Pharmaceutical preparation adapted for oral administration

The invention relates to a novel pharmaceutical preparation with anabolic activity adapted for oral administration comprising a nandrolone (= 19-nor-testosterone)-17.beta.-ester, the ester group of which has been derived from aliphatic carboxylic acids having 9-18 carbon atoms, in combination with a non-steroidal lipoid. The preparation may additionally contain a mineralocorticoid steroid. The invention also relates to novel nandrolone-17.beta.-esters.

The invention relates to a novel pharmaceutical preparation with anabolic 
activity adapted for oral administration, the said preparation containing 
a 17.beta.-ester of nandrolone (= 19-nor-testosterone), and to methods for 
the preparation thereof. The invention also relates to novel 
17.beta.-esters of nandrolone. 
Nandrolone and the 17.beta.-esters thereof are known as substances with 
anabolic activity, possessing only slight androgenic activity in 
comparison with testosterone and the 17.beta.-esters thereof. In 
particular, nandrolone-17.beta.-esters derived from aliphatic carboxylic 
acids with 9-18 carbon atoms are potent anabolic agents. One of the best 
known nandrolone esters is nandrolone decanoate, which as an oily solution 
under the trade name Deca-Durabolin finds use in medicine as an injection 
preparation with a pronounced and protracted protein-sparing effect. 
As already noted, the nandrolone-17.beta.-esters are administered 
parenterally, predominantly by the intramuscular route. When given orally 
they are scarcely active, or in any case much less active. An advantage of 
parenteral administration is that a good effect can be achieved with a 
relatively low dosage. The use of 17.beta.-esters results furthermore in a 
depot effect, so that an effective plasma nandrolone level is not only 
obtained rapidly after an intramuscular injection, but this nandrolone 
level may also persist for several weeks. 
There are also objections to the parenteral form of administration. A 
patient is not usually capable of giving him- or herself an injection; for 
this, a doctor or a trained nurse is almost always necessary. Furthermore, 
repated parenteral administration may cause local reactions. A further 
disadvantage associated with the parenteral administration of long-acting 
preparations is that the action thereof cannot be interrupted or stopped. 
An oral administration form would therefore be far more preferable than a 
parenteral form. 
Surprising, it has now been found that certain nandrolone esters, 
specifically the esters derived from aliphatic carboxylic acids with 9-18 
carbon atoms, are orally active if they are administered in combination 
with a non-steroidal lipoid substance. This is the more surprising since 
the nandrolone-17.beta.-esters derived from aliphatic carboxylic acids 
with less than 9 or more than 18 carbon atoms are distinctly less active 
orally under these conditions. 
The invention therefore relates to a novel pharmaceutical preparation with 
anabolic activity adapted for oral administration, containing an ester of 
nandrolone, and is characterized by the incorporation into a 
pharmaceutical form suitable for oral administration of one or more 
nandrolone-17.beta.-esters, derived from an aliphatic carboxylic acid with 
9-18 carbon atoms, together with a pharmaceutically acceptable 
non-steroidal lipoid. The invention also encompasses the method for 
preparing said preparation. 
The term "aliphatic carboxylic acid" also includes branched chain aliphatic 
and cycloaliphatic carboxylic acids. 
In the preparation according to the invention, preferably one or more 
nandrolone esters derived from an aliphatic carboxylic acid with 10-16 
carbon atoms are present. These esters have been shown to possess the 
highest activity, particularly the .alpha.- and .beta.-methyl substituted 
aliphatic carboxylic acid esters. 
As examples of aliphatic carboxylic acids with 9-18 carbon atoms, from 
which the nandrolone esters are derived, the following can be given: 
pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic 
acid, myristic acid, pentadecanoic acid, decenoic acid, undecenoic acid, 
palmitic acid, stearic acid and the branched-chain and cyclic analogues of 
these acids such as .alpha.-(and .beta.-)methyl-caprylic acid, 
.alpha.-(and .beta.-)methyl-pelargonic acid, .alpha.-(and 
.beta.-)methyl-capric acid, .beta.,.beta.-dimethyl-pelargonic acid, 
.beta.-(p-methyl-cyclohexyl)-propionic acid, 
.beta.-(p-ethylcyclohexyl)-propionic acid, .beta.-(cycloheptyl)-propionic 
acid, .alpha.-(and .beta.-)methyl-.beta.-cyclohexyl propionic acid, 
cyclododecyl-carboxylic acid, bicyclo[2,2,1]-heptyl-2'-carboxylic acid, 
adamantane carboxylic acid, adamantyl-acetic acid, 
4'-methyl-bicyclo[2,2,2]-oct-2'-enyl carboxylic acid and 
.beta.-(bicyclo[2,2,2]octyl)propionic acid. The nandrolon ester is 
preferably derived from capric acid, undecanoic acid, lauric acid, 
tridecanoic acid, myristic acid and more preferably from the .alpha.- or 
.beta.-methyl-substituted and cyclic isomers of these acids. 
Various of the nandrolone esters indicated above are novel compounds. The 
present invention therefore also comprises novel nandrolone esters with 
interesting anabolic properties, said novel nandrolone esters having the 
formula: 
##STR1## 
wherein n = 0 or 1 and preferably 0; R.sub.1 = alkyl (1-10 C), preferably 
CH.sub.3 ; R.sub.2 = H or alkyl (1-10 C), preferably H; R.sub.3 = an 
aliphatic group having 1-16 C-atoms, preferably 6-12 C-atoms, which group 
may contain one or more rings having 5-12 C-atoms, preferably 5-8 C-atoms, 
or R.sub.1 and R.sub.3 form together with the C-atom to which they are 
attached a cycloaliphatic group having 7-12 C-atoms, preferably 8-10 
C-atoms, which cycloaliphatic group is or may be substituted by an 
aliphatic group having 1-6 C-atoms, with the proviso that the total number 
of C-atoms in the ester group is in the range of 9-18 C-atoms, preferably 
9-16 C-atoms and still more preferably 10-14 C-atoms. 
The novel esters can be prepared according to methods known in the art, for 
example by reacting nandrolone with the organic carboxylic acid or with a 
functional derivative thereof, such as the acid chloride or the acid 
anhydride, in a solvent and in the presence of a water-binding agent or a 
base, such as pyridine. 
By pharmaceutically acceptable non-steroidal lipoids are meant plant and 
animal oils and fats consisting of the mono-, di- and triglycerides of 
various fatty acids or containing these as main constituents; fatty acid 
esters of alcohols; higher aliphatic alcohols; saturated and unsaturated 
fatty acids; the commercially available synthetic and semisynthetic 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 10.degree. C to about 35.degree. C. The 
nandrolone ester is then dissolved in the lipoid substance and the 
solution is incorporated into a preparation or, as the case may be, 
converted into a pharmaceutical form. At normal temperature, 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 
nandrolone esters according to the invention appears to be 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 
monooleate, cetyl alcohol, stearyl alcohol, capric acid, undecenoic acid, 
undecanoic acid, lauric acid, oleic acid, synthetic glycerides of 
saturated fatty acids, with 8 to 10 or 12 carbon atoms such as the 
commercial products Syndermin GTC and Miglyol 812, polyoxyethylene 
derivatives of glycerol, such as the commercial product Labrafil 1944, 
bee's wax and mixtures of two or more of these substances. 
The invention herein referred to provides an oral pharmaceutical 
preparation with anabolic activity. By incorporating an orally active 
mineralocorticoid into the preparation, the invention also offers the 
possibility of preparing an orally active pharmaceutical formulation which 
possesses mineralocorticoid properties in addition to anabolic properties. 
Pharmaceutical preparations with both anabolic and mineralocorticoid 
actions, effective on subcutaneous administration, are known. As an 
example, the commercially available preparation Docabolin, for 
intramuscular injection, can be cited. 
Such preparations, which in addition to powerful protein-sparing and 
roborant properties also have a normalizing effect on a reduced blood 
pressure, are used for various indications including hypotension, 
debilitating conditions, conditions associated with exhaustion, during 
convalescence, burns and infantile dystrophy. 
As orally active mineralocorticoid, one or more esters of 
desoxycorticosterone are incorporated into the anabolic preparation 
according to the invention, such esters being preferably derived from an 
aliphatic carboxylic acid with 9-18 carbon atoms. 
The desoxycorticosterone ester may be derived from the same aliphatic 
carboxylic acid as the nandrolone ester, and is preferably derived from 
the carboxylic acids with 10-12 carbon atoms. 
The presence of the oily component results in a surprising intensification 
of the oral activity of the desoxycorticosterone ester. 
The preparation according to the invention may be administered per os in 
various dosage forms, for example in the form of tablets, capsules, 
grains, pills, boli, dragees, powders, granulates, microcapsules or 
chewable tablets. In addition to the anabolic ester(s), the lipoid 
substance and optionally the mineralocorticoid compound, the dosage form 
may contain one or more of the usual excipients, for example benzyl 
alcohol to increase the solubility of the active agent in the oily 
component, water, thickening agents such as gelatine or agar-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 coating 
agents may optionally be present. 
The capsules may be soft or hard gelatine capsules, in which the active 
principle and the lipoid may be present in granular or finily divided 
intimate admixture or may be present in the form of an oily solution or 
suspension. 
The combination of nandrolone-17.beta.-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 
nandrolone-17.beta.-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 nandrolone-17.beta.-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 
or processed to coated pills or tablets. 
As already noted above, the nandrolone esters according to the invention 
are preferably administered dissolved in lipoid substances liquid at 
normal temperature, such as, for example, vegetable and animal oils, oleic 
acid, linoleic acid or undecanoic acid. When a mineralocorticoid is 
present, this is preferably also present dissolved in the oil, in addition 
to the nandrolone ester. 
The most suitable oral administration form for this liquid form of the 
preparation according to the invention is the soft-shell gelatine capsule 
or microcapsule. In accordance with a method usual in the technique, the 
oily solution containing the active component(s) and optionally other 
ingredients is encapsulated to soft-shell gelatine capsules or 
microcapsules with the desired dimensions and containing the desired 
amount(s) of active substance(s). The microcapsules can also be processed 
to tablets or pills according to well-known pharmaceutical formulation 
methods. 
The nandrolone-17.beta.-ester(s) concentration in the preparation according 
to the invention can vary within considerable limits, on the understanding 
that the amount of nandrolone-17.beta.-ester(s) by weight does not exceed 
the amount of lipoid substance by weight or in other words the 
nandrolone-17.beta.-ester(s) concentration in the preparation is 50% by 
weight or less and is usually in the range of 1-25% by weight. 
As indicated above, the amount of lipoid by weight in the preparation 
according to the invention is equal to or higher than the amount of 
nandrolone-17.beta.-ester by weight. Depending on the other constituents 
present in the preparation (excipients, capsule, shell, coating) the 
amount of lipoid substance per dosage unit will vary from 5 to 95% by 
weight and is usually in the range of 20-80% by weight. The amount of 
nandrolone-17.beta.-ester(s) per dosage unit, for example a capsule or a 
tablet, may also vary within wide limits, for example from 0.1 mg to 100 
mg, and is preferably between 1 mg and 50 mg. 
When the desoxycorticosterone ester is present in the preparation according 
to the invention, the amount thereof per dosage unit is within the range 
0.5 to 50 mg, and the requirement, that the amount of desoxycorticosterone 
ester by weight does not exceed the amount of lipoid substance by weight, 
also applies. 
The exceptional anabolic properties of the preparations according to the 
invention have been demonstrated in the known Hershberger test with 
castrated rats. A number of nandrolone-17.beta.-esters were administered 
orally twice daily for 7 days as solutions in arachis oil. Nandrolone 
itself was also tested in this way. 
With nandrolone, its lower esters such as acetate and propionate, and the 
nandrolone esters derived from aliphatic carboxylic acids with more than 
18 carbon atoms, given in dosages of 2.times.2.0 mg/day, the weight of the 
M-levator ani was shown to increase by 40-60%, while with the esters 
derived from aliphatic carboxylic acids with 9-18 carbon atoms, such as 
the decanoate, the undecanoate, the dodecanoate, the tetradecanoate etc., 
the increase proved to be 100-150%, being therefore 2 - 3 times as great. 
For cyclic esters, for example adamantyl carboxylate, and for branched 
chain esters, for example .alpha.-methyl-decanoate, said increase is even 
more than 150%. 
Experiments with other lipoid substances, such as sesame oil, soya bean 
oil, glyceryl trioleate, oleic acid and undecenoic acid, gave similar 
results. It was obvious that nandrolone-17.beta.-esters derived from 
aliphatic carboxylic acids with more than 8 and less than 18 C-atoms, in 
the presence of a lipoid substance, are much more active on oral 
administration than the other esters, and that specifically the esters 
with 10-14 carbon atoms, particularly the branched chain isomers, are very 
active. In clinical studies a distinct protein-sparing effect was 
demonstrated when a daily dosage of 1-3 dosage units of an anabolic 
preparation according to the invention was given for a few weeks.

The invention is further illustrated by means of the following examples: 
EXAMPLE I 
Soft-shell gelatine capsules 
A sterile solution of nandrolone-17.beta.-undecanoate in arachis oil, 
containing 83.33 g per liter, was prepared, and this solution was 
encapsulated in soft-shell gelatine capsules, with due regard for aseptic 
precautions. The soft-shell gelatine capsules obtained had a content of 
0.12 ml, so that the amount of active substance present was 10 mg per 
capsule. The capsule wall consisted of 68.1% gelatine, 15.5% glycerol, 
13.7% sorbitol, 0.4% sodium ethyl/propyl p-hydroxybenzoate, 0.5% TiO.sub.2 
and 1.8% Cochineal Red (dye). 
A number of nandrolone-17.beta.-esters in various lipoid substances were 
processed in a similar way to give soft-shell capsules, for which details 
are given in table A. 
Table A 
______________________________________ 
mg active 
lipoid capsule substance 
ester substance content capsule 
______________________________________ 
17.beta.-undecanoate 
oleic acid 0.12 5 
17.beta.-decanoate 
capric acid 0.08 10 
17.beta.-undecanoate 
undecenoic acid 
0.18 25 
17.beta.-undecanoate 
soya bean oil 
0.12 10 
17.beta.-dodecanoate 
ethyl oleate 
0.12 20 
17.beta.-tetradecanoate 
linseed oil 0.12 10 
17.beta.-.alpha.-methyl- 
oleic acid 0.08 5 
decanoate 
17.beta.-adamantyl- 
arachis oil 0.12 5 
carboxylate 
17.beta.-.alpha.-methyl-.beta.- 
linseed oil 0.08 5 
cyclohexylpropio- 
nate 
______________________________________ 
EXAMPLE II 
______________________________________ 
Tablets 
______________________________________ 
Nandrolone-17.beta.-undecanoate 
10.0 mg 
Capric acid 20.0 mg 
Lactose 140.0 mg 
Potato starch 80.0 mg 
250.0 mg 
______________________________________ 
Nandrolone-17.beta.-undecanoate was dissolved with gentle warming in capric 
acid, after which the solution was homogenously absorbed in the lactose. 
After mixing with potato starch and a little water, the granulate thus 
obtained was dried. The dry granulate was tabletted in the usual way. 
Tablets of the following compositions were prepared in a similar way: 
______________________________________ 
Nandrolone-17.beta.-.alpha.-methyldecanoate 
5.0 mg 
Glyceryl mono-oleate 50.0 mg 
Lactose 150.0 mg 
Potato starch 95.0 mg 
300.0 mg 
Nandrolone-17.beta.-dodecanoate 
10.0 mg 
Desoxycorticosterone undecanoate 
10.0 mg 
Stearyl alcohol/bee's wax 
20.0 mg 
Lactose 130.0 mg 
Potato starch 80.0 mg 
250.0 mg 
______________________________________ 
EXAMPLE III 
Hard-shell gelatine capsules 
______________________________________ 
(a) (b) 
______________________________________ 
Nandrolone-17.beta.-dodecanoate 
20.0 mg 10.0 mg 
Desoxycorticosterone dodecanoate 
-- 10.0 mg 
Lauric acid 100.0 mg 100.0 mg 
Lactose 130.0 mg 130.0 mg 
250.0 mg 250.0 mg 
______________________________________ 
Nandrolone-17.beta.-dodecanoate was dissolved in lauric acid at 50.degree. 
C (in case (b) together with the desoxycorticosterone dodecanoate). The 
solution was homogenously absorbed in the lactose and the cooled solid 
mixture was powdered. Hard-shell gelatine capsules were filled with the 
finely-divided mixture (250 mg mixture per capsule). 
EXAMPLE IV 
Soft-shell gelatine capsules 
Soft-shell gelatine capsules with contents as specified below were prepared 
in a way similar to that described in example I: 
______________________________________ 
a) Nandrolone-17.beta.-undecanoate 
10.0 mg 
Desoxycorticosterone decanoate 
5.0 mg 
Oleic acid to 0.18 ml 
b) Nandrolone-17.beta.-.alpha.-methyldecanoate 
5.0 mg 
Desoxycorticosterone decanoate 
10.0 mg 
Arachis oil to 0.24 ml 
______________________________________ 
EXAMPLE V 
Preparation of novel esters 
To a solution of 5 g nandrolone in a mixture of 50 ml pentane and 5 ml 
pyridine were added dropwise in 1 hour 5 ml of .alpha.-methylcapric acid. 
The reaction mixture was stirred for 1 hour and then neutralized with an 
aqueous solution of sodiumbicarbonate, whereafter the organic layer was 
separated, washed with a solution of sodiumbicarbonate and with water till 
neutral. The organic layer was evaporated till dryness. The residue was 
chromatographed over a column of silicagel with toluene/acetone 9/1, 
yielding 6.3 g nandrolone-17.beta.-.alpha.-methylcaprate, oil with 
[.alpha.].sub.D.sup.20 = +33.degree. (in dioxane). 
In a similar manner the following 17.beta.-esters of nandrolone were 
prepared: 
.beta.-methyl-caprate 
.alpha.,.alpha.-dimethylcaprate 
.alpha.-methyl-.beta.-cyclohexyl-propionate 
.beta.-cyclohexyl-butyrate 
cyclo-octyl-carboxylate 
.beta.,.beta.-diethyl-capronate 
.beta.-butyl-oenanthate 
.alpha.-methyl-tridecylate 
.beta.,.beta.-dimethyl-pelargonate 
bicyclo[2,2,1]-heptyl-2'-carboxylate 
bicyclo[2,2,1]-heptyl-2'-acetate