Note: Descriptions are shown in the official language in which they were submitted.
CA 02097732 2002-04-11
COMPOSITION COMPRISING R-ALPHA-LIPOIC ACID AND
VITAMIN E FOR TREATING DIABETES MELLITUS
Alpha-lipoic acid is 1,2-dithia-cyclopentane-3-valeric acid.
Alpha-lipoic acid is widespread in plants and animals in the
form of the R-enantiomer; it acts as a coenzyme in many
enzymatic reactions, constitutes a growth factor for certain
bacteria and protozoa and is used to treat death-head mushroom
poisoning. The alpha-lipoic acid racemate also has
anti-inflammatory, antinociceptive (analgesic) and
cytoprotectide, neuroprotective, .anti-.allergic and antitumour
properties.
Of the purely optical isomers of alpha-lipoic acid (R- and
S-form, i.e. R-alpha-lipoic acid and S-alpha-lipoic acid), a.n
contradistinction to the racemate, the R-enantionmer has a
predominantly anti-inflammatory and the S-enantiomer a
predominantly antinociceptive effect, the anti-inflammatory
effect of the R-enantiomer being for example 10 times stronger
than that of the racemate.
The antinociceptive (analgesic) effect of the S-enant:iomer is
for example up to 6 times stronger than that of the racemate.
The enantiomers thus constitute very much more specific and
stronger acting active substances as compared to the racemate.
These effects are described in EP-A 901213405.
The combination partner vitamin A is essential for growth, for
bone development, normal function of the reproductive organs and
the eyes and, above all, for the structure and function of
mucous membrane epithelium.
-, 209~'~3~
- 2 -
The combination partner vitamin E essentially maintains the
function of all cells, also those of the nervous system. Its
main function is to protect lipids from peroxidation. Japanese
published patent 3-193778 describes esters of lipoic acid with
tocopherols. These tocopherol esters of lipoic acid are used to
treat W-erythemas.
The combination partner vitamin B1 is mainly active in thiamine
deficiency syndrome, i.e. with severely deficient diet,
long-term parenteral feeding, zero-diet, hemodialysis,
malabsorption and alcohol abuse.
The combination partnerwitamin B2 mainly acts in deficiency
symptoms caused~by alcohol abuse or insufficient intake of m:iik
and milk products.
The combination partner vitamin B6 mainly acts in deficiency
symptoms caused by alcohol abuse or chronic medicament intake
(oral contraceptives, isoniazid).
The combination partner vitamin B12 mainly acts in strict
vegetarians, after gastric resection and atrophy of the mucous
membrane or intestinal disorders which lead to deficiency
symptoms such as anaemias, precipitations of the peripheral and
central nervous system and polyneuropathies.
The combination partner vitamin C is part of the biochemical
redox system and is involved in numerous electron transport
reactions. These include inter alia collagen synthesis,
noradrenaline, dopamine.and serotinin synthesis and the
degradation of 4-hydroxyphenylpyruvate. It also encourages the
absorption of iron and has a stimulating effect on leucocyte
phagocytosis activity. Together with carotinoids, vitamin A and
E, vitamin C has been shown to have an antitumour effect.
~o~~~~
The invention provides the preparation of improved
medicaments with analgesic, anti-inflammatory, antidiabetic,
cytoprotective, anti--ulcer, antinecrotic, neuroprotective,
detoxifying, heavy metal antidote, anti-ischemio, liver
function regulating, anti-allergic, immune-stimulating and
antioncogenic effect.
The tocopherols (vitamin E) used in the preparation
according to this invention can be alpha-tocopherol, B-
tocopherol, gamma-tocopherol or delta-tocopherol. These can
0 be used from natural oils (d-form) as well as from synthetic
material (dl-form).
It is also possible to use tocopherol acetate as well as
other esters of physiologically acceptable acids.
It has surprisingly been found that in the combination
5 of active substances, such as vitamin E with the pure optical
isomers of alpha-lipoic acid (R- and S-form, i.e. R-alpha-
lipoic acid and S-alpha-lipoic acid) in contrast to the
racemate of alpha-lipoic acid alone, the R-enantiomer has an
anti-inflammatory and antidiabetic action, i.e. it reduces
0 blood sugar, and the S-enantiomer has an antinociceptive
effect in combination with vitamin E, the anti-inflammatory
effect of the R-ena-ntiomer in combination with vitamin E is
surprisingly also stronger than that of the racemate of
alpha-lipoic acid. The antinociceptive (analgesic) effect of
5 the S-enantiomer in combination with vitamin E is for example
stronger than that of the racemate of alpha-lipoic acid. The
enantiomers in combination with vitamins A, B1, B2, B6, B12,
C and E are therefore very much more specific and stronger
acting active substances compared to the racemate of alpha-
0 lipoic acid.
There are in particular the following differences
compared to alpha-lipoic acid (racemate) in combination with
the vitamins: A, B1, B6, B12, C or E.
5
- 3 -
In aqueous solutions the salts are preferably used with
pharmaceutically acceptable salt formers.
The preparation of alpha-lipoic acid, dihydrolipoic acid
or of the oxidized or reduced R-alpha-lipoic acid and of S
alpha-lipoic acid or the metabolites of alpha-lipoic acid as
well as their salts in combination with the vitamins listed
is effected in known manner, or by analogy thereto (DE-OS 41
37 773).
Salt formers for the active substances can for example
0 be conventional bases or cations which are physiologically
acceptable in the salt form. Examples hereof are: alkaline
or alkaline earth metals, ammonium hydroxide, basic amino
acids such as arginine and lysine, amines of formula N R12 R2
R3 where the radicals R1, R2 and R3 are the same or different
5 and represent hydrogen, C1-C4-alkyl or C1-C4-oxyalkyl such as
mono and diethanolamine, 1-amino-2-propanol, 3-amino-1-
propanol; alkylene diamine with one alkylene chain composed
of 2 to 6 carbon atoms such as ethylene diamine or
hexamethylene tetramine, saturated cyclic amino compounds
0 with 4 - 6 ring carbon atoms such as piperidine, piperazine,
pyrrolidine, morpholine; N-methylglucamine, creatine and
tromethamine.
RESULTS OF THE COMBINATIONS IN VARIOUS TEST MODELS:
5
1 ) Analgesia
In the acetic acid writhing pain test in the mouse and
the Randall Selitto inflammation pain test in the rat
0 the S-enantiomer (S-alpha-lipoic acid) for example shows
an analgesic effect which is superior to that of
alpha-lipoic acid alone (i.e. the racemate) or of
vitamin E alone (peroral application).
5
- 4 -
2) Anti-inflammatory action
- 5 -
In carragheen-edema in the rat the R-enantiomer
(R-alpha-lipoic acid) fox example shows an anti-inflammatory
effect which is superior to that of alpha-lipoic acid
(alone) or to vitamin E alone (peroral application).
Cytoprotective, antinecrotic and anti-ulcer effect
In addition, a cytoprotective effect is for example apparent
in animal experiments both for the oxidized or reduced R-
and S-foxxa of alpha-lipoic acid in combination with.vitamin
E starting from a dose as low as 20 mg/kg R- or S-isomer of
alpha-lipoic acid in combination with 50 mg/kg vitamin E per
os.
4) Antidiabetic effect
Tn the alloxan diabetes model or the streptocytozine
diabetes model the R-enantiomer (R-alpha-lipoic.acid) in
combination with vitamin E for example displays for example
an antidiabetic, i.e. blood sugar-reducing effect, which is
superior to that of alpha-lipoic acid (alone) or to vitamin
E alone (peroral application).
5j Liver metabolism regulating effecti
In the rat, the R-enantiomer (R-alpha-lipoic acid) in
combination with vitamin E disglays for example a liver
enzyme-regulating effect which is superior to that of
alpha-lipoic acid.(alone) or to vitamin E alone (peroral
application).
2~~'~'~~2
- 6 -
6D Detoxifying (heavy metal antidote) effect
In the heavy metal intoxication model in the rat, reduction
in the heavy metal content in the liver, and thus a
detoxifying effect, is for example present both for the
oxidized or reduced racemates or R- and S-foray of
alpha-lipoic acid in combination with vitamin E from as low
a dose as 30 mg/kg R- or S-isomer of alpha-lipoic acid in
combination with 50 mg/kg vitamin E per os.
~) Immune stimulating effect
In cats infected with panleucopenia virus an immune
stimulating effect occurs for example in animal experiments
both for the oxidized or reduced R- and S-form of
alpha-lipoic acid in combination with vitamin E from as low
as dose as 35 mg/kg R- or S-isomer of alpha-lipoic acid in
combination with 50 mg/kg vitamin E per os. .
8) Growth-inhibiting effect on retroviruses
In addition, R- and S-alpha-lipoic acid in combination with
vitamin E have a growth inhibiting effect against
retroviruses, in particular the human immune deficiency
virus HIV (HIV-1, HIV-2) and are therefore also suitable for
the treatment of diseases caused by viruses of this type.
They have a good, growth-inhibiting effect on HIV (types 1
and 2) which can for example be shown in vitro in the
following virological-cell biological animal procedures:
1. Plague reduction test
2. CPE reduction test
3. Determination of reverse transcriptase in the culture
supernatant
4. Determination of p24 antigen in the culture supernatant
2~~7'~32
Thus, for example, with a single administration of 0.035
mg/ml R- or S-isomer in combination with 0.1 mg vitamin E the
number of infectious viruses (for example HIV-1) in the cell
culture supernatant is reduced from 100% in the positive
control to 0~. A virus-inhibiting effect can be shown in
this test procedure in very low doses, far example 0.001
mg/ml.
As a general dose range for the effect (experiment as
above) it is for example possible to use:
0 0.0035 - 0.091 mg/ml R- or S-isomer in combination with 0.001
- 0.01 mg/ml vitamin E, in particular 0.035 - 0.070 mg/ml R-
or S-isomer in combination with 0.01 - 0.1 mg/ml vitamin E.
For the in vitro trials the active substance or the
combination of active substances is for example used in
5 benzyl alcohol as solvent.
For the in vitro investigations of the replication
performance of retroviruses, in particular HIV, the following
substrates can for example be used:
0 1. Virus-containing RPMI 1640 medium, for example 1X liquid
041-01875 (Gibeo synthetic culture medium according to
Moose, Gerner and Franklin, H.A. (1967), J.A.M.A. 199;
519) with a concentration of 2 x 103 - 1 x 103
infectious units (PFU)/ml.
5
2. The cell lines Jurkat Clone E6-1, Sup T1 and HeLa CT4.
The combinations of the active substances with, the
vitamins display a good analgesic, anti-inflammatory, anti
0 arthrotic and cytoprotective effect in the following
investigatory models:
MgS04 writhing test in the mouse after GYIRES et al. (Arch.
int. pharmacodyn, therap. 267, 131-140, 1984) adjuvans-
arthritis in the rat after NEWBOULL7 (Brit. J. Pharmacol. 21.,
5 127-136, 1963) Na-monoiodacetate-induced arthrosis in rats
- 7 _
and chickens according to KALBHEN in: Arthrosis deformans,
Eular-Verlag, Basel/Switzerland, 1982; intestinal ulceration
in rats after DEL SOLDATO (Agents and Actions 23, 1/2, 1988).
The combinations of the active substances with the
vitamins A, B1, B6, B12 C or G show a cytoprotective,
detoxifying effect in the following investigatory models:
Examination of acute cell toxicity in mouse fibroblasts
(L 929) or the like after: LINDL et al. in: Zell and
Gewebekultur, Gustav Fischer Verlag, Stuttgart, New York, 2nd
0 edition, 1989, pages 164-167.
The combination of the active substances with the above
vitamins show a good effect on metabolic activity in the
following investigatory.models:
Examination of the influence of a substance on metabolic
5 activity after: LINDL et al. in: Zell and Gewebekultur,
Gustav Fischer Verlag, Stuttgart, New York, 2nd edition,
1989, pages 167-168.
The combinations of the active substances with the above
vitamins,show a good growth-inhibiting effect in the
0 following investigatory models:
Examination of the growth-inhibiting properties of a
substance using mouse fibroblasts (L929) or human fibroblasts
(MRC9) after: LINDL et al. in: Zell and Gewebekultur,
Gustav Fischer Verlag, Stuttgart, New York, 2nd edition,
5 1989, pages 162-164.
The combinations of the active substances with the above
vitamins show a good phagocytosis-inhibiting effect in the
following investigatory model in macrophages:
Examination of the phagocytosis activity of macrophages after
0 G. ROSSI, in: Zellkultur-Methoden, Berlin Oct. 7-9, 1987
Publ. H.R. Maurer, Inst. fur Pharmazie der freien universitat
Berlin, Sept. 29, 1987, page 163.
5
_ g _
_ g _
TOXICOLOGY OF THE COMBINATIONS COMPARED TO THE INDIVIDUAL ACTIVE
SUBSTANCES
The acute toxicity of R-alpha-lipoic acid and S-alpha-lipoic
acid in the mouse (expressed as the LD50 mg/kg; LITCHFIELD and
WILCOXON method, J. Pharmacol. Exp. Ther. 95, 99 (1949) ) is for
example in excess of 1000 mg/kg with oral application.
TOXICITY
alpha-lipoic acid (racemate)
LD50 p.o.mg/kg Species
502 mouse, male
460 mouse, female
1190 rat, male
1210 rat, female
Vitamin H1
LD50 p.o.mg/kg i.v.mg/kg ' Species
8200-13300 85 - 125 mouse
12300 200. - 250 rat
Vitamin B6
LD50 p.o.mg/kg i.v.mg/kg Species
8400 1020 . mouse
5500-15900 1450 rat
Vitamin B12.
LD50 p.o.mg/kg Species
1600 mouse
Vitamin C
LD50 p.o.mg/kg i.v.mg/kg Species
8021 1058 mouse
>5000 i000 rat
Vitamin E
L050 p.o.mg/kg i.v.mg/kg Species
>50,000 >2100 yaouse
>5000 >1500 rat
Examples: TOXICOLOGY OF THE COMBINATIONS
alpha-lipoic acid (racematej with 30 mg/kg vitamin E
LD50 p.o. . Species
>1200 mg for alpha-lipoic acid mouse
Vitamin E (30 mg/kg p.o.~ with R-enantiomer of alpha-lipoic acid
LD50 ~ p.o. Species
>1200 mg for the R-enantiomer of mouse
alpha-lipoic acid
Vitamin E (30 mg/kg p.o.) with S-enantiomer of alpha-lipoic acid
. 0 ~5~ p.o. Species
>1200 mg for the S-enantiomer of mouse
alpha-lipoic said
PHARMACEUTICAL FORMULATIONS
5
The pharmaceutical formulations of the combination of the
active substances of with the vitamins generally contain
between 1 mg to 3 g as single dose, preferably 2 mg to 1.2 g
R- or.S-alpha-lipoic acid for example in combination with 1
0 to 450 mg vitamin E. The active substance levels/kg body
weight achieved should be between 1. 5 and 200- mg for R- and
S-alpha-lipoic acid, preferably between 4 and 100 mg, in
particular between 8 and 70 mg/kg for the R- or S-form of
5
- 10 -
20~~'~32
' ~ - 11 -
alpha-lipoic acid and for example for the vitamin E preferably
between 0.01 and 20 mg/kg BW, particularly between 0.1 and 8
mg/kg BW.
Administration can for example be in the form of tablets,
capsules, pills, coated tablets, aerosols or in liquid form.
Liquid forms of application that may for example be used are:
alcoholic or aqueous solutions as well as suspensions. and
emulsions.
Preferred forms of application are for example tablets
containing between 10 mg and 2000 mg or solutions containing
between 10 ml to 0.2 g/ml liquid of active substances.
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The single dose of active substance of the combination
partner in the combination for example with vitamin E can for
example be:
a) in the oral medicinal form between 50 mg - 3 g, preferably
100 mg - 1.2 g.
b) in the parenteral medicinal form (for example intravenous,
intramuscular) between 50 mg - 2 g, preferably 100 mg - 3 g.
0
C) in medicinal forms for inhalation (solutions or aerosols)
between 100 micrograms - 2 g, preferably 200 micrograms - 1.2
g. The doses according to a) to c) may for example be given
1 to 6 times, preferably 1 to 4 times daily or also as long-
s term infusion, for example with the aid of an infusionate.
The daily dose of R- or S-alpha-lipoic acid in the
combination for example with vitamin E in man may for example
be 2 - 40 mg per kg weight; the single dose for example 1 -
0 10 mg per kg weight, this dose appropriately being given up
to 4 times daily.
The daily dose may for example be between 100 - 600 mg: the
medicaments therefore preferably contain 100 - 600 mg of R-
5 or S-alpha-lipoic acid in a pharmaceutical formulation, a
dose of this kind preferably being given up to 4 times.
For treatment it is for example possible to recommend 1 to 4
tablets 3 times daily with a content of 10 mg to 2 g active
0 substance or for example in intravenous injection 1 to 4
times daily one ampoule/infusion vial of 1 to 100 ml content
with 200 mg to 6 g active slibstance in combination with
0.001 - 2 g of the vitamins.
5
_ 14 -
~~~'~'~32
In oral administration the minimum daily dose of the
active substances in combination with the vitamins is for
example 100 mg; the maximum daily dose in oral administraion
should not exceed 12 g.
The single doss of active substance of the combination
partner vitamins in the combination with the R- or S-isomer
of alpha-lipoic acid can for exampe be for vitamin E:
a) in the oral medicinal form between 10 mg - 2 g,
0 preferably 20 mg - 800 mg, in particular 25 mg - 300 mg.
b) in the parenteral medicinal forms (for example
intramuscular) between 0.1 - 25 mg/kg body weight,
preferably 0.2 - 15 mg/kg body weight, in particular
5 1 - 190 mg/kg body weight.
c) in medicinal forms for inhalation (solwtions or
aerosols) between 0.01 - 15 mg/kg body weight,
preferably 0.1 mg - to mg/kg body weight, in particular
0 0.5 - 5 mg/kg body weight.
The doses according to a) to c) can for example be given
1 to 6 times, preferably 1 to 4 times daily. The daily oral
dose of vitamin E in combination with the oxidized or reduced
5 racemate or R- or S-isomer of alpha-lipoic acid in man can
for example be 0.1 - 12 mg/kg body weight; the single dose of
vitamin E in the combination for example 0.1 - 25 mg per kg
weight, this dose appropriately being given up to 4 times per
day. The daily dose of vitamin E is preferably 200 - 800 mg:
0 the medicaments therefore preferably contain 10 - 250 mg of
vitamin E in a pharmaceutical formulation, a dose of this
kind preferably being given 4 times.
For purposes of treatment it is for example possible to
recommend far the vitamin E in the combination 3 times daily
5 1 to 4 tablets containing 0.001 mg to 800 mg vitamins or for
- 15 -
~ 0 ~'~'~ ~ 2
example in intravenous,injection 1 to 4 times daily one
ampoule/injection vial of 1 to 100 ml content with 0.10 mg to
200 mg of vitamins
In the case of oral administration the minimum daily .
dose for example of vitamin E in the combination is 50 mg;
the maximum daily dose in oral administration should not
exceed 1.5 g.
The medicaments can be used in human medicine alone or
in a mixture with other pharmacologically active substances.
0 The active substances R- or S-alpha-lipoic acid can also be
combined with any other agent active against retroviruses, in
particular HIV, for example didexocyinosine, dideoxycytidine,
however in particular with alpha-interferon and/or
azidothymidine (AZT) or with cytostatics such as for example
5 ifosfamide and endoxan.
The dose amounts cited for the active substances of
always relate to the free acids of alpha-lipoic acid,
dihydrolipoic acid or of oxidized or reduced R- or S-alpha-
lipoic acid. Should these be used in the form of their salts,
- 0 the stated dosages/dosage ranges should be correspondingly
increased to the higher mol weight.
In combinations with other antiretrovirally-effective
substances (component b) only one, but also 2 and more
(preferably 2) antiretrovirally active substances may be used
5 as component b, in the latter case the dosages quoted for
this purpose always apply to the sum of the antiretrovirally
active substances in each case. The expression "dosage unit°'
always relates to a single dose which can also be
,. administered several times per day.
0 Should the dose be quoted in the form of enzyme units,
this is the dose which applies for an entire day, a dose of
this kind being given once, preferably, however, distributed
over one day
5
16 -
209'~'~32
_ 17 _
(for example in infusion form). The dose information in enzyme
units applies in particular to alpha-interferon.
It is for example possible for the combination of vitamin E with
R- or S-alpha-lipoic acid with the component b for example AzT
to mix the two components in each case for example in a ratio of
0.01 to 100 to 100 to 1 equimolar parts of active substance, in
particular in a ratio of 1 to 10 to 10 to 1, preferably in a
ratio of 0.1 to 3 up to 3 to 1 parts. In the case of a
combination of vitamin E with R- or S-alpha=lipoic acid and
alpha-interferon the three components may be present fox example
in the.following ratios: 15 mg - 50 mg - 6 g R- or
S-alpha-lipoic acid (component a) to 8 x 106 enzyme units to 1
x 105 enzyme units alpha-interferon, in particular 0.5 - '3 g
component a to 1-4 x i06 enzyme units alpha-interferon.
~In the combination of for example vitamin E with R- or
S-alpha-lipoic acid and other c~ponents according to b) both
components may be present as a mixture. In general the
components are however present separately Pram one another in a
pharmaceutical formulation, it being possible to use
conventional pharmaceutical formulations in this case: for
example one component as a tablet or lacquered tablet, the other
component as a powder, both in a capsule and vice versa, one
component in the form of pellets, the other as a powder, coated
tablet or tablets and vice versa'and where the two forms are for
example present in a capsule; or in the form of multi-layer or
coated tablets. Reference is made in this connection fox example
to the book by Karl Thoma, Arzneimittelstabilitat, Frankfurt
1978, for example page 207 et seq.
The combination of the invention may, however, also be present
as a product in which in each case the two individual active
substances are_present in formulations totally separate from one
another, it being possible in particular for the component b,
but also both components (a and b) to be contained in ampoules
and/or infusion vials so that they can also be administered
separately or also at different times.
.. 209~'~32
- ,$ -
Should such~totally separate formulations be present, these are
adapted to one another and contain' the appropriate active
substances in the dosage unit in the same amounts and
corresponding weight ratios in which they can be present~in the
combined mixture.
In a product for'separate application it is also possible for
both combination partners not to be administered simultaneously.
In such cases it is, for example, possible to give vitamin E
intramuscularly and R- or S-alpha-lipoic acid as long-term
infusion (dose for example 2 - 5 g per day) and the third
component b simultaneously (dose for example 50 - 800 mg or 1-8
x 106 enzyme units, preferably intramuscular) or also as
long-term infusion per day or R- or S-alpha-lipoic acid can for
example.be given 4 times daily (single dose for example 0.5 - 2
g) and the other component b simultaneously (dose for example 50
- 200 mg or 0.5-3 x 106 enzyme units). It is then for example
possible for 1 to 3 further doses of component b (for example
between 50 - 200 mg or 0.5-3 x 106 enzyme units) to follow at
intervals of in each case 6 and/or 12 hours.
The formulations/products of the invention can preferably also
contain additional vitamins such as pantothenic acid and/or
folic acid.
To treat diseases caused by retroviruses, in particular HIV
viruses, appropriate medicaments should also contain such an
amount of for example vitamin E in combination with R- or
S-alpha-lipoic acid or these should be given in such amounts
that single or multiple application results~in an active level
of vitamin E in the body of between 0.001 and 12 mg/kg,
preferably between 0.1 and l0 mg, in particular between 0.2 and
8 mg/kg body weight. -
The general dose range for the combinations with the above
mentioned vitamins with R- or S-alpha-lipoic acid for analgesic
effect is for example:
~09'~'~32
' - 19 -
0.5 - 20 mg/kg body weight oral vitamin E in combination with 1
- 100 mg/kg body weight R- or S-isomer of alpha-lipoic acid.
The general dose range of combinations with the above mentioned
vitamins with R-alpha-lipoic acid for anti-inflammatory and
cytoprotective effect is for example:
0.5 - 15 mg/kg body weight oral vitamin E in combination with 1
- 100 mg/kg body weight R- or S-isomer of alpha-lipoic acid
for the detoxifying, heavy metal antidote effect one can use far
example:
0.5 - 25 mg/kg body weight oral vitamin E in combination with 1
- 100 mg/kg~body weight R- or S-isomer of alpha-lipoic acid
for the anti-allergic and immune-stimulating effect one can use
for example:
0.5 - 20 mg/kg body weight oral vitamin E in combination with 1
- 100 mg/kg body weight R-'or S-isomer of alpha-lipoic acid
fox the anti-tumour effect one can use for example:
0.5 - 25 mg/kg body weight oral vitamin E in combination with 1
- 100 mg/kg body weight R- or S-isomer of alpha-l.ipoic acid
for the anti-diabetic effect one can use for example:
0.5 - 20 mg/kg body~weight oral vitamin E in combination with i
- 100 mg/kg body weight R- or S-isomer of alpha-lipoic acid
The following indications may for example be considered:
inflammatory, degenerative articular and extra-articular -
rheumatic disorders, non-rheumatic inflammations and swellings,
Arthrosis deformans, chondropathies, periarthritis, inflammatory
and non-inflammatory diseases.of the skin,. such as.neurodermitis
and psoriasis, inflammatory and non-inflammatory disorders of
~0~'~"~32
- 20 -
the gastrointestinal tract, such as gastritis, tllcus ventriculi,
ileitis, duodenitis, infections with Campylobacter pylorici,
jejunitis, colitis, diabetes mellitus Types I and II, insulin
resistance, polyneuropathy of diabetogenic, alcoholic, hepatic
and uremic origin, liver parenchyme degeneration, hepatitis,
fatty liver and fatty cirrhosis, heavy metal poisonings such. as
copper, xinc, cadmium, nickel, lead and arsenic as well as
radioactive isotope intoxication as well as chronic liver
diseases, inflammatory respiratory tract diseases, such as
Asthma bronchiale, sarcoidosis, ARDS (acute respiratory distress
syndrome), degenerative diseases of the CNS, acute ischemic .
states, myocardial infarction, liver parenchyme degeneration.
In accordance with the invention, the.dosage forms of the
combinations for the analgesic heavy metal antidote,
detoxifying, antidiabetic, immune-stimulating and
cytoprotective, antinecrotic and/or anti-inflammatory effect are
for example 0.01 to 800 fig vitamin E, preferably 0.1 to.600 mg
vitamin E in combination with 0.l to 2000 mg, preferably 15 to
600 mg and in particular 50 to 200 mg R-alpha-lipoic acid or
S-alpha-lipoic acid
In accordance with the invention, a daily dose of the
combinations of the above named vitamins with the optical
isomers of alpha-lipoic acid (R- or S-form) can be from 0.1 to
800 mg vitamin E, preferably 1 to 600 mg vitamin E in
combination with the optical isomers of alpha-lipoic acid (R- or
S-form in each case) 10 - 600 mg, preferably 25 to 400 mg or 10
to 200 mg. The maximum daily dose for the cytoprotective effect
and for the treatment of states of pain and inflammation should
not exceed 1.2 mg for the racemate or R- or S-form of
alpha-lipoic acid and 800 mg for vitamin E. The daily doses may
be used in the form of a single administration of the entire
amount or in the form of 1 to 6, in particular 7 - 4 partial
doses per day.
2D9'~'~32
In general administration of 1 to 4 times, in particular
1 to 3 times daily is preferred.
For example, the preferred daily dose in the combination
with vitamin E (0.1 - 800 mg for the oral administration of
vitamin E in the combination and 0.1 - 20 mg/kg for the
intramuscular administration of vitamin E in the combination)
both for R-alpha-lipoic acid and also for S-alpha-lipoic acid
is preferably 100 mg for the parenteral form of application
and 400 mg for the oral form.
0 For example the daily dose for the parenteral form of
application of the R- or S-isomers of alpha-lipoic acid in
the combination with vitamins can in particular be 300 mg and
600 mg for the oral form.
The medicaments are preferably given orally. For
5 example the vitamin E in the combination with R-alpha-lipoic
acid and S-alpha-lipoic acid can in particular also be
applied in the form of a solution, for example peroral,
topical, parenteral (intravenous, intra-articular,
intramuscular, subcutaneous), inhalative, transdermal. The
0 medicaments containing as active substance for example
vitamin E in combination with R-alpha-lipoic acid or S-alpha-
lipoic acid can for example be formulated in the form of
tablets, capsules, pills or coated tablets, granulates,
pellets, plasters, solutions or emulsions, the active
5 . substances in each case optionally being combined with
appropriate auxiliary substances and carriers. In the case
of solutions in each case of 10 - 600 mg, fox example from 25
to 400 mg or 10 to 200 mg administered. The maximum daily
dose for the antidiabetic, immune-stimulating, anti-allergic,
0 cytoprotective effect and for the treatment of pain and
inflammatory states should for example for the combination of
vitamin E with the R- or S-isomers of alpha-lipoic acid for
the vitamin E not exceed 800 mg orally and for the R- and S-
isomers of alpha-lipoic.acid 1.2 g.
5
- 21 -
209'~'~3~
- 22 -
The maximum daily dose for the detoxifying, heavy metal antidote
effect should fox example for the combinati~n of vitamin E with
the R- or S-isomers of alpha-lipoic acid for the vitamin E not
exceed 1200 mg orally and 1200 mg for the R- or S-isomers~of
alpha-lipoic acid.
The daily doses can bemused in the form of a single
administration of the entire amount or in the form of 1 to 6, in
particular 1 - 4 partial doses per day. In general an
administration of 1 to 4 times, in particular 1 to 3 times daily
is preferred.
The preferred daily dose in the combination both for the vitamin
E is for example 800 mg orally, preferably 600 mg oral and
parenteral for vitarain E 15 mg/kg body weight intramuscular and
for R-alpha-lipoic acid and also.for S-alpha-lipoic acid
preferably 80 mg for the parenteral form of application and 200
mg for the oral form.
The R-alpha=lipoic acid and S-alpha-lipoic acid.in the
combination witli for example vitamin E can for example also be
applied in particular in the form of a solution, for example
peroral, topical, parenteral (intravenous, intra-articular,
intramuscular, subcutaneous), inhalative, transdermal.
Medicaments containing as active substances for example vitamin
E in the combination with R-alpha-lipoic acid or S-alpha-lipoic
acid can for example be formulated in the form of tablets,
capsules, pills or coated tablets, granulates, pellets,
plasters, solutions or emulsions, where the active substance is
in each case optionally combined with appropriate auxiliary
substances and carriers. In the case of solvents these contain
for example 0.5 to 20 weight%, preferably 1 to 10 weight% of one
of the optical isomers of alpha-lipoic acid (in each case R-form
or S-forms together with 0.001 to 10 weight% of the appropriate
vitamin.
..
- 23 -
The dosage unit of medicaments with for example vitamin E in
. combination with the optical isomers of alpha-lipoic acid or a
therapeutically acceptable salt thereof (R-form or S-form in
each case) can for example contain:
a) in the case of oral medicaments:
to 1200 mg, preferably 20 to 600 mg, in particular 50 to
400 mg of the optical isomers of alpha-lipoic acid in
combination with for example vitamin E 0.'1 to 800 mg,
preferably 1 to 400 mg, in particular 1 - 300 mg.
The doses can for example be given l to 6 times, preferably
1 to 4 times, in particular 1 to 3 times daily. However a
total dose of the optical isomers of alpha-lipoic acid of
1200 mg and for example of vitamin E of 800 mg per day
should not be exceeded for the cytoprotective effect and for
the treatment of states of pain and inflammation. The same
also applies to the following medicinal forms listed under
b) to e).
In addition a total dose of the optical R- or S-isomers of
alpha-lipoic acid of 2000 mg and for example of vitamin E of
1200. mg per day should not be exceeded for the detoxifying
and heavy metal antidote effect.
b) in the case of parenteral medicinal forms for example
intravenous, intramuscular or intra-articular), 10 to 600
mg, .preferably 15 to 500 mg, in particular 20 to 300 mg of
the optical isomers of alpha-~lipoic acid in the combination
for example with vitamin E 0.01 - 20 mg/kg body weight
intramuscular, preferably 0.1 -- 12 mg/kg body weight in
particular 1 - 10 mg/kg body weight intramuscular.
The doses can for example be administered 1 to 6 times,
preferably 1 to 4 times, in particular 1 to 3 times daily.
c) in the case of medicinal forms for application to the
skin and mucous membranes (for example as solutions,
lotions, emulsions, ointments, plasters and the like) in
the combination:
10 to 500 mg R-alpha-lipoic acid or S-alpha-lipoic acid,
preferably 40 to 250 mg, in particular 50 to 200 mg with
for example the combination partner vitamin E 0.1 - 600
mg, preferably 1 - 400 mg, in particular 5 - 200 mg.
These doses can for example be given 1 to 6 times,
0 preferably 1 to 4 times, in particular 1 to 3 times
daily.
d) in the case of medicinal forms for inhalation (solutions
or aerosols):
5 0.02 to 300 mg, preferably 0.25 to 150 mg, in particular
0.5 to 80 mg R-alpha-lipoic acid or S-alpha-lipoic acid
combination with for example vitamin E preferably 0.001
- 20 mg/kg, in particular 0.01 to 10 mg/kg. These doses
may for example be administered 1 to 6 times, preferably
0 1 to 4 times, in particular 1 to 3 times daily.
If solutions are used, the optical isomers of alpha-
lipoic acid and the vitamins contained in the combination are
preferably used in the form of a salt.
5 It is of course also possible to prepare pharmaceutical
formulations which contain 2 up to for example 6 times the
., above stated dosage units. In particular tablets or capsules
contain 20 to 800 mg of the active substances in combination
with a vitamin, for example vitamin E 1 - 1200 mg, pellets,
0 powders or granulates 20 to 400 mg of the active substances
of in combination with a vitamin, for example vitamin E 1 -
800 mg, suppositories 20 to 300 mg pf the active substances
in combination with a vitamin, for example 1 - 600 mg of
vitamin E R-alpha-lipoic acid or S-alpha-lipoic acid.
5
- 24 -
To combat retroviruses (for example AIDS) the daily dose
is for example 4 - 6 g R- or S-isomer of alpha-lipoic acid in
the combination with for example vitamin E 1 - 1200 mg-
Corresponding medicaments consequently preferably contain in
the combination with 5 mg - 1 g vitamin E R-alpha-lipoic acid
or S-alpha-lipoic acid in the single dose (dosage unit) for
example in an amount of 600 mg to 1.5 g.
The above stated dosages always relate to combinations
0 with the cited vitamins with, for example, the free optical
isomers of alpha-lipoic acid. If the optical isomers of
alpha-lipoic acid are used in the form of a salt, the stated
dosages/dosage ranges should be increased accordingly on
account of the higher mol weight.
5
In the event of the combination with the vitamins such
as for example vitamin E being used with the optical isomers
of alpha-lipoic acid in animals, the following indications
may in particular be considered: panleucopenia, distemper,
0 hepatoses, Arthrosis deformans, arthritis and dermatitis.
For the treatment of animals it is for example possible
to use the following dosages (vitamin E both in combination -
with the R-form and with the S-form of alpha-lipoic acid):
5
For the treatment of cats the oral single dose is
generally between about 2 mg/kg and 50 mg/kg of the active
substances in combination for example with vitamin E 0.1 to
100 mg/kg, preferably 1 to 8o mg/kg, in particular 2 - 40
0 mg/kg body weight, the parenteral dose is between 0.5 and .40
mg/kg body weight of the active substances in combination
with the vitamins for example vitamin E 0.01 mg/kg to 1 0
mg/kg, pref erably 0. 1 to 8 mg/kg, in particular 1 - 4
mg/kg.
5
- 25 -
_ 2~~'~'~32
For the treatment of arthroses in horses and cattle the
oral single dose in general in the combination for the active
substances is between about 2 mg/kg and 100 mg/kg body weight
and for the vitamins between about 2 mg/kg and 100 mg/kg body
weight, the parenteral dose in the combination for the active
substances is about between 0.5 and 50 mg/kg body weight and
for the vitamins about between 0.005 and 20 mg/kg body
weight.
The vitamins active substances such as the optical
0 isomers of alpha-lipoic acid are suitable for the preparation
of pharmaceutical compositions and formulations. The
pharmaceutical compositions or medicaments contain for
example the optical isomers of alpha-lipoic acid as active
substance, optionally in a mixture with the vitamins or other
5 pharmacological or pharmaceutically active substances. The
medicaments are prepared in known manner, it also being
possible to use known and conventional pharmaceutical
auxiliary substances as well as other conventional carriers
and diluting agents. Carriers arid auxiliary substances that
0 may for example be considered are those recommonded or quoted
in the following literature references as auxiliary
substances for use in pharmaceuticals, cosmetics and related
fields:
Ullmanns Enzyklopgdie der technischen Chemie, Volume 4
5 (1953), page 1 to 39; 3ournal of Pharmaceutical Sciences,
Volume 52 (1963), page 91.8 et seg., H. v. Czetsch-Lindenwald,
Hilfsstoffe fUr Pharmazie and angrenzende Gebiete; Pharm.
Ind., Issue 2 (1961j, page 72 at seq., Dr. H.P. Fiedler,
Lexikon der Hilfsstoffe f6r Pharmazie, Kosmetik and
0 angrenzende Gebiete, Cantor KG, Aulendorf in Wurttemberg
(1989).
The pharmaceutical and galenic handling of the vitamins and
of the active substances of such as for example R- or S-
alpha-lipoic acid is effected using conventional standard
5 methods.
- 26 -
209~~3~
For example in 1 to 5 ml vitamin E for example 250 mg
dihydrolipoic acid or in 10 ml vitamin E for example 250 mg
R-alpha or S-alpha-lipoic acid and/or auxiliary or carrier
substances are well mixed by stirring or homogenizing (for-
example using conventional mixing apparatus) (clear
solution), working generally being at temperatures between 20
and 50°C, preferably 20 to 40°C, in particular at room
temperature. Reference is also made to the following
standard textbook: Sucker, Fuchs, Speiser, Pharmazeutische
0 Technologic, Thieme-Verlag Stuttgart, 1978. Application of
the vitamins with the active substances such as for example
R- or S-alpha-lipoic acid or of the medicaments can be to the
skin or mucous membrane or to the inside of the body, for
example oral, enteral, pulmonal, nasal, lingual, intravenous,
5 intra-arterial, intracardial, intramuscular, intraperitoneal,
intracutaneous, subcutaneous.
The parenteral formulation forms are in particular
sterile or sterilized products.
If, for example, the vitamin E is used in combination with R-
0 or S-alpha-lipoic acid in the form of their salts, the salt
formers can also be used in excess, that is in a higher
amount that equimolar.
Examples fox the carriers and auxiliary substances are
gelatin, natural sugars such as cane sugar or lactose,
5 lecithin, pectin, starches (for example corn starch or
amyloses), cyclodextrins and cyclodextrin derivatives,
dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum
arabic; alginic acid, tylose, talcum, lycopodium, silicic
acid (for example colloidal), cellulose, cellulose
0 derivatives (for example cellulose ethers in which the
cellulose hydroxy groups are partially etherified with lower
saturated aliphatic alcohols and/or lower saturated aliphatic
oxyalcohols, for, example methyloxypropyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl
5 methyl cellulosephthalate, fatty acids as well as magnesium,
- 27 -
2U9'~'~32
calcium or aluminium salts of fatty acids with 12 to 22
carbon atoms, in particular saturated (for example
stearates), emulsifiers, oils and fats, in particular
vegetable (for example peanut oil, castor oil, olive oil, .
sesame oil, cotton seed oil, corn oil, wheat germ oil,
sunflower seed oil, cod liver oil, in each case also
hydrated); glycerol esters and, polyglycerol esters of
saturated fatty acids C12H24~2 to C18H36~2 and their
mixtures, where the glycerol-hydroxy groups are totally or
0 also only partially esterified (for example.mono, dl and
triglycerides), pharmaceutically acceptable mono~or
multivalent alcohols and polyglycols such as polyethylene
glycols (molecular weight range for example 300 to 1500) as
well as derivatives hereof, polyethylene oxide, esters of
5 aliphatic saturated or unsaturated fatty acids (2 to 22
carbon atoms, in particular 10 - 18 carbon atoms) with
monovalent aliphatic alcohols (1 to 20 carbon atoms) or
multivalent alcohols such as glycolen, glycerol, diethylene
glycol, pentaerythritol, sorbitol, mannitol and the like,
0 which may optionally also be etherified, esters of citric
acid with primary alcohols, acetic acid, urea, benzyl
benzoate, dioxolanes, glyzerol formals, tetrahydrofurfuryl
alcohol, polyglycolesters with C1-C12-alcohols,
dimethylacetamide, lactamides, lactates, ethylcarbonates,
5 silicons (in particular medium-viscous
polydimethylsiloxanes), calcium carbonate, sodium carbonate,
calcium phosphate, sodium phosphate, magnesium carbonate and
the like. Other auxiliary substances that may be considered
are substances which'effect disintegration (so-called
0 disintegrants) such as cross-linked polyvinyl pyrrolidone,
sodiumcarboxymethyl starches, sodiumcarboxymethyl cellulose
or microcrystalline cellulose. It is also possible to use
known covering materials. Agents of this type that may for
example be used are:
5
- 28 -
209~~32
Polymerisates as well as copolymerisates of acrylic acid
and/or methacrylic acid and/or their esters, copalymerisates
of acrylic and methacrylic acid esters with a lawer ammonium
group content (for example Eudragi~ RS), copolymerisates of
acrylic and
0
5
0
5
0
5
- 28a -
- 20~'~°~3~
- 29 -
methacrylic acid esters and trimethylammonium methacrylate (for
example Eudragit"" RL); polyvinylacetate; fats, oils, waxes,
fatty alcohols;
hydroxypropyl methyl cellulose phthalate or -acetate ruccinate;
cellulose acetate phthalate, starch acetate phthalate as~weli as
polyvinylacetate phthalate; carboxymethyl cellulose; methyl
cellulose phthalate, methyl cellulose succinate, -phthalate
succinate as well as methyl cellulose phthalic acid half esters;
zein; ethyl cellulose as well as ethyl cellulose succinate;
shellack, gluten; ethylcarboxyethyl cellulose; ethacrylate
malefic acid anhydride copolymer; malefic acid anhydride
vinyLaethylether copolymer; styrol-malefic acid copolymerisates;
2-ethyl-hexyl-acrylate malefic acid anhydride; crotonic
acid-vinyl acetate copolymer;
glutaminic acid/glutaminic acid ester-copolymer;
carboxymethylethyl cellulose glycerol mono-octanoate;
celluloseacetate succinate; polyarginine. Plasticizing agents
for covering substances that may be used are: .
citric and tartaric acid esters (acetyltriethyl citrate,
acetyltributyl-, tributyl-, triethyl citrate); glycerol and
glycerol esters (glycerol diacetate, - triacetate, acetylated
monoglycerides, castor oil); phthalic acid esters (dibutyl-,
diamyl-, diethyl-, dimethyl, dipropyl-phthalate, di-(2-methoxy-
or 2-ethoxyethyl)-phthalate, ethylphthalyl-glycolate~
butylphthalyl ethylglycolate and butylglycolate; alcohols
(propylene glycol, polyethylene glycol of various'chain
lengths), adipates (diethyladipate, di-(2-methoxy- or
2-ethoxyethyl)-adipate); benzophenone; diethyl- and
dibutylsebacate, dibutylsuccinate, dibutyltartrate;
diethyleneglycol dipropionate; ethylene glycoldiacetate,
-dibutyrate, -dipropionate, trib~itylphosphate, -tributyrin,
polyethylene glycol sorbitane monooleate (polysorbates such as
polysorbate 80); sorbitane monooleate. For the preparation of
solutions or suspensions it is for example possible to use water
or physiologically acceptable organic solvents such as alcohols
(ethanol, propanol, isopropanol, 1,2-propylene glycol,
. 209"l'~3~
- 30 -
polyglycols and their derivatives, fatty alcohols, partial
esters of glycerol), oils (for example peanut oil, olive oil,
sesame oil, almond oil, sunflower oil, Soya bean oil, castor
oil), paraffins, dimethylsulfoxide, txiglycerides and the like.
For injectable solutions or suspensions it is for example
possible to use non-toxic parenterally acceptable dissolution
agents or solvents, such as:.water, 1,3-butane diol, ethanol,
1,2-propylene glycol, polyglycols mixed with water, glycerol,
Ringer's solution, isotonic sodium chloride solution or also
solidified ails including synthetic mono- or diglycerides or
fatty acids such as oleic acid.
To prepare the formulations it is possible to use known and
conventional solubilizers or emulsifiers. Solubilizers and
emulsifiers that may for example be used are: polyvinyl
pyrrolidone, sorbitane fatty acid esters such as sorbitane
trioleate, phosphatides such as lecithin, acacia, tragacanth,
polyoxyethylated sorbitane monooleate and other ethoxylated
fatty acid esters of sorbitane, polyoxyethylated fats,
polyoxyethylated oleotriglycerides, -linolisated
oleotriglycerides, polyethylene oxide condensation products of
fatty alcohols, alkyl phenols or Fatty acids or also
'-methyl-3-(2-hydroxyethyl) imidazolidone-(2).
In this context polyoxyethylated means that the appropriate
substances contain polyoxyethylene chains, the degree of
polymerization of which generally lies between 2 and ~0 and in
.' particular between 10 to 20. Polyoxyethylated substances of this
type may for example be, obtained by reacting hydroxyl
group-containing compounds (for example mono- or diglycerides or
unsaturated compounds such as those containing oleic acid
radicals) with ethylene oxide (for example 40.mo1 ethylene oxide
r per 1 mol glyceride). Examples of oleotriglycerides are olive
. oil, peanut oil, castor oil, sesame oil, cotton seed oil, corn
oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur
Pharmazie, Kosmetik and angrenzende Gebiete'° 1971, p. 191-
195.
In addition it is also possible to add conserving agents,
stabilizers, buffers, flavour correcting agents, sweeteners,
colourants, antioxidants, complex formers and the like.
Complex formers that may for example be considered are:
chelate formers such as ethylenediamino tetraacetic acid,
0 nitrilotriacetic acid, diethylene triamine pentaacetic acid
as well as their salts. It is also ssible to use as complex
formers those containing the vitamins in combination with for
example Ror S-alpha-lipoic acid in a cavity.
Hxamples hereof are urea, thiourea, cyclodextrins, amylose.
5 It is optionally necessary to stabilize the active substance
molecule with physiologically acceptable bases or buffers to
a pH range of approx 6 to 9. In general as neutral to weakly
basic (up to pH 8) a pH value as possible is preferred.
Antioxidants that may for example be used are sodium sulfite,
0 sodium hydrogen sulfite, sodium metabisulfite, ascorbic acid,
ascorbyl palmitate, -myristate, -stearate, gallic acid,
gallic acid alkyl ester, butylhydroxyanisol,
nordihydroguaiacic acid, tocopherols as well as synergists
(substances which form heavy metals through complex
5 formation, for example lecithin, ascorbic acid, phosphoric
acid ethylene diamine tetraacetic acid, citrates, tartrates).
The addition of synergists considerably raises the
antioxygenic effect of the antioxidants.
0 Conserving agents that may for example be used are sorbic
acid, p-hydroxybenzoic acid ester (for example lower alkyl
ester), benzoic acid, sodium benzoate, trichloroisobutyl
alcohol, phenoli cresol, benzethonium chloride,
chlorohexidine and formalin derivatives.
5
- 31 -
Example 1
Suppositories with 50 mg dihydrolipoic acid or with R- or S-
alpha-lipoic acid and 200 mg alphatocopherol or 200 mg
alphatocopherol acetate
5 g ascorbyl palmitate and 5 g Oxynex LM**) (E. Merck,
Darmstadt) are suspended in 175 g molten hard fat*,). 20 g
alpha tocopherol and 5 g dihydrolipoic acid are then mixed
0 thereto and the mixture is cast into hollow cells of 2.3 ml
after homogenization and cooled. Before sealing the hollow
cells are gassed with nitrogen.
A suppository weighing 2.1 g contians 50 mg dihydrolipoic
5 acid and 200 mg alphatocopherol.
Suppositories with R- or S-alpha-lipaic acid may be prepared
in the same manner by using the same amount of either R- or
w S-alpha-lipoic acid instead of dihydrolipoic acid.
0
*) hard fat is a mixture of mono-, di- and triglycerides of
saturated fatty acids of C1pH2002 to CigH3g02
**) Oxynex LM is a trade mark commercial additive for fats
5 and fat-containing foodstuffs. It is a light brown to brown,
waxy mass which melts on heating to 55°C to a clear brown
liquid and contains tocopherol, ascorbyl palmitate, citric
acid and lecithin.
0 Example 2
.,_ Capsules containing 200 mg dihydrolipoic acid or R- or S-
alpha-lipoic acid arid 500 mg alphatocopherol or
alphatocopherol acetate
5
- 32 -
~0~~'~32
200 g R-alpha;lipoic acid are mixed with 500 g
alphatocopherol. 595 g MiglyolLnJ neutral oil and 100 g
sorbitol syrup, 25 g glycerol are then mixed thereto and the
mixture filled into size 00 capsules. One capsule weighing
1.42 g contains 200 mg R- or S-alpha-lipoic acid and 500 mg
alphatocopherol.
In the same manner it is possible to prepare capsules with
dihydrolipoic acid or with S-alpha-lipoic acid by using the
0 same amount of either dihydrolipoic acid or S-alpha-lipoic
acid instead of R-alpha-lipoic acid.
Miglyo~ is a commercial mixture of medium-chain
triglycerides
5
Example 3
Ampoules containing 250 mg R- or S-alpha-lipoic acid and 250
mg vitamin C (ascorbic acid) in 10 ml
0
250 g R-alpha-lipoic acid are dissolved with stirring
together with 352.3 tromethamine
(2-amino-(hydroxymethyl)-1,3-propanediol) in a mixture of 8
litres of water for injection purposes and 200 g
5 1,27propylene glycol with stirring. 250 mg vitamin C are
then dissolved into this batch. The solution is made up to
litres with water for injection purposes and then filtered
through a membrane filter of pore size 0.2 um with glass
fibre prefilter. The filtrate is filled under aseptic
0 conditions in 10 m1 portions into sterilized 10 ml ampoules.
One ampoule contains 250 ml R-alpha-lipoic acid as
tromethamine,salt and 250 mg vitamin C in 10 ml injection
., solution.
5
- 33 -
- ~4 -
In the same manner it is possible to prepare ampoules with
S-alpha-lipoic acid by using the same amount of S-alpha-lipoic
acid instead of R-alpha-lipoic acid.
Example 4
Tablets with 50 mg S- or R-alpha-lipoic acid and 50 mg vitamin C
ascorbic acid
250 g S-alpha-lipoic acid and 250 g vitamin C are evenly ground
With 550 g micxocrystalline cellulose. After sieving the
mixture, 250 g starch (starch 1500/Colorcon), 682.5 g laotose,
15 g magnesium stearate and 2,5 g highly disperse silicon
dioxide are added thereto arid the mixture is pressed into
tablets weighing 400.O.mg each.
One tablet contains 50 mg S-alpha-lipoie.acid and 50 mg vitamin
C.
In the same manner it is possible to prepare tablets with 50 mg
R-alpha-lipoic acid by using the same amount of R-alpha-lipoic
acid instead of 250 g S-alpha-lipoic acid.
The tablets may optionally be provided,with a gastric juice
soluble or gastric juice permeable film coating using
,. conventional methods.
Example 5
Ampoules containing 50 mg dihydrolipoic acid or 50 mg R- or
S-alpha-lipoic acid and 200 mg,alphatocopherol acetate in 4 ml
injection solution
,.'
. ~ ~ - 35 -
50 g R-alpha-lipoic acid are dissolved with 750 g
alphatocopherol acetate. The solution is filled up with 3200 g
neutral oil.
The solution is sterilized using gamma or beta radiation-and
filled in 10 ml portions into sterilized 10 ml ampoules under
aseptic conditions. One 4 ml ampoule contains 50 mg
R-alpha-lipoic acid and 200 mg alphatocopherol acetate.
In the same manner it is possible to prepare ampoules with
dihydrolipoic acid or with S-alpha-lipoic acid by using the same
amount of either dihydrolipoic acid or S-alpha-lipoic acid
instead of R-alpha-lipoic acid.
Example 6
Ointment with 2% dihydrolipoic acid or 2% R- or S-alpha-lipoid
acid and with 2% alphatocopherol.
20 g R-alpha-lipoic acid are mixed With 20 g alphatocopherol
. with 400 g Vaselinum album and 100 g sorbitol 70% and 100 g
Alcohol cetylicus et stearylicus and 360 g wool wax.
This mixture~is filled under sterile conditions into_50 g tubes
after homogenization.
The ointment contains 2% R-alpha-lipoic acid and 2%
alphatocopherol acetate.
In the same manner it is possible to prepare an ointment with
dihydrolipoic acid or with S-alpha-lipoic acid by using the same
amount of either dihydrolipoic acid or S-alpha-lipoic acid
instead of R-alpha-lipoic acid.
Example 7
,,
:;;,--:.. ' °_~
- 36 -
Tablets containing 120 mg S- or R-alpha-lipoic acid and 67 mg
vitamin C ascorbic acid
825 g S-alpha-lipoic acid and 425 g vitamin C are evenly ground
with 550 g microcrystalline cellulose. After the mixture has
been sieved 250 g starch (starch 1500/Colorcon), 682.5 g
lactose, 15 g magnesium stearate and 2.5 g highly disperse
silicon dioxide are mixed thereto and the mixture is pressed
into tablets weighing 400.0 mg each.
One tablet contains 120 mg S-alpha-lipoic acid and 61 mg vitamin
C.
In the same manner it is possible to prepare tablets with 'e~U rr~g
R-alpha-lipoic acid by using the same amount of R-alpha-lipoic
acid instead of S-alpha-lipoic acid.
The tablets may optionally be provided with a gastric juice
soluble or gastric juice permeable film coating using
conventional methods.
2097'~3~
--,
37 -
A synergistic combination of medicaments containing as active
substance alpha-lipoic acid,, dihydrolipoic acid, their
metabolites as.well as the oxidized and reduced enantionmers of
alpha-lipoic acid such as R-alpha-lipoic acid or S-alpha-lipoic
acid as well as metabolites of alpha-lipoic acid with the
'. vitamins A, B 1-6, 812, C and E.
