CA1113926A - Pharmaceutical preparation adapted for oral administration - Google Patents
Pharmaceutical preparation adapted for oral administrationInfo
- Publication number
- CA1113926A CA1113926A CA365,887A CA365887A CA1113926A CA 1113926 A CA1113926 A CA 1113926A CA 365887 A CA365887 A CA 365887A CA 1113926 A CA1113926 A CA 1113926A
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- nandrolone
- beta
- alpha
- base
- acid
- Prior art date
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to a novel nandrolone-17.beta.-esters and their preparation. The new compounds possess anabolic activity. They are 17.beta.-esters of nandrolone with carboxylic acids of the formula
The invention relates to a novel nandrolone-17.beta.-esters and their preparation. The new compounds possess anabolic activity. They are 17.beta.-esters of nandrolone with carboxylic acids of the formula
Description
~L3~3Z6 The invention relates to novel esters having anabolic activity adapted for oral administration, and more particularly to certain novel 17~-esters of nandrolone (= l9-nor-testosterone), and to methods for the prepar-ation thereof.
Nandrolone and many 17~-esters thereof are known as substances with anabolic activity, possessing only slight a~drogenic actlvity in comparison with testosterone and the 17~-esters thereof. In particular, nandrolone-17~-esters derived from aliphatic carboxylic acids with 9-1~ carbon atoms are potent anabolic agents. One of the best known nandrolone esters is nandrolone decanoat~, which as an oily solution under the trade maTk Deca-~urabolin finds use in medicine as an injection preparation with a pronounc-ed alld protracted protein-sparing effect.
As already noted, the nandrolone-17~-esters are administered parenterally, predominantly by the intramuscular route. When given orally they are scarcely active, or in any cas0 much less active. An advantage of parenteral administration is that a good effect can be achieved with a re-latively lo~ dosage. The use of 17~-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. Further-more, repeated yarenteral 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 stop-ped. An oral administration form would therefore be far more preferable . . ", :~ :.. : . , : : ", :
- :-: . : , . . . : . :: . : ~ , :
~: .: ,, : . ~ , . .
~L3~Z6 than a parenteral form.
It has 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~-esters derived from aliphatic carboxylic acids ~ith less than 9 or more than 18 carbon atoms are distinctly less active orally under these conditions.
The invention relates to a group of such esters which are novel.
Accordingly, the invention provides novel 17~-esters of nandrolone having the formula Rl O - C - (CH2)n ~ 1 3 R2 (1) l I
O ~ ~\~.
, ~Yherein n ~ O or l; ~1 ~ alkyl Cl-lQ C~; R2 ~ ~ or alkyl ~1-10 C~; R3 = an aliphatic or cycloaliphatic gr~oup having 6-~12 C-atoms, ~hic~ group may contain one or more rings having 5-12 C-atoms, with the proviso that the total number of C-atoms in the ester group is in the range oE 9-16 C-atoms.
According to the invention, the novel esters are prepared by a process which comprises reacting nandrolone with an appropriate organic carboxy-lic acid or functional derivative thereof in a sol~ent and in the presence of a watel~-binding agent or a base. Functional derivatives include particularly the acid chloride and the acid anhydride. A suitable base which may be used ;~
- ; :, ' , ' ' , ", ~ ,, , r `: ':: :, ', .;, . ` ' for the reaction is pyridine.
in the new compounds according to the invention, it is preferred that n is zero, Rl is methyl, R2 is hydrogen, and ~3 is an aliphatic group having 6-12 carbon atoms ~hich may contain one or more rings having 5-8 car-bon atoms.
As examples of aliphatic carboxylic acids from which the nandrolone esters o~ the invention are deri~ed, the following can be given: ~-(and ~-) methyl-caprylic acid, ~-~and ~-~methyl-pelargonic acid, ~-(and ~-)methyl-capric acid, ~, ~-dimethyl-pelargonic acid and ~-~and ~-)methyl-~-cyclohexyl propionic acid. The nandrolone ester is preferably deri~ed from the ~- or ~-etl~yl-substitllted and cyclic isomers of capric acid, undecanoic acid, lauric .ICid, tridecanoic acid, or ~yristic acid.
The esters may be formulated ~ith a pharmaceutically acceptable nonsteroidal lipoid for oral administration. By pharmaceutically acceptable nonsteroidal 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; hi~her aliphatic alco-hols; saturated and unsaturated fatty acids; the commercially available syntlletic 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. T~e lipoid substance is preferably liquid at normal temperature, that is, at a temperature in the range of about 10C to about 35C. The ~androlone 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 pharmace-ltical form. At normal temperature, part of the ester may be pre-sent in the liquid lipoid as a suspension, in which case the quanti~ies of ester and lipoid substance are mutually adjusted in such a way that at body . . ~ , , . . .: .
, ;
- ~ ,.: .: . . :- . . :.
. ~ :....... : . : .;. . :. .: :, :, ::: : .; . . ::; .,, :
:;. . ;, 3~Z6 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 the greatest ~hen a lipoid substance liquid at normal tempeTature is used.
E~amples of lipoid substance which may be used in ~he preparation according to the invention are: arachis oil, castor oil, sesame oil, lin-seed oil, soya bean oil, sunflower seed oil, olive oil, fish liver oil, ethyl oleate, oleyl oleate, glyceryl trioleate, glyceryl diolate, glyceryl mono-oleate, cetyl alcohol, stearyl alcohol, capric acid, undecenoic acid, unde-canoic 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 conlmercial 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 of~ers the pos-sibility of preparing an orally active pharmaceutical formulation which pos-sesses mineralocorticoid properties in addition to anabolic properties.
Pharmaceutical preparations with both anabolic and ~ineralocorti-coid actions, effective on subcutaneous administration, are known. As ~n e~ample, the commercially available preparation Docabolin*, for intramuscular injection, can be cited.
Such preparationsJwhich 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, debilitat-ing conditions, conditions associated with exhaustion, during convalescence, * Trade mark _ ~ _ . .-: - . ~ : , ~ , . - ,. . .
,;:;
~ :, .. .
. .
~39~6 burns and infantile dystrophy.
As orally active mineralocorticoid, one or more esters of desoxy-corticosterone are incorporated into the anabolic preparation according to the invention, such esters being preferably derived from an aliphatic car-boxylic acid with 9-18 carbon atoms.
The desoxycorticosterone ester may be derived rom the same alipha-tic carboxylic acid as the nandrolone ester, and is preferably derived from the carboxylic acids with lO-12 carbon atoms.
The presence o~ the oily component results in a surprising intensi-fication of the oral activity of the desoxycorticosterone ester.
The preparation according to the invention may be administered ~er 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 ~orm 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 preserva~ives, emulsifying agents, stabilizing agents, wetting agents, flavours, dyes, fillers, binding agents and/or coating agents may optionally be present.
The capsules may be so~t or hard gelatine capsules, in which the active principle and the lipoid may be present in granular or Einely divid-ed intimate admixture or may be present in the form of an oily solution or suspension.
The combination of nandrolone-17~-ester and lipoid, when li~uid or semi-liquid, may also be processed to solid oral ormulations such as pills :. ::.: . ` . . :, , . : , :, . ....
~ h ~ 33Z~i or tablets. For that pur~ose the oily solution of nandrolonc-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 nandrolone-17~-esters with lipoids, such as glycerylmono-oleate or capric acid, wllich are solid or semi-solid at Toom temperature, but are liquid at body temperature, may be granulated and 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 9~ 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 micro-capsules with the desired dimensions and containing the desired amount(s) of active substance~s). The micro-capsules can also be processed to tablets or pills according ~o well-known pharmaceutical formulation methods.
The nandrolone-17~-ester~s) concentration in the preparation ac-cording to the invention can vary within considerable limits, on the under-standing that the amount of nandrolone-17~-ester~s) by weight does not e~ceed the amount of lipoid substance by weight or in other words the nandro-lone-17~-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 prepara-.. . , .
.. : . .
: . . .
- .
- , ' ': ~
3!~:6 tion according ~o the invention is equal to or higher than the amount o~
nand~olone-17~-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~-ester(s) pcr dosage unit, for example a capsule or a tablet, may also vary within l~ide limits, for example from 0.1 mg to 100 mg, and is preferably between l mg and 50 mg.
When the desoxycorticosterone ester is present in the preparation according to the invention, the amount thereo~ per dosage unit is within the range 0.5 to 50 mg, and the requirement, that the amount of desoxycortico-sterone ester by weig]lt 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~-esters were administered orally twice daily for 7 days as solutions in arachis oil. Nandrolone itself was also tested in this way.
Nith 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 2x2.0 mg/day, the weight of the M-levator ani was shown to increase by ~0%-60%, wllile with the es~ers of tlle invention derived from aliphatic carboxylic acids with 9-18 carbon atoms, such as the ~-methyl-decanoate, said increase is 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~-esters derived from aliphatic : ., .,,: . ~
-:. : ;. : : . . .
.,:. .~ , ~, ,.
;. , ~, -;:: ~ .. : . - :
~,,:, :
- " . ~ .
. . ~., ,. . :
392~
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 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 prepara-tion according to the invention was given for a few weeks.
The invention is further illustrated by means of the following examples:
Exam~
Soft-shell gelatine capsules A sterile solution of a nandrolone-17~-ester according to the in-vention in arachis oil, containing 83.33 g per litre, 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%
TiO2 and 1.8% Cochineal Red ~dye).
Two nandrolone-17~-esters in various lipoid substances were pro-cessed in this way to give soft-shell capsules, for which details are given in table A.
Table A ;~
lipoid capsule mg active ester substance content substance/capsule -17~-a-methyl- oleic acid 0.08 5 decanoate -17~-~-methyl-~- linseed oil 0.08 5 cyclohexylpropio-nate ~ __ .. ..
.
~39Z6 Example II
Tablets Nandrolone-17~-ester 10.0 mg Capric acid 20.0 mg Lactose 1~0.0 mg Potato starch 80.0 mg 250.0 mg The nandrolone-17~-ester e.g. nandrolone-17~ -methyldecanoate, was dissolved with gentle warming in capric acid, after which the solution was homogenously absorbed in the lactose. Ater 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~-ester 5.0 mg Glyceryl mono-oleate 50.0 mg Lactose 150.0 mg Potato starch ~5.0 mg 300.0 mg Nandrolone-17~-ester 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 _ g _ :: : :. . : : :
; , : :: : , ,: : .: -:: : . .~ ~
~3~Z~;
Example III
Hard-shell gelatine capsules (a) (b) Nandrolone-17~-ester 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 The nandrolone-17~-ester was dissolved in lauric acid at 50C (in case tb) together with the desoxycorticosterone dodecanoate). The solution was homogenously absorbed in the lactose and the cooled solid mixture was powdered. ~lard-shell gelatine capusles were filled wi~h the ~inely-divided mixture ~250 mg mixture per capsule).
Example IV
Soft-shell gelatine capsules Soft-shell gelatine capsules with contents as speci~ied below were prepared in a way similar to that described in example I, using, for example, nandrolone-17~- ~-methyldecanoate.
a) Nandrolone-17~-ester 10.0 mg Desoxycorticosterone decanoate 5.0 mg Oleic acid to 0.18 ml b) Nandrolone-17~-ester 5.0 mg Desoxycorticosterone decanoate 10.0 mg Arachis oil to 0.24 ml . :. .. ..
- ,. . . . -.. : . . . .
.. .. . . .
~3~Z~
Example V
Preraration 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 ~-methylcapric acid.
The rcaction mixture was stirred for 1 hour and then neutralised with an aqueous solution of sodium-bicarbonate, whereafter the organic layer was separated, washed with a solution of sodium-bicarbonate and with water till neutral. The organic layer was evaporated till dryness. The residue was chromatograp~led over a column of silicagel with toluene/acetone 9/1, yield-ing 6.3 g nandrolone-17~- ~-methylcaprate, oil with [~]D0 = +33 ~in dioxane).
In a similar manner the following 17~-esters of nandrolone were prepared:
~-methylcaprate, oil with [u]20 = +35.7 ~,~-dimethylcaprate, ~a]D = +39.6 ~-methyl-~-cyclohexyl-propionate, [~]20 = +35 ~-cyclohexyl-butyrate, ~]20 = +350 ~-methyl-tridecylate, [~]D0 = +27.3 3',5',5'-trimethylcaproate, oil with [~]D0 = +47 4 3',7'-dimethylcaprylate, oil with ~]D = +35.8 ~,~ -diethyl-caproate ~-butyl-oenanth~te ~,~ -dimethyl-pelargonate : , ,
Nandrolone and many 17~-esters thereof are known as substances with anabolic activity, possessing only slight a~drogenic actlvity in comparison with testosterone and the 17~-esters thereof. In particular, nandrolone-17~-esters derived from aliphatic carboxylic acids with 9-1~ carbon atoms are potent anabolic agents. One of the best known nandrolone esters is nandrolone decanoat~, which as an oily solution under the trade maTk Deca-~urabolin finds use in medicine as an injection preparation with a pronounc-ed alld protracted protein-sparing effect.
As already noted, the nandrolone-17~-esters are administered parenterally, predominantly by the intramuscular route. When given orally they are scarcely active, or in any cas0 much less active. An advantage of parenteral administration is that a good effect can be achieved with a re-latively lo~ dosage. The use of 17~-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. Further-more, repeated yarenteral 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 stop-ped. An oral administration form would therefore be far more preferable . . ", :~ :.. : . , : : ", :
- :-: . : , . . . : . :: . : ~ , :
~: .: ,, : . ~ , . .
~L3~Z6 than a parenteral form.
It has 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~-esters derived from aliphatic carboxylic acids ~ith less than 9 or more than 18 carbon atoms are distinctly less active orally under these conditions.
The invention relates to a group of such esters which are novel.
Accordingly, the invention provides novel 17~-esters of nandrolone having the formula Rl O - C - (CH2)n ~ 1 3 R2 (1) l I
O ~ ~\~.
, ~Yherein n ~ O or l; ~1 ~ alkyl Cl-lQ C~; R2 ~ ~ or alkyl ~1-10 C~; R3 = an aliphatic or cycloaliphatic gr~oup having 6-~12 C-atoms, ~hic~ group may contain one or more rings having 5-12 C-atoms, with the proviso that the total number of C-atoms in the ester group is in the range oE 9-16 C-atoms.
According to the invention, the novel esters are prepared by a process which comprises reacting nandrolone with an appropriate organic carboxy-lic acid or functional derivative thereof in a sol~ent and in the presence of a watel~-binding agent or a base. Functional derivatives include particularly the acid chloride and the acid anhydride. A suitable base which may be used ;~
- ; :, ' , ' ' , ", ~ ,, , r `: ':: :, ', .;, . ` ' for the reaction is pyridine.
in the new compounds according to the invention, it is preferred that n is zero, Rl is methyl, R2 is hydrogen, and ~3 is an aliphatic group having 6-12 carbon atoms ~hich may contain one or more rings having 5-8 car-bon atoms.
As examples of aliphatic carboxylic acids from which the nandrolone esters o~ the invention are deri~ed, the following can be given: ~-(and ~-) methyl-caprylic acid, ~-~and ~-~methyl-pelargonic acid, ~-(and ~-)methyl-capric acid, ~, ~-dimethyl-pelargonic acid and ~-~and ~-)methyl-~-cyclohexyl propionic acid. The nandrolone ester is preferably deri~ed from the ~- or ~-etl~yl-substitllted and cyclic isomers of capric acid, undecanoic acid, lauric .ICid, tridecanoic acid, or ~yristic acid.
The esters may be formulated ~ith a pharmaceutically acceptable nonsteroidal lipoid for oral administration. By pharmaceutically acceptable nonsteroidal 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; hi~her aliphatic alco-hols; saturated and unsaturated fatty acids; the commercially available syntlletic 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. T~e lipoid substance is preferably liquid at normal temperature, that is, at a temperature in the range of about 10C to about 35C. The ~androlone 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 pharmace-ltical form. At normal temperature, part of the ester may be pre-sent in the liquid lipoid as a suspension, in which case the quanti~ies of ester and lipoid substance are mutually adjusted in such a way that at body . . ~ , , . . .: .
, ;
- ~ ,.: .: . . :- . . :.
. ~ :....... : . : .;. . :. .: :, :, ::: : .; . . ::; .,, :
:;. . ;, 3~Z6 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 the greatest ~hen a lipoid substance liquid at normal tempeTature is used.
E~amples of lipoid substance which may be used in ~he preparation according to the invention are: arachis oil, castor oil, sesame oil, lin-seed oil, soya bean oil, sunflower seed oil, olive oil, fish liver oil, ethyl oleate, oleyl oleate, glyceryl trioleate, glyceryl diolate, glyceryl mono-oleate, cetyl alcohol, stearyl alcohol, capric acid, undecenoic acid, unde-canoic 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 conlmercial 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 of~ers the pos-sibility of preparing an orally active pharmaceutical formulation which pos-sesses mineralocorticoid properties in addition to anabolic properties.
Pharmaceutical preparations with both anabolic and ~ineralocorti-coid actions, effective on subcutaneous administration, are known. As ~n e~ample, the commercially available preparation Docabolin*, for intramuscular injection, can be cited.
Such preparationsJwhich 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, debilitat-ing conditions, conditions associated with exhaustion, during convalescence, * Trade mark _ ~ _ . .-: - . ~ : , ~ , . - ,. . .
,;:;
~ :, .. .
. .
~39~6 burns and infantile dystrophy.
As orally active mineralocorticoid, one or more esters of desoxy-corticosterone are incorporated into the anabolic preparation according to the invention, such esters being preferably derived from an aliphatic car-boxylic acid with 9-18 carbon atoms.
The desoxycorticosterone ester may be derived rom the same alipha-tic carboxylic acid as the nandrolone ester, and is preferably derived from the carboxylic acids with lO-12 carbon atoms.
The presence o~ the oily component results in a surprising intensi-fication of the oral activity of the desoxycorticosterone ester.
The preparation according to the invention may be administered ~er 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 ~orm 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 preserva~ives, emulsifying agents, stabilizing agents, wetting agents, flavours, dyes, fillers, binding agents and/or coating agents may optionally be present.
The capsules may be so~t or hard gelatine capsules, in which the active principle and the lipoid may be present in granular or Einely divid-ed intimate admixture or may be present in the form of an oily solution or suspension.
The combination of nandrolone-17~-ester and lipoid, when li~uid or semi-liquid, may also be processed to solid oral ormulations such as pills :. ::.: . ` . . :, , . : , :, . ....
~ h ~ 33Z~i or tablets. For that pur~ose the oily solution of nandrolonc-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 nandrolone-17~-esters with lipoids, such as glycerylmono-oleate or capric acid, wllich are solid or semi-solid at Toom temperature, but are liquid at body temperature, may be granulated and 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 9~ 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 micro-capsules with the desired dimensions and containing the desired amount(s) of active substance~s). The micro-capsules can also be processed to tablets or pills according ~o well-known pharmaceutical formulation methods.
The nandrolone-17~-ester~s) concentration in the preparation ac-cording to the invention can vary within considerable limits, on the under-standing that the amount of nandrolone-17~-ester~s) by weight does not e~ceed the amount of lipoid substance by weight or in other words the nandro-lone-17~-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 prepara-.. . , .
.. : . .
: . . .
- .
- , ' ': ~
3!~:6 tion according ~o the invention is equal to or higher than the amount o~
nand~olone-17~-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~-ester(s) pcr dosage unit, for example a capsule or a tablet, may also vary within l~ide limits, for example from 0.1 mg to 100 mg, and is preferably between l mg and 50 mg.
When the desoxycorticosterone ester is present in the preparation according to the invention, the amount thereo~ per dosage unit is within the range 0.5 to 50 mg, and the requirement, that the amount of desoxycortico-sterone ester by weig]lt 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~-esters were administered orally twice daily for 7 days as solutions in arachis oil. Nandrolone itself was also tested in this way.
Nith 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 2x2.0 mg/day, the weight of the M-levator ani was shown to increase by ~0%-60%, wllile with the es~ers of tlle invention derived from aliphatic carboxylic acids with 9-18 carbon atoms, such as the ~-methyl-decanoate, said increase is 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~-esters derived from aliphatic : ., .,,: . ~
-:. : ;. : : . . .
.,:. .~ , ~, ,.
;. , ~, -;:: ~ .. : . - :
~,,:, :
- " . ~ .
. . ~., ,. . :
392~
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 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 prepara-tion according to the invention was given for a few weeks.
The invention is further illustrated by means of the following examples:
Exam~
Soft-shell gelatine capsules A sterile solution of a nandrolone-17~-ester according to the in-vention in arachis oil, containing 83.33 g per litre, 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%
TiO2 and 1.8% Cochineal Red ~dye).
Two nandrolone-17~-esters in various lipoid substances were pro-cessed in this way to give soft-shell capsules, for which details are given in table A.
Table A ;~
lipoid capsule mg active ester substance content substance/capsule -17~-a-methyl- oleic acid 0.08 5 decanoate -17~-~-methyl-~- linseed oil 0.08 5 cyclohexylpropio-nate ~ __ .. ..
.
~39Z6 Example II
Tablets Nandrolone-17~-ester 10.0 mg Capric acid 20.0 mg Lactose 1~0.0 mg Potato starch 80.0 mg 250.0 mg The nandrolone-17~-ester e.g. nandrolone-17~ -methyldecanoate, was dissolved with gentle warming in capric acid, after which the solution was homogenously absorbed in the lactose. Ater 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~-ester 5.0 mg Glyceryl mono-oleate 50.0 mg Lactose 150.0 mg Potato starch ~5.0 mg 300.0 mg Nandrolone-17~-ester 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 _ g _ :: : :. . : : :
; , : :: : , ,: : .: -:: : . .~ ~
~3~Z~;
Example III
Hard-shell gelatine capsules (a) (b) Nandrolone-17~-ester 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 The nandrolone-17~-ester was dissolved in lauric acid at 50C (in case tb) together with the desoxycorticosterone dodecanoate). The solution was homogenously absorbed in the lactose and the cooled solid mixture was powdered. ~lard-shell gelatine capusles were filled wi~h the ~inely-divided mixture ~250 mg mixture per capsule).
Example IV
Soft-shell gelatine capsules Soft-shell gelatine capsules with contents as speci~ied below were prepared in a way similar to that described in example I, using, for example, nandrolone-17~- ~-methyldecanoate.
a) Nandrolone-17~-ester 10.0 mg Desoxycorticosterone decanoate 5.0 mg Oleic acid to 0.18 ml b) Nandrolone-17~-ester 5.0 mg Desoxycorticosterone decanoate 10.0 mg Arachis oil to 0.24 ml . :. .. ..
- ,. . . . -.. : . . . .
.. .. . . .
~3~Z~
Example V
Preraration 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 ~-methylcapric acid.
The rcaction mixture was stirred for 1 hour and then neutralised with an aqueous solution of sodium-bicarbonate, whereafter the organic layer was separated, washed with a solution of sodium-bicarbonate and with water till neutral. The organic layer was evaporated till dryness. The residue was chromatograp~led over a column of silicagel with toluene/acetone 9/1, yield-ing 6.3 g nandrolone-17~- ~-methylcaprate, oil with [~]D0 = +33 ~in dioxane).
In a similar manner the following 17~-esters of nandrolone were prepared:
~-methylcaprate, oil with [u]20 = +35.7 ~,~-dimethylcaprate, ~a]D = +39.6 ~-methyl-~-cyclohexyl-propionate, [~]20 = +35 ~-cyclohexyl-butyrate, ~]20 = +350 ~-methyl-tridecylate, [~]D0 = +27.3 3',5',5'-trimethylcaproate, oil with [~]D0 = +47 4 3',7'-dimethylcaprylate, oil with ~]D = +35.8 ~,~ -diethyl-caproate ~-butyl-oenanth~te ~,~ -dimethyl-pelargonate : , ,
Claims (23)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing novel 17.beta.-esters of nandrolone having the formula:
(I) , wherein n = O or 1; R1 = alkyl (1-10 C); R2 = H or alkyl (1-10 C); R3 = an aliphatic or cycloaliphatic group having 6-12 C-atoms, which group may contain one or more rings having 5-12 C-atoms, with the proviso that the total number of C-atoms in the ester group is in the range of 9-16 C-atoms, which process com-prises reacting nandrolone with an appropriate organic carboxylic acid or func-tional derivative thereof in a solvent and in the presence of a water-binding agent or a base.
(I) , wherein n = O or 1; R1 = alkyl (1-10 C); R2 = H or alkyl (1-10 C); R3 = an aliphatic or cycloaliphatic group having 6-12 C-atoms, which group may contain one or more rings having 5-12 C-atoms, with the proviso that the total number of C-atoms in the ester group is in the range of 9-16 C-atoms, which process com-prises reacting nandrolone with an appropriate organic carboxylic acid or func-tional derivative thereof in a solvent and in the presence of a water-binding agent or a base.
2. A process according to claim 1, wherein n is 0, R1 is methyl, and the total number of C-atoms in the ester group is from 10 to 14.
3. A 17.beta.-ester of nandrolone having the formula I defined in claim 1, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
4. A 17.beta.-ester of nandrolone having the formula I given in claim 1 wherein R2 and R3 are as defined in claim 1 and n and R1 as well as the total number of C-atoms in the ester group are as defined in claim 2, when prepar-ed by the process claimed in claim 2, or by an obvious chemical equivalent thereof.
5. A process for the preparation of nandrolone-17.beta.(.alpha.-methylcaprate) which comprises esterifying nandrolone with .alpha.-methylcapric acid in a suitable solvent and in the presence of a base.
6. Nandrolone-17.beta.-(.alpha.-methylcaprate) when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of nandrolone-17.beta.-(.beta.-methylcaprate) which comprises esterifying nandrolone with .beta.-methylcapric acid in a suitable solvent and in the presence of a base.
8. Nandrolone-17.beta.-(.beta.-methylcaprate) when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
9. A process for the preparation of nandrolone-17.beta.-(.alpha.,.alpha.-dimethylcap-rate) which comprises esterifying nandrolone with .alpha.,.alpha.-dimethylcapric acid in a suitable solvent and in the presence of a base.
10. Nandrolone-17.beta.-(.alpha.,.alpha.-dimethylcaprate) when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
11. A process for the preparation of nandrolone-17.beta.-(.alpha.-methyl-.beta.-cyclo-hexyl-propionate) which comprises esterifying nandrolone with .alpha.-methyl-.beta.-cyclohexylpropionic acid in a suitable solvent and in the presence of a base.
12. Nandrolone-17.beta.-(.alpha.-methyl-.beta.-cyclohexyl-propionate) when prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
13. A process for the preparation of nandrolone-17.beta.-(.beta.-cyclohexyl-butyrate) which comprises esterifying nandrolone with .beta.-cyclohexylbutyric acid in a suitable solvent and in the presence of a base.
14. Nandrolone-17.beta.-(.beta.-cyclohexyl-butyrate) when prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
15. A process for the preparation of nandrolone-17.beta.-(.alpha.-methyl-tridecy-late) which comprises esterifying nandrolone with .alpha.-methyltridecylic acid in a suitable solvent and in the presence of a base.
16. Nandrolone-17.beta.-(.alpha.-methyl-tridecylate) when prepared by the process of claim 15 or by an obvious chemical equivalent thereof.
17. A process for the preparation of nandrolone-17.beta.-(3',5',5'-trimethyl-caproate) which comprises esterifying nandrolone with 3',5',5'-trimethyl-caproic acid in a suitable solvent and in the presence of a base.
18. Nandrolone-17.beta.-(3',5',5'-trimethylcaproate) when prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
19. A process for the preparation o nandrolone-17.beta.-(3',7'-dimethyl-caprylate) which comprises esterifying nandrolone with 3',7'-dimethylcaprylic acid in a suitable solvent and in the presence of a base.
20. Nandrolone-17.beta.-(3',7'-dimethylcaprylate) when prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
21. A process according to claim 5, 7 or 9 wherein the base is pyridine.
22. A process according to claim 11, 13 or 15 wherein the base is pyridine.
23. A process according to claim 17 or 19 wherein the base is pyridine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA365,887A CA1113926A (en) | 1975-08-27 | 1980-12-01 | Pharmaceutical preparation adapted for oral administration |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL75.10104 | 1975-08-27 | ||
| NL7510104A NL7510104A (en) | 1975-08-27 | 1975-08-27 | PROCESS FOR THE PREPARATION OF AN ORAL ACTIVE PHARMACEUTICAL PREPARATION. |
| CA259,950A CA1092025A (en) | 1975-08-27 | 1976-08-26 | Pharmaceutical preparation adapted for oral administration |
| CA365,887A CA1113926A (en) | 1975-08-27 | 1980-12-01 | Pharmaceutical preparation adapted for oral administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113926A true CA1113926A (en) | 1981-12-08 |
Family
ID=27164614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA365,887A Expired CA1113926A (en) | 1975-08-27 | 1980-12-01 | Pharmaceutical preparation adapted for oral administration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1113926A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816440A (en) * | 1985-09-26 | 1989-03-28 | Cetus Corporation | Stable formulation of biologically active proteins for parenteral injection |
| US5208032A (en) * | 1988-07-15 | 1993-05-04 | Rutgers, The State University Of New Jersey | Increasing the growth of turkeys using implant of 19-nortestosterone |
| WO2016142775A1 (en) * | 2015-03-06 | 2016-09-15 | Institut de Recherche en Semiochimie et Ethologie Appliquee | Semiochemical compositions for the prevention of hematophagous diptera insects from landing and biting animals |
-
1980
- 1980-12-01 CA CA365,887A patent/CA1113926A/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816440A (en) * | 1985-09-26 | 1989-03-28 | Cetus Corporation | Stable formulation of biologically active proteins for parenteral injection |
| US5208032A (en) * | 1988-07-15 | 1993-05-04 | Rutgers, The State University Of New Jersey | Increasing the growth of turkeys using implant of 19-nortestosterone |
| WO2016142775A1 (en) * | 2015-03-06 | 2016-09-15 | Institut de Recherche en Semiochimie et Ethologie Appliquee | Semiochemical compositions for the prevention of hematophagous diptera insects from landing and biting animals |
| CN107529747A (en) * | 2015-03-06 | 2018-01-02 | 信息化学和应用神经研究所 | Semiochemical compositions for preventing hematophagous diptera insects from landing and biting animals |
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