Note: Descriptions are shown in the official language in which they were submitted.
~73.~
The use of glucocorticoid compounds ~or the production of
compositions ~or the treatment of disorders in which
glucocorticoids are indicated.
Descri~tion
The invention relates to the use of glucocor-
ticoid compounds for the production of compositions which
are employed for disorders where parenteral
administration of glucocorticoids is indicated, and to a
method for the parenteral treatment of such disorders.
Various compositions based on glucocorticoids and
used to treat, for example, bronchial asthma and other
disorders such as acute inflammatory episodes in rheuma-
tic diseases are known.
The introduction of glucocorticoids into asthma
therapy and for the treatment of acute inflammatory
episodes in rheumatic diseases has led to a decisive
therapeutic advance. In an acute attack of asthma,
parenteral, in particular intravenous administration is
necessary, while the subsequent treatment should take
place with oral administration of the glucocorticoids and
the smallest possi~le individually adjusted do~e. The
duration of therapy before the full efficacy of the
glucocorticoids is reached depends on the ~everity of the
obstruction. There i9 dilatation of the airways~
inhihition of discharge, reduc~ion in hyperreactivity,
protection from immediate reaction after allergen
provocation, and reduction in effort asthma (Schul~e-
Werninghaus, Debelic (Editors): "Asthma - Grundlagen
Diagnostik, Therapie~ r Springer Verlag Berlin~
Heidelberg, 1988, page 327). After the obstruction
decreases the patient responds again to beta-2
adrenergics, i.e a permiscive ac~ion of the
glucocorticoids ha~ occurred.
The lea~t risk when glucocorticoids are adminis-
tered for a~thma occurs on treatment by inhalation, but
the action which can be achieved thereby is inadequate
for an acute attack of asthma, just a3 little as is oral
2~67~
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moreover.
The object therefore is to find a glucocorticoid
dosage form which is effective sufficiently quickly and
for sufficiently long for the acute attack of asthma
~status asthmaticus). The recommendation made at present
for parenteral (for example intravenous) treatment of the
acute attack of asthma is as follows: administration of
2 - 4 mg/kg of bodyweight prednisolone equivalents at
intervals of 4 - 6 hours until there is a distinct
improvement in airway function (Sybrecht: "Stellenwert
der Steroide beim akuten Asthmaanfall", from Fabel
tEditor) ~Corticosteroide bei Atemwegserkrankungen",
Verlag fur angewandte Wissenschaften, Munich, 1985, page
43). The requirements in this respect are met only
inadequately by the products currently available. In
particular, the duration of the action after i.v.
administration is often insufficient, for which reason
i.v. administration must be repeated.
Some of the compositions based on glucocorticoids
for the treatment of bronchial asthma and acute inflam-
matory episodes of rheumatic diseases or other disorders
for which the use of glucocorticoids is indicated are
combination products with other active su~ tances;
another portion i~ administered as ingle~drug product.
Thus, dexamethasone (9-fluoro~ ,17,21-trihydroxy-
16~-methyl-1,4-pregnadiene-3,20-dione) is administered as
such for intramuscular administration in the form of a
combination~ product with lidocaine or for the :same
administration as suspension of crystals in the form of
the ~cetate, of the isonicotinate or of the trioxaunde-
canoate, and furthermore in the form of the ~m-sul-
fobenzoate (i.eO 21-(3-sulfobenzoate), sodium salt) as
eye drops or in the form of the phosphoric ester sodium
salt in injectable form as single~drug product (compare
Goodman and Gilman: ~'The Pharmacological Basis of Thera-
peutics", 7th Edition, MacMillan Publishing Company,
New York, 1985, pages 1476 and 1477). This citation also
discloses the preparation of injectable solutions from
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the sodium salts of the succinic esters of hydrocortisone
and of prednisolone. These two substances are marketed in
the form of a powder from which the injectable solution
is then to be prepared immediately before the injection.
A procedure of this type i9 by its nature inconvenient
and associated with risks because strict care must be
taken that solutions which are to be injected otherwise
than intramuscularly contain no remaining crystals, not
even microcrystals.
The statutory provisions applying in Germany
require that glucocorticoid~ be supplied no longer in
combination products but now only as a single-drug
product, although combination products had proven most
suitable for treating the acute attack of asthma.
However, for the reasons mentioned previously, the
abovementioned composi.tions available as single drug
products have met prac ical requirements only
incompletely.
It is known of the partial esters of the gluco-
corticoids (see US Patent 3276959) that they can be
hydrolyzed relatively easily and that aqueous solutions
thereof tend to become cloudy - ~ consequence of in-
solubility - and to change pH. It is therefore generally
customary to prepare aqueous solutions of these partial
esters only shortly before their administration.
Finally, it is known from in~estigations into the
intramuscular administration of various glucocorticoids
to horses that the latter are still detectable in the
urine after more than 4 days, specifically on administra-
tion both of salts and of e~ters such aS the acetate, thei onicotinate, the trioxaundecanoate, the m-sulfobenzsate
and the phosphate (the two latter administered as sadium
salts), and it is expressly stated that the residence
time in the body on administra~ion of the acatate, the
isonicotinate and the trioxaundecanoate is longer than on
administration of the phospha~e and the m-sulfobenzoate
(Chapman, D.I., Moss, M.S. and Whi~e~ide J., Vet. Record,
100: 447-450, in particular paye 44g, left-hand column,
2 ~ 3 l~
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paragraph 2 (1977)). It was to be concluded from this
that precisely the administration of tha products in the
form of salts was less effective and disadvantageous
compared with that of salt-free compounds.
It has now been found that monoesters of gluco-
corticoids on the one hand and physiologically tolerated
organic acids which still contain at least one hydro-
philic group, specifically hydroxyl and/or the sulfonic
acid residue, on the other hand are distinguished by a
hitherto unknown property, namely of remaining in the
human body for a long time. The said esters are therefore
outstandingly suitable for the production of compositions
which can be administered parenterally and have a depot
action and in which they are present in dissolved form,
as are required in human medicine for the treatment of
disorders for which glucocorticoids are indicated.
Whereas it is evident from the tudy by Chapman
et al. that dexamethasone phosphate and dexamethasone
m-sulfobenzoate have equivalent pharmacokinetic behavior
and are pharmacokinetically inferior to the acetate and
other esters in horses, i~ has been found, surprisingly,
that the ester with the inoryanic phosphoric acid behaves
quite differently in human rnedicine than the ester o the
or~anic acid carrying at least one hydrophilic group.
Thus, pharmacokinetic investigations comparing pred-
nisolone phosphate, dexamethasone phosphate and dexame-
thasone m-sulfobenzoate have revealed the following:
whereas dexamethasone and prednisolorle are liberated
immediately ~rom the phosphoriG esters after intravenous
injection (free dexamethasone is detectable in e~tremely
high concentration immediately after injection, and this
/then falls steeply and exponentially (Fig. 2)), the
picture which emerges for the m-sulfoben7Oic ester is
different. Following intravenous bolus injection of
dexamethasone m-sulfobenzoate, the ester is detectable in
the plasma of the subjects initially in the expected
~concentrations (at least 100 ng/ml) (Fig. 1), whereas
liberated dexamethasone i5 detectable only after a delay
and in lower concentrations (at least 10 ng/ml) but, on
the other hand, for a longer time (Fig. 2). The
pharmacokinetic data on intravenous an~ intramuscular ad-
ministration do not dif~er (Fig. 1). The plasma
concentration of dexamethasone remains virtually constant
for more than 40 hours. The terminal half-life (a
pharmacokinetic indicator of the bioavailability) for
dexamethasone is 10.4 hours after administration as
sulfobenzoic ester and 4.6 hours after administration as
phosphate.
It was not hitherto known that dexamethasone
m-sulfobenzoate and the other esters used according to
the invention behave in this way in the human body.
Surprisingly, this action has not been identified in the
combination products customary to date, nor has it
evidently occurred. This is probably attributable to
partial cleavage of the esters, for exAmple the
sulfobenzoates, under the production conditions
(sterilization conditions) and the action of the other
components during production of these combination
products to be administered parenterally. Thus, for
example, US Patent 3276959 expressly points out that the
glucocorticoid esters are unstable in solution especially
when the~ are kept at above 20C for a lengthy period.
Our own investigations have shown that at the expiry of
the customary term of such combination pharmaceuticals
about one third of the esters is already in the form of
the individual components.
The fact that the esters used according to the
invention are cleaved only very slowly into their com-
ponents in the body and, because they do not act as such,
thus Pxert a depot action is of considerable therapeutic
importance for the treatment of disorders. This is
because it becomes possible in this way no longer to
impose on the patient an administration at the hitherto
customary intervals of about 4 - 6 hours, on the contrary
it is possible to dispense with an additional administra-
tion or at most to necessitat~ a single further
2 ~
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individual dose. In other words, it becomes possible with
the aid of the invention to administer to a certain
extent a depot form with parenteral do~es. This result of
the longer activity is confirmed by the pharmacodynamic
data obtained at the same time.
Thus, one object of the invention accordingly
also comprises providing dosage units, in particular in
the form ready for injection, for the treatment of the
disorders. Dosage units of this type expediently contain
the acti~e substance in an amount whose action corres-
ponds to 3 to 6 mg dexamethasone. The amount of the
individual glucocorticoid compounds depends, inter alia,
on the so-called equivalence dose of the glucocorticoid
component. Thus, for example, for dexamethasone with an
equivalence dose of 1 (relative strength of action 30
based on hydrocortisone with 1) a range of 3-6 mg is
regarded as dosage necessary for the attack of asthma. On
use of methylprednisolone, the equivalent requirements
would be 18-36 mg. Other dosage ranges are suitable
depending on the disorder and depending on the
equivalence dose of the glucocorticoid component.
~ he cleavage of the esters used according to the
invention takes place rather uniformly in the body over
a long time without a peak occurring immediately after
the injection. This has the advantage, which is very
important therapeutically, ~hat the risk of the
occurrenca of side effects when the ef~icacy is adequate
is distinctly reduced. 5ide effacts o this typa comprise
on short-term treatment using tha products hithe~to
customary, for example, impairment of dafences against
infection, increase in the intraocular pressure,
psychological changes and a diminished glucose tolerance.
The pharmacauticals obtained according t~ the
invention comprise aqueous solution with a prolonged
(depot) action, this term also including those solutions
which also contain physiologically tolerated solubilizers
in minor amounts, for exampla up to 35, preferably up to
30 per cent by weight ~based on the solution), such as
-- 7 --
lower glycols, glycerol and, in particular, 1,2-propane-
diol. It may also be e~pedient for adjustment of the
desired pH, which of course ought to be in the physiolo-
gically tolerated range, that is to say expediently from
5 to 8, to add suitable amounts of neutralizing sub-
stances such as sodium hydroxide solution or potassium
hydroxide solution or hydrochloric acid. It i5 also
possible to incorporate a small excess of the free acid
component, for example citric, tartaric or malic acid.
The products to be produced according to the
invention differ fundamentally from those of the prior
art in that they represent slow release solutions ready
for injection. Slow release crystal suspensions read~ for
injection, for example dexamethasone acetate, have
already been disclosed. However, these have the disad-
vantage that they can be injected only intramuscularly,
but not intravenously. The compositions obtained accord-
ing to the invention can, however, also be administered
additionally as infusion, intraarticularly or
transdermally from dPpot plasters, which was likewise not
possible with the known compositions. Intramuscular
administration i9, of course, also possible. All these
administration forms are comprised for the purpose of the
present invention under the term parenteral, and the
invention is by its natur~ important in particular for
administration forms other than intramuscular, because
intramuscular administration is not uncommonly as60ciated
wi~h unwanted side ef~ects such as muscle atrophy.
The pharmaceuticals obtained according to the
invention are single-drug products; however, these can in
some cases contain other glucocorticoids such as pred-
nisolone, but no other active su~stances.
The pharmaceuticals obtained according to the
invention are suitable for the treatment of disorders of
a wide variety of types; for example of bronchial asthma,
acute phases of rheumatoid arthritis or of psoriatic
arthritis; acute rheumatic f Pver; acute deterioration in
lupus erythematosus; temporal arteriitis, idiopathic
-- 8 --
thrombocytopenic purpura; sarcoidosis; acute alv601itis;
serum sickness, transfusion accidents; celiac disease
(gluten-related enteropathy); severe hypersensitivity to
insect bites; anaphylactic shock; angioneurotic edema
(for example Quincke edema); cerebral edema associated
with naoplasmen; pseudo croup (especially in children);
acute severe dermato~e~; acute complications o ulcera-
tive colitis (so-called toxic colon). A particularly
important area of use comprises treatment of acute
episodes of rheumatic diseases.
Suitable as glucocorticoid components of the
esters are conventional substances (steroid alcohols)
such as the endogenous cortisol and derivatives thereof such
as corticosterone, 11-dehydrocorticosterone, 17-hydro-
corticosterone, cortisone, fluorohydrocortisone, 1-dehy-
drocortisone, prednisolone, testosterone, fluorinated
methylprednisolones such as dexamethasone, betamethasone
or flumethasone. Suitable as acid components are residues
of physiologically tolerated organic acids which, apart
from the acid groups bonded in the manner o~ an ester,
can also contain additionally one, and expediently, a
maximum of two hydrophilic groups ~uch as SO3H, COOH or OH
groups. Examples of suitable residues are the sulfoben-
zoate, in particular the m-sulfobenzoate residue, fur-
thermore the monotartaric acid, monomalic acid andmonocitric acid residue. The sulfobenzoate residue is
advantageou~ly unsubstituted but can~also be substituted.
In this case it expediently contains on the
benzene radical no more than two other substituents,
specifically an alkyl radical with 1 to 2 C atoms or
another hydroxyl or sulfonic acid residue or a
combination thereof. All these compounds are preferably
administered in the form of their water-soluble
physiologically tolerated salts, in particular of an
alkali metal salt and, of the~e, the sodium salt.
The pharmacokinetic propertie~ of the pharmaceu-
ticals according to the invention are evident from the
two graphs hereinafter (Fig. 1 and Fig. 2). The values
'
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are shown in the graphic representation in semilogarith-
mic scale, from which the effects are clearly evident to
the person skilled in the art. Figure 1 shows the plasma
concentration (mean of 12 subjects) for dexamethasone
sulfobenzoate after intravenous (o) and intramuscular (o)
injection of 9.1 mg of dexamethasone sulfobenzoate
(equivalent to 6 mg of dexamethasone); Figure 2 shows the
plasma concentration (mean of 12 subjects plus/minus
standard deviation) of liberated dexamethasone after
intravenous injection of 9.1 mg of dexamethasone
sulfobenzoate (-) (equivalent to 6 mg of dexamethasone)
and 6.6 mg of dexamethasone dihydrogen pho~phate (~)
(equivalent to 6 mg of dexamethasone).
Example
lS An ampoule which contains 5 ml of an aqueous
injection solution is produced. This contains 9.15 mg of
the sodium salt of dexamethasone 21-(3-sulfobenzoate),
which amount is equivalent to 6 mg of dexamethasone. To
improve the solubility o the active substance, the
solution contains 30% (m/v) 1,2-propanediol.
On administration, the dosage is individually
adapted to the disease process; as a rule, in acute and
threatening situations, for example severe attacks of
asthma and similar states associated with chronic bron-
chitis, initially 1-2 ampoules are slowly admini tered
intravenously. This dosage usually suffices, so that
further treatment thereafter is no longer necessary.
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