Note: Descriptions are shown in the official language in which they were submitted.
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The invention relates to a novel pharmaceutical preparation with
oestrogenic activi~y adapted for oral administration, the said preparation
containing a 17~ester of oestradiol, and two methods for the preparation
thereof.
Oestradiol and 17~-esters thereof are known. In medicine, these
oestrogenic compounds are predominantly used for the treatment of women after
ovarectomy, for climacteric complaints, for menstrual disorders and also
after the menopause to prevent deprivation manifestations. In such cases,
the oestrogens serve to compensate for a lack of endogenous oestrogen (sub-
stitution theraw ). Oestrogens are further used in the treatment of certaintypes of inoperable mammary carcinoma in postmenopausal women and in the
treatment of prostatic carcinoma of the man. The action of oestradiol-17~-
esters is attributable to that of oestradiol, which is formed in the body by
hydrolysis of the ester.
Oestradiol is administered parenterally, predominantly in the form
of one of its 17~-esters. In this way a good effect is achieved with a
relatively low dosage. Furthermoreg the use of 17~-esters results in a
depot effect, so that an effective oestrogen level in the plasma, persisting
for several weeks, can be obtained with an intra-muscular injection. By
taking a mixture of 17~-esters with various absorption rates from the depot
andlor different hydrolysis rates in the plasma, an oestrogen preparation
with a prolonged action can be obtained, where the action commences very
rapidly after the intramuscular administration and continues, for example,
for several weeks.
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There are however objections to the parenteral form of administrat-
ion. Patients are not normally capable of giving themselves an injection,
and a doctor or medically trained personnel (a nurse) is therefore almost
always necessary. Furthermore, repeated parenteral administration may cause
local reactions. The parenteral administration of long-acting preparations
is associated with a further disadvantage, in that the action thereof cannot
be interrupted or stopped. An oral administration form would therefore be
infinitely preferable to a parenteral form.
The above-noted effects of the parenteral form of administration
cannot however be achieved by administration of oestradiol or the 17~-esters
thereof by the oral route when the same quantities of active substance are
used; much larger quantities are necessary, sometimes 5-20 times as much.
The greatest part of the oestradiol or oestradiol-17~-ester given
orally is rapidly inactivated by the liver and excreted as a metabolite.
Only a fraction of the given dose is available for the final desired effect.
It is obvious that on frequent administration in this way, the liver and
other organs, such as the kidneys, are taxed more, as a result of which un-
desired side-effects may appear.
It has been possible to substantially increase the effective
activity on oral administration by introducing substituents into the oestra-
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diol molecule. Known examples of such co~pounds are : ethinyl-oestradiol
~17~-ethinyl-~ '3'5~1)-oestratrien-3,17~-diol~; mestranol (3-methoxy-17~-
ethinyl-~1'3~5(1)-oestratrien-17~-ol), quinestrenol ~3-cyclopentyloYy-17~-
ethinyl-~1'3'5~1)-oestratrien-17~-ol). The drawback of these "unnatural"
oestradiol derivatives is that the activity profile usually differs from that
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of oestradiol~ as a result of which, despite the advantages of the lower
dosages, other associated effects, which are not always desired, particularly
during longterm administration, have to be taken into account.
Surprisingly, it has now been found that the oral activity of
oestradiol can be considerably improved if oestradiol is administered in the
form of its 17~-esters with a straight-chain aliphatic carboxylic acid with
9-16 carbon atoms and in the presence of a pharmaceutically acceptable non-
steroidal lipoid. The lower and higher aliphatic carboxylic esters of
oestradiol proved to have much less effect when given under these circum-
stances in the same dosages.
The invention therefore provides a novel pharmaceutical preparat-
ion with oestrogenic activity adapted for oral administration which comprises
at least one 17~-ester of oestrad;ol, with a straight-chain aliphatic
carboxylic acid having 9-16 carbon atoms, and a pharmaceutically acceptable
carrier, said carrier comprising a non-stero;dal lipoid, the proportion of
said ester being 50% by weight or less of the preparation.
In the preparation according to the invention, preferably one or
more oestradiol esters derived from a straight-chain aliphatic carboxylic
acid with 10-14 carbon atoms are present. These esters have been shown to
possess the highest activity.
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As examples of aliphatic carboxylic acids with 9-16 carbon atoms,
from which the oestradiol esters are derived, the following can be given:
pelargonic acid, capric acid, undecanoic acid, lauric acid, tradecanoic acid,
myristic acid, pentadecanoic acid, decenoic acid, undecenoic acid and
palmitic acid.
By pharmaceutically acceptable non-steroidal lipoids are meant
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plant and animal oils and fats conslsting of the mono-, di- and triglycerides
of various fatty acids or containing these as main constituents; fatty acid
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esters of alcohols; higher aliphatic alcohols; saturated and unsaturatedfatty acids; the commercially available synthetic and semi-synthetic mono-,
di-, and triglyceride oils and glycerol ethers; certain types of wax and
mixtures of two or more of the above-noted substances. The lipoid substance
is preferably liquid at normal temperature, that is, at a temperature in the
range of about 10C to about 30C. The oestradiol ester is then dissolved
in the lipoid substance and the solution is incorporated into a preparation
or, as the casc may be, converted into a pharmaceutical form. At normal
temperature a part of the ester may be present in the liquid lipoid as a
suspension, in which case the quantities of ester and lipoid substance are
mutually adJusted in such a way that at body temperature the ester is
completely dissolved in the lipoid substance. The intensification of the oral
activity of the oestradiol esters according to the invention appears to be
the greatest when a lipoid substance liquid at normal temperature is used.
Examples of lipoid substances which may be used in the preparation
according to the invention are: arachis oil, castor oil, sesame oil, linseed
oil, soya bean oil, sunflower seed oil~ olive oil, fish liver oil, ethyl
oleate, oleyl oleate, glyceryl trioleate, glyceryl diolate, glyceryl mono-
oleatej cetyl alcohol, stearyl alcohol, capric acid, undecenoic acid, un-
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decanoic acid, lauric acid, ~leic acid, synthetic glycerides of saturated
fatty acids, with 8 to 10 or 12 carbon atoms such as the commercial products
Syndermin~- GIC and Miglyol~' 812, poloxyethylene derivatives of glycerol such
as the commercial product Labrafil7- 19~4, bee's wax and mixtures of two or
more of these substances.
me invention provides an oral pharmaceutical preparation with
oestrogenic activity. The invention also offers the possibility of providing
an orally active pharmaceutical preparation, which in addition to oestrogenic
properties also possesses androgenic or gestagenic properties, by incorpor-
ating an orall~ active androgen or gestagen in the preparation.
Orally active pharmaceutical preparations with both oestrogenicand androgenic activity are known. Such a preparation usually contains an
orally active oestrogen, such as 17<~-ethinyl--oestradiol or mestranol, as the
oestrogenic component, and an orally active androgen, such as 17~-methyl-
testosterone, as the androgenic component, the two components being present
in a certain ratio. Conditions in which such preparations are used include
climacteric complaints, for improvement of sleep and the feeling of wellbeing
in older women, in cases of frigidity, hypogonadism, peripheral vascul~r
disorders, osteoporosis and after castration. Such a preparation has a
positive influence on protein and calcium meta~olism, and may reduce or even
rectify a disorder of the hormonal balance in the climacteric or after
castration. When used in cases of frigidity, the androgenic component in-
; creases the libido and the oestrogenic component contributes to the recovery
of a possibly atrophic mucosa. In osteoporosis, the oestrogenic component
brings about a decrease in osteoclastic activity and the androgenic component
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stimulates the building up of the bone matrix.
As an orally active androgen for incorporation in the oestrogen
preparation according to the invention, preference is given to one or more
testosterone esters and/or 5~-dihydrotestosterone esters, derived from an
aliphatic carboxylic acid with 9-16 carbon atoms, preferably 10-12 carbon
atoms.
The androgen ester may be derived from the same aliphatic carboxy-
lic acid as the oestradiol ester and is preferably derived from capric acid,
undecanoic acid or lauric acid.
The presence of the oily component in the preparation according to
the present invention also results in intensification of the oral androgenic
activity of the testosterone and/or 5~L-dihydrotestosterone esters. In this
way, an oral preparation possessing both oestrogenic and androgenic activity
is obtained, which furthermore possesses the advantage that the action of
the preparation is based on that of natural hormones, which are formed in the
body by hydrolysis of the esters.
Orally active pharmaceutical preparations with both oestrogenic
and gestagenic activity are also known. This combination is mainly known
from oral contraceptives of the so-called combination type, in which an
orally active gestagenic substance, such as chlormadinone acetate, lynestrenol,
norethisterone, norethynodrel or norgestrel, has been combined with an orally
active oestrogenic substance~ such as ethinyl-oestradiol or mestranol. In
such preparations, the oestrogen component can be replaced by one or more
oestradiol esters, derived from an aliphatic carboxylic acid with 9-16 C-
atoms, together ~ith a lipoid substance according to the invention. With
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respect to the combination of an oestrogen with a gestagen, within the con-
text of the present invention, thought is however primarily directed at
combination preparations which find use during and after the menopause7 after
castration and in hypogonadism, and where attemp~s are made to produce resti-
tution of the hormonal balance to such an extent that in addition to other
positive effects o~ body functions, osteoporosis in particular is checked.
(See in this connexion, for example, ~he article by J. C. Gallagher and
B.E.C. Nordin in 'IThe Hormone", ~olume XXXVII, pages 59-73 (1973) entitled:
"Hormones and calcium metabolism"). For the preparation of formulations
which can be used for such an indication, an orally active gestagenic agenf
is appropriately also incorporated into the preparation according to the
invention, for example, norethisterone, lynestrenol or ethynodiol diacetateO
The preparation according to the invention can be administered
; orally in various dosage forms, for example in the form of tablets, capsules,
grains, pills, boli, dragees, powders, granulates or microcapsules. In
addition to the oestrogen ester (s)~ the lipoid substance and optionally
the androgenic or gestagenic compound, the dosage form may contain one or
more of the usual excipients, for example benzyl alcohol to increase the
solubility of the active substance in the oil component, water, thickening
~O agents such as gelatine or agar, polyethylene glycols, lactose, starch, talc
or magnesium stearate. Other agents, such as preservatives, emulsifying
agents, stabilizing agents, wetting agents, flavours, dyes, fillers, binding
agents and/or encapsulating agents may optionally also be present.
The capsules m~ be soft or hard gelatine capsules, in which the
active principle and the lipoid may be present in granular or finely divided
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intimate admixture or may be present in the form of an oily solution orsuspension.
The combination of oestradiol-17~-ester and lipoid, when liquid or
semi-liquid, may also be processed to solid oral formulations such as pills
or tablets. For that purpose the oily solution of oestradiol-17~-ester is,
for example, absorbed on calcium phosphate, lactose or cellulose derivatives
and then processed to tablets or pills in the usual way. Combinations of
oestradiol-17~-esters with lipoids, such as glycerylmono-oleate or capric
acid, which are solid or semi-solid at room temperature, but are liquid at
body temperature, may be granulated and processed to coated pills or tablets.
~ s already noted above, the oestradiol esters according to the
invention are preferably administered dissolved in lipoid subs-tances liquid
at normal tempera~.ure, such as, for example, vegetable and animal oils,
oleic acid9 linoleic acid or undecenoic acid. When the androgenic or gesta~
genic component is present, this is preferably also dissolved in the oil, in
additioD to the oestradiol ester.
The most suitable oral administration form for this liquid form of
the preparation according to the invention is the soft gelatine capsule or
microcapsole. In accordance with a method usual in the technique, the oily
solution containing the active components and optionally other ingredients
is~encapsulated to soft gelatine capsules or microcapsules with the desired
dimensions and containing the desired amount~s) of active substances. The
microcapsules can also be processed to tablets or pills according to well-
known pharmaceutical formulatlon methods.
The oestradiol-17~-esters(s) concentration in the preparation
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according to the invention can vary within considerable limits, on the under-
standing that the amount of oestradiol-17~-ester(s) by weight does not exceed
the amount of lipoid substance by weight or in other words the oestradiol-17~-
ester(s) concentration in the preparation is 50% by weight or less and is
usually in the range of 0.01-10% by weight.
As indicated above, the amount of lipoid by weight in the prepar-
ation according to the invention is equal to or higher than the amount of
oestradiol-17~-ester by weight. Depending on the other constituents present
in the preparation (excipients, capsule shell, coating) the amount of lipoid
1() substance per dosage unit will vary from 25 to 95% by weight and is usually
in the range of 50-80% by weight. The amount of oestradiol-17~-ester~s)
per dosage unit, for example a capsule or a tablet, may also vary within
wide limits, for example from 0.001 mg to 2 mg, and is preferably between
0.005 mg and 1 mg.
When an androgen ester is present in the preparation according to
the invention, the amount thereof per dosage unit is within the range 0.5
to 400 mg, and the requirement, that the amolmt of androgen 0ster by weight
does not exceed the amount of lipoid substance by weight, also applies.
When a gestagenic substance is present in the preparation according to
the invention, the amount thereof per dosage unit is within the range 0.1 to
20 mg, and is preferably between 0.2 and 10 mg.
The exceptional oestrogenic properties of the preparations accord-
ing to the invention have been demonstrated using the known Allen-Doisy test
(J.A.M.A. (1923), 81, pages 819-821~ in castrated female rats. The oestra-
diol-17~-esters were administered orally, dissolved in arachis oil. The
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results are given in Table A.
Table A
Dosage
Oestradiol-17~-ester
8 ~g 16 ~g 32 ~g
-formate 0/8 0/8 1/8
-pentanoate 0/8 0/8 0/8
-octanoate 0/8 1/8 2/8
! -decanoate 2/8 6/8 7/8
-undecanoate 2/8 7/8 8/8
-dodecanoate 2/8 6/8 7/8
-tetradecanoate 1/8 6/8 6/8
-hexadecanoate 0/8 0/8 6/8
-octadecanoate 0/8 D/8 2/8
Studies with other lipoid substances, such as sesame oil, soya bean
oil, glyceryl trioleate, oleic acid and undec:enoic acid gave similar results.
It appears obvious that oestradiol-17~-esters derived from carboxylic acids
with 8 or less, or l8 or:more, C-atoms are much less active than the esters
used aceording to the invention, and that in particular the esters with 10-14
carbon atoms in the ester group are very active.
Clinical trials in ovarlectomized and m menopausal women, given a
daily dosage of 0.1-0.5 mg oestradiol-17~ester, administered in an oral prep-
aration according to the invention, revealed favourable oestrogenic effects,
whlch suggest the potency of the preparation in EDS-therapy.
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During clinical trials in post-menopausal women, given a daily
dosage of 1-3 dosage units of an oestrogen and of an oestrogen-gestagen pre-
paration according to the invention for 6 weeks, a distinct decrease in the
plasma calcium level was noted, which suggests an anti-osteoporotic effect.
The invention is further illustrated by means of the following
examples.
Example I
Softl~elatine capsules
A sterile solution of oestradiol-l~R-decanoate in arachis oil,
containing 4.167 g per litre, was prepared. This solution was encapsulated
in soft gelatine capsules with due regard for aseptic precautions. The soft
gelatine capsules obtained had a content of 0.1~ ml, so that the amount of
active agent present was 0.5 mg per capsule. The capsule wall consisted of
70 % gelatine, 16 % glycerol, 12 % sorbitol, 0.4 % of the sodium salts of
ethyl/propyl-p-hydroxybenzoate, 0.5 % TiO2 and 1.1 % Cochineal Red ~dye).
In a similar way, a mlmber of oestradiol-17~-esters in various
lipoid substances were processed to give soft gelatine capsules, details of
which are given in Table B.
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Table B
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-17~-ester lipoid substance content of mg active sub-
capsule stance/capsule
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-decanoate oleic acid 0.12 0.25
-undecanoate soya bean oil 0.12 0.2
-dodecanoate ethyl oleate 0.12 0.25
-tetradecanoate linseed oil 0.18 0.5
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Example II
Tablets
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Oestradiol-17~-decanoate 0.5 mg
Capric acid 82.5 mg
Lactose 145.0 mg
Potato starch 20.0 mg
Magnesium stearate 1.5 mg
Citric acid 0.5 mg
5 0O mg
Oestradiol-17~-undecanoate was dissolved with gentle warming in
capric acid, after which the solution was homogenously absorbed in the lac-
tose. After mixing wlth potato starch~ citric acid and a little water, the
thus-obtained granulate was dried. The dry granulate was mixed with the
magnesium stearate and tabletted in the usual way.
Tablets with the following composition were prepared in a similar
way:
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oestradiol-17~-undecanoate0.5 mg
testosterone undecanoate40.0 mg
glyceryl mono-oleate 150.0 mg
lactose 48.0 mg
methyl cellulose 20.0 mg
magnesium stearate 1.5 mg
250.0 mg
Example III
Hard gelatine capsules
Oestradiol-17~-dodecanoate0.25 mg
Chlormadinon acetate 4.00 mg
Lauric acid 95.75 mg
lOO.O mg
Oestradiol-17~-dodecanoate and chlormadinon acetate are dissolved
in laurîc acid at 50C. After cooling, the solid mixture is powdered, and
hard gelatine capsules ar0 filled with the finely--divided mixture (100 mg
mixture per capsule).
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Example IV
Soft gelatine capsules
Soft gelatine capsules with contents as indicated below were pre-
pared in a way similar to that described in example I.
a) Oestradiol-17~-decanoate 0.02 mg
Testosterone-17~-decanoate 10.00 mg
Oleic acid to 0.18 ml
b) Oestradiol-17~-undecanoate 0.1 mg
Norethisterone 2.0 mg
Arachis oil to 0.12 ml
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