~™ iiiiiii nun iiiiiiii inn mil mil inn iiiii inn urn mill mi mi m (19) J European Patent Office Office europeen des brevets (11) EP 0 927 556 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication:ation: (51) |nt. ci.6: A61 K 31/565, A61 K 9/28 07.07.1999 Bulletin 1999/27 (21) Application number: 97202908.6 (22) Date of filing: 23.09.1997 (84) Designated Contracting States: (72) Inventor: HARTHOLT GERTJAN PETER AT BE CH DE DK ES Fl FR GB GR IE IT LI LU MC 5406 BD UDEN (NL) NL PT SE (74) Representative: Kraak, Hajo (71) Applicant: Akzo Nobel N.V. N.V. Organon, 6824 BM Arnhem (NL) Postbus 20 5340 BH OSS (NL) (54) Dosage units of steroids with a seal coating for the steroids (57) Dosage units, such as tablet cores and gran- ules, containing a composition comprising a steroid having two hydrogen atoms at position 3 of the steroid skeleton, are coated. While a conventional sugar coat- ing process involves the application of several layers including, as a surface layer, a sugar coat, it was found that a seal coat such as normally used in a sugar coat- ing process can be used as the surface layer for the pur- pose of preventing the transfer of the steroid out of the composition. From this novel use of a seal coat, novel dosage units result. The process is advantageous, as it requires fewer steps than before. < CO LO LO r»- Csl o Q_ LU Printed by Xerox (UK) Business Services 2.16.7/3.6 1 EP 0 927 556 A1 Description ing the dosage unit to coating steps comprising the application of a seal coat. For, such a process being [0001 ] The invention pertains to a dosage unit con- known, the invention is that any further coating steps taining a composition comprising a steroid having two after the application of the seal coat are refrained from. hydrogen atoms at position 3 of the steroid skeleton, s Thus, the invention resides in a process of a known such as desogestrel, allylestrenol, ethyl estrenol, or type, wherein, surprisingly, a step considered in the art lynestrenol, the dosage unit being coated with a surface to be crucial, can be refrained from. layer which serves to prevent transfer of the steroid out [0009] In yet another respect, the invention resides in of the composition. the unexpected new use of a seal coat known in itself. [0002] Such dosage units are known from EP 0 659 to Thus, the seal coat, applied on a dosage unit containing 432, wherein a sugar coat is applied as the surface a composition comprising a steroid having two hydro- layer. A sugar coat in itself is a known coating for mask- gen atoms at position 3 of the steroid skeleton, is used ing unpleasant tastes and odours, to protect an ingredi- for the purpose of preventing transfer of the steroid out ent from decomposition as a result of exposure to air, of the composition. light, or moisture, or to improve tablet appearance ad to is [001 0] The tendency of the apolar active compound to increase aesthetic appeal. As described, the sugar coat transfer out of the composition is of particular concern was found to solve another problem, viz. that of the ten- when the tablet cores or granules comprise very low dency of apolar active compounds, such as the above dosages of said apolar active compounds. This is the steroids, to transfer out of tablets and granules compris- case in tablets and granules comprising the progesta- ing them. 20 gen desogestrel, allylestrenol, ethyl estrenol, or [0003] The coated dosage units of EP 0 659 432 are lynestrenol. Tablets having desogestrel as active ingre- disclosed to be prepared by a process comprising, after dient comprise usually 25-150 aeg, and typically 25, 50, the conventional making of tablet cores and granules, 75, 100, or 150 aeg of desogestrel. Tablets having the steps of optional sealing, followed by subcoating, allylestrenol as active ingredient comprise usually 10-75 syruping, finishing and optionally polishing. The sealing 25 mg, and typically 25 mg of allylestrenol, and tablets hav- step refers to the application of a seal coat directly over ing ethylestrenol or lynestrenol as active ingredient the tablet cores and granules. This step is a regular part comprise usually 0.5-10 mg, and typically 2.0 or 2.5 mg of sugar-coating processes such as described in Rem- of ethylestrenol or lynestrenol. For desogestrel, ington's (18th edition, A.R. Gennaro ed., Mack Publish- allylestrenol, ethylestrenol, or lynestrenol, which are ing Co. Easton, PA, 1990), pages 1667-1668. In such 30 used as active ingredient in contraceptive or HRT (hor- processes the seal coat primarily serves the purpose of mone replacement therapy) drugs, this is not accepta- separating the tablet ingredients and water, which is a ble in view of their safety and reliability. A loss of for major constituent of the coating formulation used there- example 1 0% of the active substance within the shelf- after. A secondary function is to strengthen the tablet life has therefore a dramatic effect on the amount of core. 35 active ingredient in the tablet, and could lead to a tablet [0004] It has now been found that coated dosage units having less than the treshold amount of active ingredi- of the above type can be made in a more economical ent to exert full activity. It is now found that sugar-coat- way, while still preventing the transfer of the steroid out ing can be used for other purposes than preventing of the composition. moisture to enter the tablet or granule; it also can be [0005] For, surprisingly, the aforementioned seal coat 40 used to prevent the transfer of a steroid having two when used as an end-layer, i.e., as a surface layer coat- hydrogen atoms at position 3 of the steroid skeleton, ing the dosage unit, suitably serves this purpose. such as desogestrel, allylestrenol, ethylestrenol, or [0006] Hence, the invention is a dosage unit of the lynestrenol from the tablet or granule to the environ- above type, with the surface layer being a sealing coat ment. The sugar-coated dosage unit apart from the as normally used in a sugar coating process, hereinafter 45 steroid having two hydrogen atoms at position 3 of the referred to as "seal coat" in brief Thus, the invention steroid skeleton, such as desogestrel, allylestrenol, eth- resides in a novel pharmaceutical end-product which ylestrenol, or lynestrenol can further comprise an estro- has, as its outer surface, a layer that has only been gen. known as an intermediate layer rather than as an end- [0011] Examples of estrogens include ethinyl estra- layer. 50 diol, p-estradiol, mestranol (1 7-a-ethinyl estradiol 3- [0007] It was found that a seal coat almost completely methylether), estrone, estradiol, estradiol valerate and prevents the steroid of the above type from being trans- other estradiol esters, and other compounds with estro- ferred out of the dosage unit. genic activity. Ethinyl estradiol and p-estradiol are the [0008] In another respect, the invention resides in preferred estrogen. more economical process of preparing a coated dosage 55 [001 2] As used herein, "transfer" includes any process unit comprising making a dosage unit containing a com- in which the steroid having two hydrogen atoms at posi- position comprising a steroid having two hydrogen tion 3 of the steroid skeleton prematurely leaves the atoms at position 3 of the steroid skeleton and subject- dosage unit. 2 3 EP 0 927 556 A1 4 [0013] The term "dosage unit" generally refers to blending the dry ingredients with a solvent containing physically discrete units suitable as unitary dosages for the steroid or steroids. Vacuum mixers which are closed humans or animals, each containing a predetermined to the outside environment are preferred for workers' quantity of active material (e.g. estrogen and/or des- safety and environmental reasons since the solvent is ogestrel) calculated to produce the desired effect. 5 not released into the atmosphere, and can be collected Examples of such dosage units are tablets, granulates, for re-use. powders, and pills. [0022] The "wet" portion added to the carrier will pref- [0014] Methods and compositions for making various erably consist of the steroid or steroids, an anti-oxidant, dosage units excipients and granules are known to and a lubricant all dissolved or suspended in a solvent. those skilled in the art. For example, methods and com- 10 [0023] Lubricants are agents which improve the rate positions for making tablets and pills are described in of flow of the tablet granulation, prevent adhesion of the Remington's (18th edition, A.R. Gennaro Ed., Mack tablet material to the surface of dies and punches, Publishing Co. Easton, Pa, 1990), at pages 1633 reduce interparticle friction, and facilitate the ejection of through 1665. the tablets from the die cavity. Commonly used lubri- [0015] The concentration of steroid or steroids 15 cants are talc, long chain fatty acids, magnesium stear- included in the tableting mixture, and eventually the ate, stearic acid, calcium stearate, polyethylene glycol, dosage unit, will of course depend on the particular ster- palmitic acid, and hydrogenated vegetable oils. The oid's potency, its intended use, and the eventual mass lubricant will typically make up from 0.25 to 3% by of the dosage unit. The amount of a steroid or steroids weight of the resulting granules. used in a dosage unit will be well-known to those skilled 20 [0024] Solvents for use with the invention are prefera- in the art.