PHARMACEUTICAL PREPARATION CONTAINING A FLUORIDE SALT

Abstract: The invention relates to a pharmaceutical preparation containing a fluoride salt and a steroid with the general formula (I), wherein R1 = H2, H(OR5) or O; R2 = ( alpha R6) ( beta OR7; R3 = H or (1-4 C)alkyl in position 6 or 7; R4 = (1-4 C)alkyl; R5 = H or (1-18 C)acyl; R6 = H or (1-4 C)hydrocarbon radical; R7 = H or (1-18 C)acyl; and the broken lines indicate the presence of an additional bond in the 4,5- or 5,10-position.

Description: Pharmaceutical preparation containing a fluoride salt. The invention relates to a pharmaceutical pre¬ paration containing a fluoride salt. Such preparations are known, in particular for treating osteoporosis. Fluoride salts such as, for example, NaF and Na 2 P0 3 F stimulate the trabecular bone substance and are therefore suitable for treating osteoporosis. A disadvantage of such preparations is that they cause cortical bone loss and a change in the structure of the cortical bone. As a consequence thereof, the bone becomes more brittle, which has in turn the consequence that more frequent and ready bone fractures, in particular hip fractures, occur. It is further known that bone-protecting steroids are used to prevent and/or treat osteoporosis and more generally, diseases which are the result of excessively low bone substance. Surprisingly, it has now been found that by using certain steroids in combination with said fluoride salts for preventing and/or treating such diseases and, in particular, osteoporosis, the disadvantages associated with the use of said fluoride salts can be reduced and/or be avoided. The invention therefore relates to a pharmaceutical preparation containing a fluoride salt and a steroid with the general formula: wherein R - H 2 , H(0R 5 ) or 0; R 2 = (αR 6 ) (j80R 7 ) ; R 3 = H or (1-4 C)alkyl in position 6 or 7; R 4 = (1-4 C)alkyl; R 5 = H or (1-18 C)acyl; R 6 = H or (1-4 C)hydrocarbon radical; R 7 = H or (1-18 C)acyl; and the broken lines indicate the presence of an additional bond in the 4,5- or 5,10-position. (1-4 C)Alkyl is understood to mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. R 3 is preferably methyl and is, in addition, preferably situated in the α-position. R 4 is preferably methyl. As is already indicated by the affix (1-18 C) , (1-18 C) acyl is derived from an organic carboxylic acid containing 1-18 carbon atoms. As examples thereof mention may be made of: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, trimethylacetic acid, valeric acid, caproic acid, capric acid, pelargonic acid, undecylenic acid, lauric acid, palmitic acid, oleic acid, phenylacetic acid, phenylpropionic acid, cyclopentyl- propionic acid, cyclohexylcarboxylic acid, cyclooctyl- acetic acid, benzoic acid, fumaric acid, maleic acid, succinic acid, citric acid. (1-4 C)Hydrocarbon radical is understood to mean one of the groups designated above as (1-4 C)alkyl or an unsaturated variant thereof containing 2-4 carbon atoms, such as vinyl, ethynyl, allyl, propargyl, isopropenyl, butynyl or butadienyl. R 6 is preferably ethynyl, R 7 then preferably being H. Salts which are readily soluble in water such as NaF, KF and Na 2 P0 3 F are preferably used as fluoride salts. The greatest preference is for Na 2 P0 3 F. Examples of steroids having the formula I which may be used according to the invention are: 17α-ethyl-173-hydroxy-Δ -oestrene, 17?-hydroxy-Δ -oestren-3-one, 7 -methyl-17α-ethynyl-17^-hydroxy-Δ 5 ^ 10 ^ -oestren-3-one, 7α-methyl-17α-ethynyl-Δ 5 ( 10 )-oestren-17/3-ol, 7 -methyl-17 -ethynyl-173-hydroxy-Δ -oestren-3-one, 7 -methyl-17o:-ethyl-173-hydroxy-Δ 5 10 ' -oestren-3-one, 7α-methyl-17α-ethynyl-Δ 5 ( 10) -oestrene-3 , 173-diol, 7α-methyl-17α-ethynyl-Δ 5 ( 10 )-oestrene-33,17 / 8-diol, 7α-methyl-17α-allyl-17/3-hydroxy-Δ 5(10 )-oestren-3-one, 7 , 17α-dimethyl-170-hydroxy-Δ -oestren-3-one, 7o;-methyl-17Q!-ethynyl-Δ 4 -oeΞtrene-33, 170-diol, 6α-methyl-17/3-hydroxy-Δ 4 -oestren-3-one, 6α-methyl-17?-hydroxy-Δ -oestren-3-one, 6α-methyl-17α:-ethynyl-173-hydroxy-Δ -oestren-3-one, 6α-methyl-17α-ethyl-17/3-hydroxy-Δ 4 -oestren-3-one, 6o-methyl-17α-ethynyl-Δ -oestren-173-ol, 6α-methyl-17α-ethynyl-17?-hydroxy-Δ 5 ^ ' -oestren-3-one, 6o:-methyl-17Ω:-allyl-17/?-hydroxy-Δ 5 ( 10 ) -oestren-3-one, and esters thereof. The greatest preference is for 7α-methyl-17α-ethynyl-17/3-hydroxy-Δ 5 ^ 10 ^ -oestren-3-one. The pharmaceutical preparations according to the invention can be prepared by known galenical techniques by converting the respective steroid compound and the fluoride salt into a form which is suitable for enteral (for example, oral or rectal, and preferably oral) use. For this purpose, the steroid compound and the fluoride salt are mixed with or dissolved in a pharmaceutically acceptable carrier. Examples of such preparations are tablets, pills, dragees, pastilles, suppositories, powders, (micro)capsules, emulsions, suspensions and solutions. The quantity of steroid in the preparation to be administered is 0 " .05-10.0 mg and usually 0.1-5.0 mg. The quantity of fluoride salt in the preparations to be ad¬ ministered is 1-250 mg and usually 10-100 mg. The daily dosage is usually 1-3 dosage units. The pharmaceutically acceptable carriers may be composed of one or more of the following ingredients: starch (for example, potato starch, maize starch) , sugars (for example, lactose) , lubricants (magnesium stearate, stearic acid) , binders (for example, amylopectin, polyvinylpyrrolidone) , water, alcohol, glycerol and derivatives thereof, vegetable, animal and mineral oils and fats, fatty alcohols, silicones, lanolins, poly- alkylene glycols, cellulose derivatives, silica, dispersants, emulsifiers, surface active substances, antioxidants , preservatives, etc. The preparations according to the invention may suitably be used to prevent and/or treat diseases which occur as a consequence of an excessively low bone substance and in particular, of osteoporosis. The invention is explained on the basis of the following examples. Example 1 (tablet) 7α-Methyl-17α-ethynyl-17/3-hydroxy- Λ 5 ( 10 ) -oestren-3-one, 2.5 mg Na 2 P0 3 F 50.0 mg Potato starch 25.0 mg Magnesium stearate 1.25 mg Ascorbyl palmitate 0.5 mg Amylopectin 5.0 mg Lactose to 250.0 mg Example 2 (tablet) 7α-Methyl-17α-ethyl-173-hydroxy- Δ 5 10 ) -oestren-3-one, 2.0 mg Na 2 P0 3 F 30.0 mg Maize starch 25.0 mg Stearic acid 2.5 mg Silica ("Aerosil") 2.5 mg Polyvinylpyrrolidone 7.5 mg dl-α-Tocopherol 0.25 mg Lactose to 250.0 mg Example 3 (tablet) 7α-Methyl-17α-ethynyl-17?-hydroxy- Δ4-oestren-3-one, 5.0 mg Na 2 P0 3 F 50.0 mg Potato starch 62.5 mg Magnesium stearate 10.0 mg dl-α-Tocopherol 0.5 mg Lactose to 250.0 mg

Claims: 09058 Claims 1. Pharmaceutical preparation containing a fluoride salt and a steroid with the general formula: wherein R 2 = (αR 6 ) (00R ? ) ; R 3 = H or (1-4 C)alkyl in position 6 or 7; R 4 = (1-4 C)alkyl; R 5 = H or (1-18 C)acyl; R 6 = H or (1-4 C)hydrocarbon radical; R 7 = H or (1-18 C)acyl; and the broken lines indicate the presence of an additional bond in the 4,5- or 5,10-position. 2. Pharmaceutical preparation according to Claim 1, characterized in that the fluoride salt is water- soluble. 3. Pharmaceutical preparation according to Claim 1-2, characterized in that the fluoride salt is a sodium salt. 4. Pharmaceutical preparation according to Claim 1-3, characterized in that the fluoride salt is Na 2 P0 3 F. 5. Pharmaceutical preparation according to Claim 1-4, characterized in that the steroid is 7α-methyl-17α- ethynyl-17?-hydroxy-Δ 5 (10 '-oestren-3-one. 6. Pharmaceutical preparation according to Claim 1-5, characterized in that the quantity of steroid is 0.05-10.0 mg. 7. Pharmaceutical preparation according to Claim 1-6, characterized in that the quantity of salt is 1-250 mg,

Inventors: SCHOT LODEWIJK PIETER CORNALIS, SCHOT, LODEWIJK, PIETER, CORNALIS
Applicants: AKZO NV, AKZO N.V.
Application year: 1989
Main classification: A61K33
IPC codes: A61K31, A61K33, A61P3, A61P19, A61P43, C07J1