~13~~~~~
The present invention relates to medicinal formulations
containing thioctic acid or dihydrolipoic acid, the thioctic
acid or dihydrolipoic acid being present in the form of
inclusion compound with cyclodextrins or cyclodextrin
derivatives and in 'the form of granulates, chewable or
effervescent tablets.
Chemically speaking, thioctic acid (aliphatic-lipoic acid) is
a 1,2-dithiacylopentane-3-valeric acid. The invention not
only relates to the racemic form, but also to the pure (R)-
or (S)-thioctic acid as well as to mixtures of (R)- and (S)-
thioctic acid of any composition. Thioct:ic acid is a
constituent of cell metabolism and is therefore found in many
plants and animal organisms. It acts as one of the co-
enzymes in the oxidative decarboxylation of pyruvate and
other alpha-ketoacids. Thioctic acid has been used for some
time in various disorders, inter alia in liver damage, in
liver damage due to mushroom poisoning and in diabetic and
alcoholic polyneuropathy, a change in the peripheral nerves
associated with metabolic disorders. (R)- and (S)-thioctic
acid area for example, available in enantiomerically pure
form according to the instructions i.n EP 261 336.
Dihydrolipoic acid is 6,8-dimercapto-octanic acid.
Dihydrolipoic acid is the reduced form of thioctic acid.
Animal experiments have shown that dihydrolipoic acid
inactivates snake venom.
Currently commercially available thioctic acid-containing
tablet formulations contain a maximum of 600 mg
thioctic acid in
_ 1 -
~1.3~~3
- 2 -
an $50 mg film-coated tablet.
In the initial stage of treatment and in the treatment of AIDS,
however, high dosages of thiOCtiC acid are administered, which
can amount to several grams daily in the case of peroral
application. Up to a dosage of 300 mg thioctic acid, film-coated
tablets can be prepared in a form which it is still more or less
possible to swallow. In higher dosages, however, the moulded
pieces assume a size which has a negative effect on patient
compliance. Tablets of this kind are also poorly tolerated in
the gastro-intestinal tract and can herefore no longer be
given.
Unsuccessful attempts have been made to solve the problem by
giving a solution of thioctic acid in the form of its salts, as
already suggested in European application 0 427 246 A 2', for
example as lysine, arginine, ethylene diarnine or tromethamine
salt. However, these thioctic acid salts have an unsatisfactory
taste.
Unsuccessful attempts have also been made to solve the problem
by giving a suspension of free thioctic acid:
Thioctic acid is, however, characterised by a strong burning
taste which ~.s of long duration. Application in the form of a
drinkable suspension k~as conseguenicly also not been feasible to
date.
It is, m~reover, a disadvantage of drinkable suspensions that
they are not stable once the bohle has been opened and
con's'equently have 'to be filled into single 'dose containers. The
solution is therefore sealed into glass ampoules. The -
preparation of ampoules and of their packing is laborious: The
ampo~xle must be opened by the patient just before use: This is a
complicated procedure for oral use: In addition, the solution is
relatively heavy and takes a great deal of storage space. The
main disadvantage of the drinkable solution is, hocveverE the
~~.3~5~
_ 3 _
very unpleasant taste, with the result that subjects are very
reluctant to take it, even when it is flavoured.
There is therefore an urgent need for processes which make it
possible to apply thioctic acid perorally in high dosages with
gaol patient compliance. This objective is reached in accordance
with the invention by applying thioctic acid, not in dissolved
or pressed form, but as a granulate, or chewable tablet, or in
the form of an effervescent tablet dissolved in liquid. It is
thus an object of the invention to provide a granulate or a
chewable tablet or an effervescent tablet containing thioctic
acid or its salts as active substance. The granulate can either
be taken directly, mixed with food or suspended or dissolved in
liquid and,applied by eating or drinking. The forms of
presentation mentioned also have the advantage of better
tolerability and bioavailability. The granulate can be~filled
into bags, pressed into chewable tablets or pressed into
effervescent tablets after addition of a physiologically
acceptable effervescent mixture:
It contains, related to one part by weight of thioctic acid
0.001 - 1 parts by weight of binding agent
0.001 0.1 parts by weight of flow-enhancing agent
as weld as optionally wetting agents and physiologically
acceptable flavourings, sweeteners and/or aromatic substances:
In the case of a chewable tablet the granulate is mixed with
0,01 - 0:a2 parts by weight of an anti-adhesion agent and
optionally with additional taste-correcting agents such as
fructose, xylitol, sarbitol or mannitol and px~essed'into
tablets.
In the case o'~ an effervescent tablet, the'granulate is mixed
with 0.05 - 30 parts by weight of a conventional physiologically
acceptable effervescent mixture and pressed into tablets after
adding 0:01 0.02 parts by weight of a lubricant:
To mask the taste and improve the tolerability, it is advisable
to use the thioetic acid, not in free form; but in the form of
its salts with physiologically acceptable bases or in the form
of inclusion complexes, inclusions or coated particles. It is
also
~13~~~a
possible to use the salts of thioctic acid as inclusions or
coated particles.
Salt formers of thioctic acid that may be considered are; basic
amino acids such as arginine or lysine, physiologically
acceptable alkaline- or alkaline earth hydroxides-, carbonates
or -hydrogen carbonates, ammonium hydroxide, amines of the
formula N R1R~RS where the radicals R1, R2 and R3
are the same or different and represent hydrogen,
C1-CQ-alkyl or C1-C4-hydroxyalkyl such as mono- and
diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol; alkylene
diamine with one alkylene'chain of 2 to 6 carbon atoms such as
ethylene diamine or hexamethylene tetramine; saturated cyclic
amino compounds with 4 - 6 ring carbon atoms such as_piperidine,
piperazine, pyrrolidine, morpholine; N-methylglucamine,
creatine, tromethamine; N-methyl-morpholine. Salts with alkaline
eaxth metals (calcium, magnesium salt), basic amino acids and
tromethamine are preferred. The amounts of thioctic acid given
hereinbelow should be converted according to the molecular
weight if salts are used.
For the peroral administration of high dosages of thioctio acid
there is, as already mentioned, an urgent need for processes
which make it possible to attenuate or entirely eliminate the
burning, taste of thioc~ia acid.
The same problem exists in the case of the peroral
administration of dihydrolipoic acid: There is, howe~rer, not
ohly a need for processes which permit improved peroral
administration of thioctic acid and dihydrolipoic acid, but also
a ri~ed'for improved forms'for other forms o~ administration. The
rectal administration of thioctic acid has, far example,
hitherto been impossible since a strong burning sensation
appeared in the rectum after application: Here, too, there is a
need for formulations which permit rectal applicatioh.
The inhalative (pulmonary) applacat~,on of dihydrolipoic acid in
11~~~3
- 5 -
the form of the aqueous solution of a salt has hitherto been
impossible since the dihydrolipoic acid already oxidised when
the corresponding solution was vaporised. For this reason it is
also difficult to prepare peroral dosage forms of dihydrolipoic
acid with good long-term stability.
Enantiomers of thioctic acid have low melting paints (R-thioctic
acid: 47°C; S-thioctic acid: 46°C~. The manufacture of rapidly
disintegrating tablets on a large industrial scale is greatly
hampered because preparation of the active substances for tablet
manufacture (e.g. drying of the granulate, application and
drying of the film on film-coating) can lead to heating of the
tablets and thus to sintering of the low melting-point active
substance. This has consequences for the disintegration time of
the tablets and on the bioavailability of the active substance.
Another disadvantage of the enantiomeric forms of thioctic acid
is the fact that pure R- and S-thioctic acid easily tend to
polymerization.
It is therefore an object o~ the invention to provide dosage
dorms of thioctic acid (R-enantiamer or 5-enantiomer or
racemate) as well as dihydrolipoic acid (here, too, both
R-enantiomer or S-enantiomer or racemate) with the possibility
of the peroral application of high doses with improved taste as
well as the possibility of local (rectal, pulmonal, nasal,
dermal, vaginal, ophthalmic) application as well as the
simplified manufacture of peroral forms of administration of R-
ox S-thioctic as well as dihydrolipoic acid with improved
bioavailability.
.;
~.
The simultaneous solution of the above-described problems has
surprisingly been achieved by using thioctia acid ox
dihydrolipoic acid in the form of their inclusion compounds with
cyclodextrins or cyclodextrin deri~ratives to prepare the dosage
forms. All cyoladextrins or cyclodextrin derivatives which are
capable of forming an inclusion complex with thioctic acid or
dihydrolipoia acid are suitable for this purpose.
~13~03
- 6 -
7:t has now been found that the inclusion compound of R-thioctic
acid and cyclodextrins, for example f3-cyclodextrin is stable.
The inclusion compound of S-thioctic acid and cyclodextrins, fox
example 13-cyclodextrin is also stable.
The use of cyclodextrins for the manufacture of inclusion
compounds is in general already known. A number of patent
applications and publications describe possible areas of use.
The use of cyclodextrin derivatives has, in particular, been the
object of investigations in 'the past (see in this connection
European patent applications 0 312 352, 0 381 747, 0 463 653, 0
512 050, 0 149 197.).
EP 427 247 discloses urea, thiourea, cyalodextrins and amylose
as complex formers for R- or S-a-lipoic acid.
These complex fo~mers are used, in the context of conventional
pharmaceutical manufacturing methods. No advantageous effects
are associated with the use of the complex former. It may
optionally be necessary to add additional stabilisers, fox
example buffers.
2n the case of the compounds of the invention composed of
R-thioctic acid and f3-cyclodextrin and of S-thioctic and
!3-cyclodextrin it is gossi.ble to abstain from using additional
stabilisers.
Existing publications on the possible use of cyclodextrins
predominantly deal with improving the solubility of poorly
soluble substances or with improving the transdermal or nasal
t~a~lsport of ~activs substances .
None of these patent applications or publications describe
inclusion compounds of cyclodextrins or cyclodextrin derivatives
with tY~ioctic acid or dihydrolipoic acid; in particular not the
advantages associated with the use of the inclusion compounds
compared to free thioctic acid or dihydrolipoic acid.
~1~~~3~~
The improvement in taste of disagreeably tasting substances
achieved by the manufacture of inclusion compounds had also
already been described. It is, however, a fact that there are
many active substances for which the improvement in taste is
totally inadequate (for example azelastine). It is surprising
that, in the case of thioctic acid and dihydrolipoic acid the
strong burning taste oan be totally inhibited by incorporation
in cyclodextrins. At the same time, the bioavailability of these
substances, compared to the free acids, is not impaired, but on
the contrary even.inoreased.
Cyclodextrins that'may be used are: a-cyclodextrin
(cyolohexaamylose, with a ring structure based on 6-glucose
units'), f3-cyclodextrin '(cycloheptaamylose, with a ring
construction based on 7-glucose units); Y-cyclodextrin
(cyclooctaamylose, with a ring construction based'on 8-glucose
units),
The following derivatives of a-, t~- or y-cyclodextrins
(hereinafter designated ~D)' can be used: .
Methylated CD; examples:
2 . 6-Dimethyl-f3-CD
Methyl-~-CD
Carboxymethyl-CD
~iydroxyalkyl-CD
Examples: hydroxypropyl-B-CD
hydroxyetl~yl-13-CD
Ethylated CD
,,'
i. ; i ~ , ., i , ,
Dialkylamino ethylated CD
gulfoalky~-CD ,
Partially methylated carboxyacyl-CD
~~.3a~~~
_8-
Branched chain CD
glucosyl, diglucosyl, maltosyl,
dimaltosyl CD
Dimerised CD
(dimerization for example via diesters, diamines or
diamides).
Polymerized CD
!3-Cyclodextrin is particularly suitable, not the least because,
for example, the Japanese authorities have already accepted it
as a food additive and because it is available at law cost
(manufacturer far example: blacker Chemie GmbH, Munich).
Hydroxpropyl-f3-cyclodextrin and methyl Y-cyclodextrin are
particularly suitable for liquid formulations.
The manufacture o~f the inclusion comp7.ex of thioctic acid or
dihydrolipoic acid can be effected in various ways. The
following method is the simplest:
Thioctic acid or dihydrolipoic acid are suspended with 4.7 - 50
times, preferably 6'- 20 times, in particularly 7 - 12 times (in
each case anhydrous and amounts by weight).cYclodextrin or
cyclodextrin derivative in water at about 40°C and stirred for
several hours: This dissolves the thioctie acid or dihydrolipoic
acid. During cooling, the inclusion compound precipitates out
and can be filtered off.
The'above described process can be used to inc~.ude both R- and
also S-thioctic in enantiomerically pure form:
When easily water-soluble cyolodextrins or cyclodextrin
derivatives are used it is also possible to proceed in such a
way that, after dissolution of the thioctic acid or
dihydrolipoic acid, the solution formed is directly further
processed, for example to emulsibns, injectable solutions or eye
drops, or the inclusion compound is obtained by freeze- or
spray-drying.
~~.~~~3
_ g _
Another possibility of manufacture consists in kneading thioctic
acid or dihydrolipoic acid together with cyclodextrin or
cyclodextrin derivative and equal garts of water (related to
cyclodextrin) for several hours at 40°C and then drying the mass
obtained.
The inclusion compounds of. thioctic acid or dihydrolipoic acid
are suitable for the manufacture of granulates, powders,
tablets, chewable tablets, effervescent tablets, effervescent
granulates, pellets, capsules, suppositories, creams, ointments,
lotions, emulsions, suspensions, solutions. Application can be
peroral, intra-~ar~erial, intracardial, intravenous,
intramuscular, dermal, rectal, ophthalmic, nasal, vaginal,
pulmonal.
Compared to hitherto available formulations, the formulations
conta~.ning the inclusion compounds according to the invention
ire advantageous not only because of their improved taste, but
also because of their improved stability, tolerability,
biaavailability and easier manufacture.
The manufacture of the dotage forms mentioned occurs using
conventional processes knpwn in pharmaceutical technology, in
each case using the inclusion compound according to the
invention.
Granulates are manufactured in the following manner:
The dried inclusion compound is, for example, granulated in
con~rei~tional vmanner with' binding agents and wetting agents, '
mixed with flavouring and/or sweeteners and filled into sachets
(bags) of the appropriate dosage. In use; the contents of the
bag are stirred into water or fruit juice and drunk: This method
makes it easy to apply any level of dosage by the peroxal route.
To prepare an effervescent tablet or an effervescent granulate,
the inclusion compound'is granulated in conventional manner (for
~1~~~3
...,
- 10 -
example in a vacuum granulatar) with a carbonate or an acid
component and the mixture obtained is pressed into tablets or
filled into bags after addition of flavourings, of still missing
acid components or of the carbonate as well as other
conventional flow regulation and mould-releasing agents.
Application is also by taking the tablet or granulate in water.
The resultant suspension has an agreeable taste, i.e. does not
have the hitherto common burning and hydrogen sulfide-like
taste.
Another method of improving the taste and tolerability consists
in incorporating ~hioctic acid or salts of thioctic acid in the
following substances or mixtures of these substances:
- Digestible fats, e.g. triglyeerides of saturated fatty acids
C8H1s02 to C18H3602 and mixtures thereof,
- hydrated peanut oil, hydrated castor oil, hydrated
cottonseed oil, mixtures of mono-, di-, triesters of
palmitic and stearic acid with glycerol, glyceryl trioleate,
diglycol stearate, stearic acid.
Indigestible fats or fat-like substances, e.g. esters of
aliphatic saturated or unsaturated fatty acids (2 to 22
carbon atoms, in particular 10 to 18 carbon atoms) with
monovalen~. aliphatic alcohols (1 to 20 carbon atoms}.
Carnauba wax, beeswax, paraffin wax, fatty alcohols
(straight-chain ox° branched chain} of chain length
C8H1~OH to C3pH610H, in particular C12H250H to
'C2~H490H:
- Polymers such as polyvinyl alcohol, polyvinyl chloride,
polyacrylio acid (CarbopolR}~ anionic polymerisates of
methacrylic acid and methacrylic acid esters (EudragitRL,
EudragitRS), acrylic anc3 methacrylic acid ester
copolymerisates with trimethylammonium methacrylate
(EudragitRRL, EudragitRRS), copolymerisate of acrylic
CA 02135535 2005-O1-14
- 11 _
acid ethyl- and methacrylic acid methyl esters
(EudragitRNE 30 D), as well as of acrylic acid, methacylic
acid and their esters (ratio of the free carboxyl groups to
the ester groups 1:1) (EudragitR-L 30 D), polyethylene,
polyglycol acid, polyhydroxybutyric acid, polylactic acid,
copolymers of lactic acid and glycolic acid (manufacturer:
Boehringer Ingelheim), copolymers of lactic acid and
ethylene oxide, copolymers of glycolic acid and ethylene
oxide, copolymers of lactic acid and hydroxybutyric acid, .
hydroxypropyl methyl cellulose-phthalate or acetate
succinate; cellulose acetate phthalate, starch acetate
phthalate as well as polyvinyl acetate phthalate; methyl
cellulose phthalate, -succinate, -phthalate succinate,
methyl cellulose-phthalic acid half ester; zein; ethyl
cellulose; schellak, gluten; ethylcarboxyethyl cellulose;
ethycrylate-malefic acid anhydride copolymer; malefic acid
anhydride-vinylmethyl ether copolymer; styrol-malefic acid
copolymerisate; 2-ethylhexyl-acrylate-malefic acid anhydride;
crotonic acid-vinylacetate copolymer; glutaminic
acid/glutamic acid ester copolymer; carboxymethyl
cellulose-glycerol monooctanoate; cellulose acetate
succinate; polyarginin; cross-linked alginate; cross-linked
gelatin;
- Swelling agents such as methyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose (Pharmacoat),
propylene glycol ether of methyl cellulose (Methocel E),
alginic acid and its salts (Na-, Ca-salt, also mixtures of
sodium alginate and calcium salts, e.g. CaHPO), starch,
carboxymethyl starch, carboxymethyl cellulose and its salts
(e. g. Na-salt), galaktomannan, gum arabic, karaya gum,
ghatti gum, agar-agar, carragheen, gelatin, xanthan gum,
guar gum and its derivatives, locust bean gum, propylene
glycol alginate, pectin, tragacanth, gum acacia.
In the case of these incorporating materials, 1 part by weight
of thioctic acid is used with 0.1 - 20 parts by weight of
incorporating material,
~1~~~3a
- 12 -
preferably 0.15 - 15, in particular 1 to 10 parts by weight of
incorporating material.
The preparation of these incorporating agents occurs at
temperatures between 18°C and 80°C. The manufacture may be
effected
a) by dissolving or dispersing thioctic acid or its salts in
the stated fats or fat-like substances or mixtures thereof,
also by melting the substances named and subsequent further
cooling, pulverization. The cooling of the melts and
pulverization can also be combined in one step by dispersing
the melt in cold water or subjecting it to spray
solidification
b) by mixing thioctic acid or its salts with the stated fats,
polymers or swelling agents or mixtures of these substances,
also with applicata.on'of heat and pulverization
c? by mixing thiootic acid or its salts with solutions of the
stated fats or polymers in water or organic solvents such as
ethyl acetate, acetone or isopropanol, possibly mixing with
carrier materials such as celluloses, as well as subsequent
evaporation of the solvents or spray drying and mixing the
the active substance incorporated with to be additional
auxiliary substances
b) by moistening a mixture of thioctic acid or its salts and
the stated swelling agents with organic solvents such as
ethanol, ethyl acetate, acetone or isopropanol, possibly
'adding binding agents such as polyvinyl pyrrolidone or
copolymers of polyvinyl pyrrolidone and polyvinyl acetate.
Granulata.ng the mixture olatained;'subsequent drying.
It is also possible to improve taste and tolerability by coating
granulate that contains thiovtio acid ar salts of thioctic acid
with physiologically acceptable salt formers. In this case it is
possible to use coatings which, for example, only dissolve in
the gastric juice or intestinal tract. To prepare the coatings
it is, for example,
:~ , ~13~~3
13
possible to use: copolymerisates of dimethylamino acrylic acid
and neutral methacrylic acid esters which are insoluble in water
and saliva, but soluble in the acid range (for example
EudragitRE; manufacturer: Rohm GmbH). It is, however, also
possible to use gastric juice-resistant lacquers such as
hydroxypropylmethyl cellulose phthalate or -acetate succinate;
starch, as well as polyvinylacetate phthalate; carboxymethyl
cellulose; polyvinyl acetate; methyl cellulose phthalate, methyl
cellulose succinate, methyl cellulose phthalate succinate as
well as methyl cellulose phthalic acid half ester; zein, ethyl
cellulose as'well as ethyl cellulose succinate; schellak;
gluten; ethyl carboxyethyl cellulose; ethacrylate-malefic acid
anhydride'copolymer; malefic acid anhydride-vinyl methyl ether
copolymer; styrol-maleic'acid copolymerisate;
2-ethylhexyl-acrylate-malefic acid anhydride; crotonic acid-vinyl
acetate copolymer; glutaminic acid/glutaminic acid ester
copolymer; aarboxymethyl cellulose glycerol monooctanoate;
cellulose acetate succinate; polyarginin; fats, waxes, fatty
alcohols; anionic polymerisates of methacrylic acid and
methacrylic acid esters (EudragitRL, EudragitRS);
copolymerisat~s of acrylic- and methacrylic acid esters with a
low ammonium group content (EudragitRRS), as well as
copolymers of acrylic and methacrylic acid esters and trimethyl
ammonium methacrylate (EudragitRRL), copolymerisate of acrylic
acid ethyl;- and methacrylic acid-methyl;. esters 70:30'
(EudragitRNE 30 D),;copolymex~isate of acrylic acid,
methaarylic acid as well as esters thereof (ratio of 'free
carboxyl groups to the ester groups e.g.: 11) (EudragitRL 30
),
The~cited sub~taric~'s may in addition contain conventiarial'
soft~riers (e. gdibutyl seba~ate,'citric and tartaric acid
ester, glycerol and; glycerol.sster, phthalic acid ester. and
similar substan;ces), it is also. possible to add water soluble.
substances suoh as polye hylene glycols, po7.yvinyl pyrrolidone;
copolym~risate of,~olyvinyl pyrrolidone and polyvinyl acetate,
hydrox,ypro~yl eellulose,'hydroxypropyl, methyl cellulose. It is
CA 02135535 2005-O1-14
- 14 -
also possible to add solids such as talcum and/or magnesium
stearate to the coating.
The coating is effected by spraying on solutions in organic
solvents or water, it also being possible to add further
auxiliary substances to optimize their workability, such as
surface-active substances, pigments. Spraying on is effected for
example in a coating drum or in perforated drums or in an air
,~,
suspension process (e.g. WLSD 5 Glatt fluidised air bed
apparatus).
Coating may also be effected in a coacervation process whereby
so-called microcapsules are formed. The coating may also be
effected by coagulation of aqueous dispersions of the previously
cited substances by mixing the active substance with the
dispersion and removing the water by drying.
0.0125 - 2 parts by weight of lacquer dry substance related to
one part by weight of thioctic acid should be applied to the
granulate. It is also possible to coat the thioctic acid
granulate with xanthan and/or maltodextrin and fumaric acid, as
described in DE 34 40 288. Granulate particles are considered to
be irregularly shaped or regularly shaped (for example spherical
or cylindrical) bodies with a diameter of 0.05 to 3 mm. It is
also possible to coat thioctic acid or its.salts with
cyclodextrins or cyclodextrin derivatives. In this case it is
surprising that, despite the small amount of cyclodextrin
compared to true active substance incorporation, it is possible
to mask the burning taste. In order to mask the taste of the
thioctic acid, surface formation of inclusion complexes clearly
suffices. It is, for example, sufficient to coat thioctic acid
with 1 to 3 parts by weight of cyclodextrin related to 1 part by
weight of thioctic acid. Once again, B-cyclodextrin is.
particularly suitable.
The above described incorporated thioctic acid or dihydrolipoic
acid and their salts in cyclodextrins, various incorporating
substances or in the form of coated particles can be formulated
as a chewable or effervescent tablet or as granulate (also
~~.~~ ~3
- 15 -
effervescent granulate). If the form of the invention is an
'y ~~.~a~3
- 16 -
using conventional processes as described in the literature (for
example in the standard reference work Sucker, Fuchs, Speiser,
Pharmazeutische Technologie, Thieme Verlag, Stuttgart). The
preparation (all steps apart from drying) occurs for example at
temperatures between 10°C and 80°C, preferably 18°C to
50°C in
particular 20°C to 30°C. Drying of the granulate preferably
occurs between 30°C and 80°C, preferably between 40°C to
70°C.
In manufacture it is, for example, possible to use all
conventional pharmaceutical binding agents such as cellulose
derivatives (for example ethyl cellulose, hydroxyethyl
cellulose, carboxymethyl cellulose, methyl cellulose,
hydroxypropyl methyl cellulose), gelatin, starch, polyglycols
(mean molecular weight 1000 - 3500 Dalton), polyvinyl alcohols,
polyvinyl pyrxolidone', polyacrylic acid, vinylpyrrolidino-vinyl
acetate copolymerisate, alginates, saccharose or glucose,
polysaccharides such as natural varieties of gum, such'as gum
arabic, tragacanth, pectin, cyclodextrin, guar gum in amounts of
'f - 30 ~ by weight, preferably 5 - 20 ~ by weight, in particular
- 15 ~ by weight related to the amount of granulate
(concentration of the aqueous binding agent solution 2 - 30 ~ by
weight, preferably 'S - 15 ~ by weight). At the same time it is
also possible to use various binding agents, for example
different cellulose derivatives in association. The binding
~g~nts can be worked into the dry powder mixture or dissolved or
dispersed into the granulating liquid:
The combination of dry presented and dissolved or dispersed
binding agents is also suitable. If required; the granulate is
mixed with filling, binding, disintegrating, wetting,
flow-enhancing, lubricating andjor anti-adhesion agents.
~ ,-
Filling agents which may, far example, be used are: cellulose,
cellulose derivatives, saaaharose, lactose, glucose, fructose;
cale3um phosphates, calcium sulfates,'calcium carbonates,
starch, modified starch, sugar alcohols such as sorbitoZ or
manni: tol
<IMG>
~13)J~s3
- 18 -
The granulate, the chewable or effervescent tablet contain for
example 100 mg to a maximum of 3 g thioctic acid. Thioctic acid
is generally present in such an amount that it constitutes 10 -
80 percent by weight. Tt is also recommended to mix in
flavouring, sweetening and/or aromatic substances. Aromatic
substances that may, for example, be used are: pineapple, apple,
apricot, raspberry, cherry, cola, orange, passion fruit, lemon,
grapefruit, vanilla, chocolate. The granulate should contain
0.05 - 0.2 parts by weight of aromatic substance related to 1
part by weight of thioctic acid.
The following substances may be used as sweeteners: saccharin
and its sodium salt, cyclamic adid and its sodium salt, ammonium
glycyrrhizinate, fructose, xylitol, sorbitol, mannitol,
aspartam, acesul~am-K. A mixture of 1 part saccharin-sodium and
parts sodium cyclamate (in each case parts by weight) is
particularly preferred. The granulate should contain 0.003 - 12
parts lay weight of sweetener, related to 1 part by weight of
thioctic acid or dihydrolipoic acid:'
Example 1:
A d~inkak~le: granulate with 1000 mg thioctic acid as inclusion
compound with B-cyolodextrin
136.2 g !3-cyclodextrin are dissolved in water at 40°C. After
adding 12 g finely powdered thioctio aefd, the mixture is
further stirred atv 40°C until the thioctic acid has passed into
s'olixtion: Remains of undissolved thioetic acid are filtered'off.
The filtrate- is Gaoled to +5°C and the precipitate formed is
filtered off after 12 hours: The result is dried at 40°C until
constancy of weight is achieved: The yield is 68 g (= 85~). The
inclusion compound contains about l5~ thiactic acid: The
inclusion compound with B-cyclodextrin may also be prepared by
mixing 1261 g 13-cyclodextrin (water content about 10~) with 1250
g water and heating the mixture to 40°C. 206.3 g
~1~~~3a
- 19 -
thioctic acid axe then added and kneaded at 40°C for 4 hours.
The mass is then dried at 30°C in a vacuum at 3 mbar and sieved.
~1~~~~
- 20 -
Example 4:
A suppasitary with 50 mg thiactic acid as inclusion compound
with 13-cycladextrin
1.78 kg hard fat*) are melted and 20 g soya lecithin are worked
therein. 500 g of the inclusion compound thioctic acid /
~i-cyclodextrin prepared according to Example 1 are then stirred
into the melt and intensively homogenized. The suspension
obtained is poured into hollow cells of 2.3 g each and cooled.
*) kiard fat is a mixture of mono-, di- and triglycerides
of the saturated fatty acids C1OH20C2 to
C18H36o2
Example 5:
Eye drops with 1% thioctic acid as inclusion compounds with
hydroxypropyl,-f3-cyclodextrin
120 g hydxoxypropyl-!3-cyclodextrin (manufacturer: Wacker Chemie
GmbH, Munich) are dissolved in 750 ml water far injections. 10 g
~hioatic acid are added at a temperature of 40°C and stirred
until dissolved. The solution is filled up to 1000 m1 with water
for injections, sterile filtered through a membrane filter of
pare size 0.2 m and filled under aseptic conditions in single
dose containers of 0.4 m1 each. It is alsa possible to use
dihydralipoic acid instead of thioctia acid.
i
~13~~3':
- 21 - '
Example &;
A chewable tablet with 400 mg thioctic acid inclusion compound
with f3-cyclodextrin.
200 g of the inclusion compound thioctic acid / t3-cyclodextrin
prepared according to Example 1 are mixed with 50 g sorbitol and
0.50 g saccharin-sodium and granulated in conventional manner
with the addition of water. After drying and sieving, 10 g
talcum and a trituratian of 1 g peppermint oil in 2 g highly
disperse silicon dioxide are added and the mixture obtained is
pressed into tablets weighing 3.52 g. It is also possible to use
the l~-enantiomer or S-enantiomer instead of the racemate of
thioctic acid.
Example,?
A granulate with 1000 mg thioctic-acid as inclusion compound
with a-oyclodextrin
33>01,g thioctic acid are sieved through a sieve of mesh size
0.5 mm. 172. g a-cyclodextrin (contains approx: 10~ water) are
suspended 'in 700 g water at 50°C: 3.3 g Na-asaorbate are added
thereto. The'sieved thioctic acid is then-added. The suspension
so-obtained is stirred for 3 hours-at'S0°C. The suspension is
then 'filtered and the filtrate cooled (5°C, '!2 hours):
The precipitate hereby formed is separated by_.filtration and
dried'.in a'vacuum drying'oabinet (30°C, 2 hours, pressure < 10
mbar). The, powder so-obtained contains 157:8 mg'thioctic acid
pex'gram powder. 50 g of this inclusion compound are mixed with
1 g copolyvidon and 0.5 g'sacchara.n-sodium and granulated in
conventional manner with addition of purified water. The dried
granulate-is imi~xed with 2 g taste-correcting agent and 0:5 g
highly disperse si~.icon dioxide amd filled into bags; weighing
6.84 g each. One bag contains 1000 mg thioctic acid as inclusion
compound with «-cyclodextrin.
~13~~3
- 22 -
Example 8
A drinkable tablet with 600 mg thioctic acid
60 g sodium alginate are dissolved in 3 1 purified Water, 300 g
thioctiG acid are stirred therein and homogenized. This
suspension is sprayed with the aid of a fluidized bed spray
granulator onto a mixture consisting of 40 g highly disperse
silicon dioxide and 250 g cross-linked polyvidon. The granulate
obtained in this manner is sieved and again sprayed with a
solution consisting of 96 g calcium chloride in 900 ml purified
water in the fluidized bed spray granulator.
The product so-obtained is sieved, mixed with 5 g magnesium
stearate end 4 g highly disperse silicon dioxide and pressed
into tablets weighing 1510 mg. One tablet contains 600 mg
thioctic acid. The tablet is allowed to disintegrate in water
for use.
