United States Patent (19) (11) 4,083,973 van der Wies (45) Apr. 11, 1978

54) PHARMACEUTICAL PREPARATION ADAPTED FOR ORAL ADMNSTRATION OTHER PUBLICATIONS 75 Inventor: Johannes van der Vies, Oss, Gould et al., Jour, Amer. Chem. Soc. (vol. 79) Aug. 20, Netherlands 1957, pp. 4472-4475. Dorfman et al., “Androgens,’ John Wiley and Sons, 73 Assignee: Akzona Incorporated, Asheville, N.C. Inc., New York (1956) pp. 512 and 513. Primary Examiner-Elbert L. Roberts 21 Appl. No.: 714,454 Attorney, Agent, or Firm-Stevens, Davis, Miller & 22 Filed: Aug. 16, 1976 Mosher 30) Foreign Application Priority Data 57 ABSTRACT Aug. 27, 1975 Netherlands ...... 7510104. The invention relates to a novel pharmaceutical prepa (51) Int. Cl? ...... A61K 31/56; C07J 1/00 ration with anabolic activity adapted for oral adminis (52) U.S. C...... 424/239; 424/243; tration comprising a nandrolone (= 19-nor-testos 260/.397.3 terone)-17A-ester, the ester group of which has been (58) Field of Search ...... 424/240, 243; derived from aliphatic carboxylic acids having 9-18 260/.397.4 carbon atoms, in combination with a non-steroidal li poid. The preparation may additionally contain a miner (56) References Cited alocorticoid steroid. The invention also relates to novel U.S. PATENT DOCUMENTS nandrolone-1713-esters. 2,998,423 8/1961 De Wit et al...... 260/.397.4 3,016,388 1/1962 De Wit...... 260/.397.4 31 Claims, No Drawings 4,083,973 1. 2 highest activity, particularly the a- and 3-methyl substi PHARMACEUTICAL PREPARATION ADAPTED tuted aliphatic carboxylic acid esters. FOR ORAL ADMINISTRATION As examples of aliphatic carboxylic acids with 9-18 carbon atoms, from which the nandrolone esters are The invention relates to a novel pharmaceutical prep 5 derived, the following can be given; pelargonic acid, aration with anabolic activity adapted for oral adminis capric acid, undecanoic acid, lauric acid, tridecanoic tration, the said preparation containing a 17.6-ester of acid, myristic acid, pentadecanoic acid, decenoic acid, nandrolone (= 19-nor-testosterone), and to methods for undecenoic acid, palmitic acid, stearic acid and the the preparation thereof. The invention also relates to branched-chain and cyclic analogues of these acids such novel 1713-esters of nandrolone. 10 as a-(and 6-)methyl-caprylic acid, a-(and 6-)methyl Nandrolone and the 1713-esters thereof are known as pelargonic acid, at-(and 3-)methyl-capric acid, (3,3- substances with anabolic activity, possessing only slight dimethyl-pelargonic acid, (3-(p-methyl-cyclohexyl)- androgenic activity in comparison with testosterone propionic acid, (3-(p-ethylcyclohexyl)-propionic acid, and the 17.6-esters thereof. In particular, nandrolone A-(cycloheptyl)-propionic acid, a-(and g-)methyl-6- 17,3-esters derived from aliphatic carboxylic acids with 15 cyclohexyl propionic acid, cyclododecyl-carboxylic 9-18 carbon atoms are potent anabolic agents. One of acid, bicyclo[2.2, 1-heptyl-2'-carboxylic acid, adaman the best known nandrolone esters is nandrolone decano tane carboxylic acid, adamantyl-acetic acid, 4'-methyl ate, which as an oily solution under the trade name bicyclo[2,2,2-oct-2'-enyl carboxylic acid and 6-(bicy Deca-Durabolin finds use in medicine as an injection clo2,2,2Octyl)propionic acid. The nandrolon ester is preparation with a pronounced and protracted protein 20 preferably derived from capric acid, undecanoic acid, sparing effect. lauric acid, tridecanoic acid, myristic acid and more As already noted, the nandrolone-17B-esters are ad preferably from the a- or 3-methyl-substituted and ministered parenterally, predominantly by the intramus cyclic isomers of these acids. cular route. When given orally they are scarcely active, Various of the nandrolone esters indicated above are or in any case much less active. An advantage of paren 25 novel compounds. The present invention therefore also teral administration is that a good effect can be achieved comprises novel nandrolone esters with interesting ana with a relatively low dosage. The use of 17.6-esters bolic properties, said novel nandrolone esters having results furthermore in a depot effect, so that an effective the formula: plasma nandrolone level is not only obtained rapidly after an intramuscular injection, but this nandrolone 30 level may also persist for several weeks. There are also objections to the parenteral form of p-c-CH)--R, administration. A patient is not usually capable of giv R ing him- or herself an injection; for this, a doctor or a trained nurse is almost always necessary. Furthermore, 35 repated parenteral administration may cause local reac tions. A further disadvantage associated with the paren O teral administration of long-acting preparations is that the action thereof cannot be interrupted or stopped. An 40 wherein n = 0 or 1 and preferably 0; R = alkyl (1-10 oral administration form would therefore be far more C), preferably CH3; R = H or alkyl (1-10 C), prefera preferable than a parenteral form. bly H; R3 = an aliphatic group having 1-16 C-atoms, Surprising, it has now been found that certain nan preferably 6-12 C-atoms, which group may contain one drolone esters, specifically the esters derived from ali or more rings having 5-12 C-atoms, preferably 5-8 phatic carboxylic acids with 9-18 carbon atoms, are 45 C-atoms, or R1 and R3 form together with the C-atom to orally active if they are administered in combination which they are attached a cycloaliphatic group having with a non-steroidal lipoid substance. This is the more 7-12 C-atoms, preferably 8-10 C-atoms, which cycloali surprising since the nandrolone-1713-esters derived from phatic group is or may be substituted by an aliphatic aliphatic carboxylic acids with less than 9 or more than group having 1-6 C-atoms, with the proviso that the 18 carbon atoms are distinctly less active orally under 50 total number of C-atoms in the ester group is in the these conditions. range of 9-18 C-atoms, preferably 9-16 C-atoms and The invention therefore relates to a novel pharma still more preferably 10-14 C-atoms. ceutical preparation with anabolic activity adapted for The novel esters can be prepared according to meth oral administration, containing an ester of nandrolone, ods known in the art, for example by reacting nandro and is characterized by the incorporation into a pharma 55 lone with the organic carboxylic acid or with a func ceutical form suitable for oral administration of one or tional derivative thereof, such as the acid chloride or more nandrolone-17.6-esters, derived from an aliphatic the acid anhydride, in a solvent and in the presence of a carboxylic acid with 9-18 carbon atoms, together with water-binding agent or a base, such as pyridine. a pharmaceutically acceptable non-steroidal lipoid. The By pharmaceutically acceptable non-steroidal lipoids invention also encompasses the method for preparing 60 are meant plant and animal oils and fats consisting of the said preparation. mono-, di- and triglycerides of various fatty acids or The term "aliphatic carboxylic acid' also includes containing these as main constituents; fatty acid esters branched chain aliphatic and cycloaliphatic carboxylic of alcohols; higher aliphatic alcohols; saturated and acids. unsaturated fatty acids; the commercially available syn In the preparation according to the invention, prefer 65 thetic and semisynthetic mono-, di- and triglyceride oils ably one or more nandrolone esters derived from an and glycerol ethers; certain types of wax and mixtures aliphatic carboxylic acid with 10-16 carbon atoms are of two or more of the above-noted substances. The present. These esters have been shown to possess the lipoid substance is preferably liquid at normal tempera 4,083,973 3 4. ture, that is, at a temperature in the range of about 10 magnesium stearate. Other agents, such as preserva C to about 35 C. The nandrolone ester is then dissolved tives, emulsifying agents, stabilizing agents, wetting in the lipoid substance and the solution is incorporated agents, flavours, dyes, fillers, binding agents and/or into a preparation or, as the case may be, converted into coating agents may optionally be present. a pharmaceutical form. At normal temperature, part of The capsules may be soft or hard gelatine capsules, in the ester may be present in the liquid lipoid as a suspen which the active principle and the lipoid may be present sion, in which case the quantities of ester and lipoid in granular or finily divided intimate admixture or may substance are mutually adjusted in such a way that at be present in the form of an oily solution or suspension. body temperature the ester is completely dissolved in The combination of nandrolone-1713-ester and lipoid, the lipoid substance. The intensification of the oral ac O when liquid or semi-liquid, may also be processed to tivity of the nandrolone esters according to the inven solid oral formulations such as pills or tablets. For that tion appears to be greatest when a lipoid substance purpose the oily solution of nandrolone-17g-ester is, for liquid at normal temperature is used. example, absorbed on calcium phosphate, lactose or Examples of lipoid substances which may be used in cellulose derivatives and then processed to tablets or the preparation according to the invention are: arachis 15 pills in the usual way. Combinations of nandrolone-1713 oil, castor oil, sesame oil, linseed oil, soya bean oil, esters with lipoids, such as glycerylmono-oleate or cap sunflower seed oil, olive oil, fish liver oil, ethyl oleate, ric acid, which are solid or semi-solid at room tempera oleyl oleate, glyceryl trioleate, glyceryl diolate, glyc ture, but are liquid at body temperature, may be granu eryl monooleate, cetyl alcohol, stearyl alcohol, capric lated or processed to coated pills or tablets. acid, undecenoic acid, undecanoic acid, lauric acid, 20 As already noted above, the nandrolone esters ac oleic acid, synthetic glycerides of saturated fatty acids, cording to the invention are preferably administered with 8 to 10 or 12 carbon atoms such as the commercial dissolved in lipoid substances liquid at normal tempera products Syndermin GTC and Miglyol 812, polyoxy ture, such as, for example, vegetable and animal oils, ethylene derivatives of glycerol, such as the commer oleic acid, linoleic acid or undecanoic acid. When a cial product Labrafil 1944, bee's wax and mixtures of 25 mineralocorticoid is present, this is preferably also pres two or more of these substances. ent dissolved in the oil, in addition to the nandrolone The invention herein referred to provides an oral ester. pharmaceutical preparation with anabolic activity. By The most suitable oral administration form for this incorporating an orally active mineralocorticoid into liquid form of the preparation according to the inven the preparation, the invention also offers the possibility 30 tion is the soft-shell gelatine capsule or microcapsule. In of preparing an orally active pharmaceutical formula accordance with a method usual in the technique, the tion which possesses mineralocorticoid properties in oily solution containing the active component(s) and addition to anabolic properties. optionally other ingredients is encapsulated to soft-shell Pharmaceutical preparations with both anabolic and gelatine capsules or microcapsules with the desired mineralocorticoid actions, effective on subcutaneous 35 dimensions and containing the desired amount(s) of administration, are known. As an example, the commer active substance(s). The microcapsules can also be pro cially available preparation Docabolin, for intramuscu cessed to tablets or pills according to well-known phar lar injection, can be cited. maceutical formulation methods. Such preparations, which in addition to powerful The nandrolone-17(3-ester(s) concentration in the protein-sparing and roborant properties also have a preparation according to the invention can vary within normalizing effect on a reduced blood pressure, are considerable limits, on the understanding that the used for various indications including hypotension, amount of nandrolone-1713-ester(s) by weight does not debilitating conditions, conditions associated with ex exceed the amount of lipoid substance by weight or in haustion, during convalescence, burns and infantile other words the nandrolone-17f8-ester(s) concentration dystrophy. 45 in the preparation is 50% by weight or less and is usu As orally active mineralocorticoid, one or more es ally in the range of 1-25% by weight. ters of desoxycorticosterone are incorporated into the As indicated above, the amount of lipoid by weight in anabolic preparation according to the invention, such the preparation according to the invention is equal to or esters being preferably derived from an aliphatic car higher than the amount of nandrolone-17(3-ester by boxylic acid with 9-18 carbon atoms. 50 weight. Depending on the other constituents present in The desoxycorticosterone ester may be derived from the preparation (excipients, capsule, shell, coating) the the same aliphatic carboxylic acid as the nandrolone amount of lipoid substance per dosage unit will vary ester, and is preferably derived from the carboxylic from 5 to 95% by weight and is usually in the range of acids with 10-12 carbon atoms. 20-80% by weight. The amount of nandrolone-176 The presence of the oily component results in a sur 55 ester(s) per dosage unit, for example a capsule or a prising intensification of the oral activity of the desoxy tablet, may also vary within wide limits, for example corticosterone ester. from 0.1 mg to 100 mg, and is preferably between 1 mg The preparation according to the invention may be and 50 mg. administered per os in various dosage forms, for exam When the desoxycorticosterone ester is present in the ple in the form of tablets, capsules, grains, pills, boli, preparation according to the invention, the amount dragees, powders, granulates, microcapsules or chew thereof per dosage unit is within the range 0.5 to 50 mg, able tablets. In addition to the anabolic ester(s), the and the requirement, that the amount of desoxycortico lipoid substance and optionally the mineralocorticoid sterone ester by weight does not exceed the amount of compound, the dosage form may contain one or more of lipoid substance by weight, also applies. the usual excipients, for example benzyl alcohol to in 65 The exceptional anabolic properties of the prepara crease the solubility of the active agent in the oily com tions according to the invention have been demon ponent, water, thickening agents such as gelatine or strated in the known Hershberger test with castrated agar-agar, polyethylene glycols, lactose, starch, talc or rats. A number of nandrolone-17G-esters were adminis 4,083,973 5 tered orally twice daily for 7 days as solutions in arachis oil. Nandrolone itself was also tested in this way. -continued With nandrolone, its lower esters such as acetate and Tablets Capric acid 200 ng propionate, and the nandrolone esters derived from Lactose 1400 mg aliphatic carboxylic acids with more than 18 carbon 5 Potato starch 80.0 atoms, given in dosages of 2X2.0 mg/day, the weight of 2500 mg the M-levator ani was shown to increase by 40-60%, while with the esters derived from aliphatic carboxylic Nandrolone-1713-undecanoate was dissolved with acids with 9-18 carbon atoms, such as the decanoate, gentle warming in capric acid, after which the solution the undecanoate, the dodecanoate, the tetradecanoate 10 was homogenously absorbed in the lactose. After mix etc., the increase proved to be 100-150%, being there ing with potato starch and a little water, the granulate fore 2 - 3 times as great. For cyclic esters, for example thus obtained was dried. The dry granulate was tablet adamantyl carboxylate, and for branched chain esters, ted in the usual way. for example a-methyl-decanoate, said increase is even Tablets of the following compositions were prepared more than 150%. 15 Experiments with other lipoid substances, such as in a similar way: sesame oil, soya bean oil, glyceryl trioleate, oleic acid Nandrolone-17E8-a-methyldecanoate 5.0 rig and undecenoic acid, gave similar results. It was obvi Glyceryl mono-oleate 500 ng ous that nandrolone-1713-esters derived from aliphatic Lactose 1500 ng carboxylic acids with more than 8 and less than 18 C 20 Potato starch -90 mg atoms, in the presence of a lipoid substance, are much 3000 mg Nandrolone-173-dodecanoate 10.0 ng more active on oral administration than the other esters, Desoxycorticosterone undecanoate 10.0 mg and that specifically the esters with 10-14 carbon atoms, Stearyl alcohol/bee's wax 200 ring particularly the branched chain isomers, are very ac Lactose 300 mg 25 Potato starch 80.0 8 tive. In clinical studies a distinct protein-sparing effect 2500 ng was demonstrated when a daily dosage of 1-3 dosage units of an anabolic preparation according to the inven tion was given for a few weeks. EXAMPLE III The invention is further illustrated by means of the following examples: 30 Hard-shell gelatine capsules

EXAMPLE I (a) (b) Soft-shell gelatine capsules Nandrolone-173-dodecanoate 20.0 mg 10.0 mg desoxycorticosterone dodecanoate - 10.0 mg A sterile solution of nandrolone-1713-undecanoate in 35 Lauric acid 100.0 mg 100.0 mg arachis oil, containing 83.33 g per liter, was prepared, Lactose 1300 mg 1300 mg and this solution was encapsulated in soft-shell gelatine 2500 mg 250.0 mg capsules, with due regard for aseptic precautions. The soft-shell gelatine capsules obtained had a content of Nandrolone-1713-dodecanoate was dissolved in lauric 0.12 ml, so that the amount of active substance present 40 acid at 50 C (in case (b) together with the desoxycorti was 10 mg per capsule. The capsule wall consisted of costerone dodecanoate). The solution was homoge 68.1% gelatine, 15.5% glycerol, 13.7% sorbitol, 0.4% nously absorbed in the lactose and the cooled solid sodium ethyl/propyl p-hydroxybenzoate, 0.5% TiO, mixture was powdered. Hard-shell gelatine capsules and 1.8% Cochineal Red (dye). were filled with the finely-divided mixture (250 mg A number of nandrolone-1713-esters in various lipoid 45 mixture per capsule). substances were processed in a similar way to give soft-shell capsules, for which details are given in table EXAMPLE IV A. Soft-shell gelatine capsules Table A Soft-shell gelatine capsules with contents as specified mg active 50 below were prepared in a way similar to that described lipoid capsule substance in example I: ester substance content capsule -1713-undecanoate oleic acid 0,12 5 -176-decanoate capric acid 0.08 10 a) Nandrolone-173-undecanoate 10.0 ng -1.76-undecanoate undecenoic acid 0.18 25 Desoxycorticosterone decanoate 5.0 mg -179-undecanoate soya bean oil 0.2 O 55 Oleic acid to 0.18 ml -1713-dodecanoate ethyl oleate 0.12 20 b) Nandrolone-176-a-methyldecanoate 5.0 mg -17B-tetradecanoate linseed oil 0.12 10 Desoxycorticosterone decanoate 10.0 ng -1713-a-methyl- oleic acid 0.08 5 Arachis oil to 0.24 ml decanoate -179-adamantyl- arachis oil 0,12 5 carboxylate -1713-a-methyl-f3- inseed oil 0.08 5 cyclohexylpropio EXAMPLE V nate Preparation of novel esters To a solution of 5 g nandrolone in a mixture of 50 ml EXAMPLE II pentane and 5 ml pyridine were added dropwise in 1 65 hour 5 ml of a-methylcapric acid. The reaction mixture was stirred for 1 hour and then neutralized with an Tablets aqueous solution of sodiumbicarbonate, whereafter the Nandrolone-173-undecanoate 10.0 mg organic layer was separated, washed with a solution of 4,083,973 7 8 sodiumbicarbonate and with water till neutral. The 12. The pharmaceutical composition of claim 1 organic layer was evaporated till dryness. The residue wherein said ester is nandrolone-17f8-tetradecanoate. was chromatographed over a column of silicagel with 13. The pharmaceutical composition of claim 1 toluene/acetone 9/1, yielding 6.3 g nandrolone-17f8-a- wherein said ester is nandrolone-17f8-a-methyl-decano methylcaprate, oil with a = +33 (in dioxane). ate, In a similar manner the following 17A-esters of nan 14. The pharmaceutical composition of claim 1 drolone were prepared: wherein said ester is nandrolone-1713-adamantyl-car boxylate. f$-methyl-caprate 15. The pharmaceutical composition of claim 1 o,o-dimethylcaprate wherein said ester is nandrolone-1713-a-methyl-6- a-methyl-g-cyclohexyl-propionate 10 cyclohexylpropionate. f-cyclohexyl-butyrate 16. The pharmaceutical composition of claim 1 cyclo-octyl-carboxylate wherein said ester is nandrolone-17f8-a-methylcaprate. A3,6-diethyl-capronate 17. The pharmaceutical composition of claim 1 f-butyl-oenanthate wherein said ester is nandrolone-17f-f3-methyl-caprate. o-methyl-tridecylate 15 18. The pharmaceutical composition of claim 1 As.f3-dimethyl-pelargonate wherein said ester is nandrolone-1713-a,c-dimethylca bicyclo2,2,1-heptyl-2'-carboxylate prate. bicyclo[2.2, 1-heptyl-2'-acetate 19. The pharmaceutical composition of claim 1 wherein said ester is nandrolone-1713-a-methyl-6- I claim: 20 cyclohexyl propionate. 1. A pharmaceutical composition with anabolic activ 20. The pharmaceutical composition of claim 1 ity adapted for oral administration comprising wherein said ester is nandrolone-1713-3-cyclohexyl at least one 176-ester of nandrolone, the ester group butyrate. thereof having been derived from an aliphatic car 21. The pharmaceutical composition of claim 1 boxylic acid having 9 to 18 carbon atoms and 25 wherein said ester is nandrolone-1743-cyclo-octyl-car a pharmaceutically acceptable non-steroidal lipoid boxylate. 22. The pharmaceutical composition of claim 1 carrier, in unit dosage form comprising per dosage wherein said ester is nandrolone-17f8-3,6-diethyl unit, an anabolically effective amount of said ester capronate. in the range of from about 0.1 to about 100 mg., 23. The pharmaceutical composition of claim 1 said ester constituting up to 50% by weight of said 30 wherein said ester is nandrolone-17f8-3-butyl-Oenan composition and said non-steroidal lipoid carrier thate. being present in an amount at least equal to the 24. The pharmaceutical composition of claim 1 amount of said ester. wherein said ester is nandrolone-17f-o-methyl-tridecy 2. The pharmaceutical composition of claim 1 late. wherein said ester has been derived from an aliphatic 35 carboxylic acid having 10 to 14 carbon atoms. 25. The pharmaceutical composition of claim 1 3. The pharmaceutial composition of claim 1 wherein wherein said ester is nandrolone-1713-p3,3-dimethyl said non-steroidal lipoid carrier is liquid at room tem pelagonate. perature. 26. The pharmaceutical composition of claim 1 4. The pharmaceutical composition of claim 1 wherein said ester is nandrolone-17f8-bicyclo-2,2,1- wherein said ester is present in an amount of about 1 to heptyl-2'-carboxylate. about 25% by weight of said composition. 27. The pharmaceutical preparation of claim 1 5. The pharmaceutical composition of claim 1 wherein said ester is nandrolone-17f8-bicyclo2,2,1- wherein said non-steroidal lipoid carrier constitutes 5 to heptyl-2'-acetate. 95% by weight of said composition. 28. The pharmaceutical composition of claim 1 fur 6. The pharmaceutical composition of claim 5 45 ther comprising an orally active mineralocorticoid. wherein said non-steroidal lipoid carrier constitutes 20 29. The pharmaceutical composition of claim 28 to 80% by weight of said composition. wherein said orally active mineralocorticoid is an ester 7. The pharmaceutical composition of claim 1 of desoxycorticosterone, the ester group thereof having wherein said unit dosage form consists of a soft gelatin been derived from an aliphatic carboxylic acid having 9 capsule containing a solution of said ester of nandrolone 50 to 16 carbon atoms. in said non-steroidal lipoid carrier. 30. A process for conducting protein-sparing therapy 8. The pharmaceutical composition of claim 1 in a patient requiring such therapy comprising wherein said non-steroid lipoid carrier is selected from orally administering daily to said patient the pharma the group consisting of arachis oil, castor oil, sesame oil, ceutical composition of claim 1. linseed oil, soya bean oil, sunflower seed oil, olive oil, 55 31. A 176-ester of nandrolone of the formula: fish liver oil, ethyl oleate, oleyl oleate, glyceryl triole ate, glyceryl dioleate, glyceryl monooleate, cetyl alco fH, hol, stearyl alcohol, capric acid, undecenoic acid, un O-C-C-R decanoic acid, lauric acid, oleic acid, synthetic glycer ides of saturated fatty acids with 8 to 12 carbon atoms, O O polyoxyethylene derivatives of glycerol, bees' wax, and mixtures thereof. 9. The pharmaceutical composition of claim 1 wherein said ester is nandrolone-1713-undecanoate. O 10. The pharmaceutical composition of claim 1 65 wherein said ester is nandrolone-1743-decanoate. wherein R3 is an aliphatic group having 7 to 11 carbon 11. The pharmaceutical composition of claim 1 atoms. wherein said ester is nandrolone-17 3-dodecanoate.