical dispersions such as acrylate/methacrylate dispersions.
Tablets soluble in gastric fluid which are coated with the polyurethanes according to the invention show a disintegration time which is only slightly prolonged by comparison with the core, i.e. the film coating dissolves very rapidly in simulated gastric fluid.
In the case of hydroxypropylmethylcellulose in the form of Pharmacoat 606 as coating material, disintegration takes distinctly longer (see Examples 2, 3 and Comparative Example). In addition, the use according to the invention of the polyurethanes increases the mechanical strength of the tablets very much more than does hydroxypropylmethylcellulose.
The extent of tablet swelling depends on the ancillary substances and active ingredients used, and on the storage times and conditions, such as temperature and humidity. A rigid film coating is subject to fissuring when the core swells. This is why the elasticity of film formers is an important variable. Polyurethanes have exceptional flexibility and elasticity. Thus, the ultimate elongation may be up to 300%. Fissuring is therefore not to be expected even with severe swelling of the core.
The polyurethanes can be applied in pure form or else together with conventional ancillary substances to the core containing active ingredient. Examples of conventional ancillary substances are colored pigments for coloring, white pigments such as titanium dioxide to increase the covering power, talc and silica as antistick agents, polyethylene glycols, glycerol, propylene glycol, triacetin, triethyl citrate as plasticizer and various surface-active substances such as sodium lauryl sulfate, polysorbate 80, Pluronics and Cremophors, to improve the wetting characteristics. The substances mentioned as examples do not represent a limitation. It is possible to use all additives known to be suitable for film coatings soluble in gastric fluid.
It is furthermore possible to combine the polyurethanes with other film formers or polymers in the ratio from 1:9 to 9:1.
Examples of polymers which can be employed for this purpose are the following:
Polyvinylpyrrolidone, polyvinylpyrrolidone copolymers, water-soluble cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, acrylate and methacrylate copolymers, polyethylene glycols, polyethylene oxide/polypropylene oxide block copolymers.
The coating processes which can be used are the conventional processes such as coating in a fluidized bed or a horizontal drum coater, and dip-coating and pan-coating processes. Besides the tablet application, the polymers according to the invention can also be employed for coating other pharmaceutical formulations such as granules, pellets, crystals or capsules. The novel coatings are applied in the conventional thickness of 5-200 .mu.m, preferably 10-100 .mu.m.
When used as binders, a distinction is made between wet and dry binders depending on the method of processing. The latter are used inter alia in direct tabletting and in dry granulation or compaction. In these cases, the binder is mixed with the active ingredient, with or without other ancillary substances, and then subjected to direct tabletting, or granulation or compaction.
Wet granulation contrasts with this in that the active ingredient/ancillary substance mixture is moistened with a solution of the binder in water or an organic solvent, and the moist composition is forced through a screen and then dried. The moistening and drying can moreover take place in parallel, as, for example, in fluidized bed granulation.
For optimal processing, the binder should give low-viscosity solutions because viscous solutions result in inhomogeneous granules.
A binder is intended to result in uniform, hard, abrasion-resistant granules or tablets. Fracture resistance is particularly important for tablets because many active ingredients are difficult to compress and thus afford tablets with inadequate mechanical strength.
In addition, the disintegration of the drug forms, and the rate of release of the active ingredients should experience negligible adverse effects from the binder.
Examples of the most commonly used binders are polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymers, gelatin, starch paste, maltodextrins, hydroxyalkylated and carboxyalkylated cellulose derivatives such as hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, and types of natural gums such as gum arabic, pectin or alginate.
Many of these binders have a high viscosity in solution and are difficult to process. The high viscosity means that the powder particles to be granulated are wetted poorly and inhomogeneously so that the result is inadequate granule strength and an unfavorable particle size distribution.
Many binders are moreover hygroscopic and swell when water is absorbed. This may result in drastic alterations in the properties of granules and tablets.
It has now been found, surprisingly, that the polyurethanes according to the invention have excellent binding effects and moreover have a negligible effect on disintegration at concentrations in the range from 0.5 to 20% by weight, preferably 1 to 10% by weight, of the complete formulation. Because of the good wetting characteristics of the polyurethanes it is moreover possible for the release of active ingredients of low solubility to be improved.
When the polyurethanes are used as binders, the resulting granules and tablets have exceptional mechanical strength and are stable even over long storage periods.
Claim 1 of 11 Claism
We claim:
1. A coating or binder for pharmaceutical preparations, said coating or
binding comprising a water-soluble or water-dispersible polyurethane
consisting of
a) 0.1-30% by weight of at least one polyol,
b) 20-45% by weight of at least one polyetherpolyol
c) 10-45% by weight of at least one diamine comprising an ionic group,
d) 30-50% by weight of at least one polyisocyanate with or without
e) further additives.
____________________________________________
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