Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-03-21
2004-07-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S489000, C424S490000
Reexamination Certificate
active
06761907
ABSTRACT:
The invention pertains to a dosage unit containing a composition comprising a steroid having two hydrogen atoms at position 3 of the steroid skeleton, such as desogestrel, allylestrenol, ethylestrenol, or lynestrenol, the dosage unit being coated with a surface layer which serves to prevent transfer of the steroid out of the composition.
Such dosage units are known from EP 0 659 432, wherein a sugar coat is applied as the surface layer. A sugar coat in itself is a known coating for masking unpleasant tastes and odours, to protect an ingredient from decomposition as a result of exposure to air, light, or moisture, or to improve tablet appearance and to increase aesthetic appeal. As described, the sugar coat was found to solve another problem, viz, that of the tendency of apolar active compounds, such as the above steroids, to transfer out of tablets and granules comprising them.
The coated dosage units of EP 0 659 432 are disclosed to be prepared by a process comprising, after the conventional making of tablet cores and granules, the steps of optional sealing, followed by subcoating, syruping, finishing and optionally polishing. The sealing step refers to the application of a seal coat directly over the tablet cores and granules. This step is a regular part of sugar-coating processes such as described in
Remington's
(18th edition, A. R. Gennaro ed., Mack Publishing Co. Easton, Pa. 1990), pages 1667-1668. In such processes the seal coat primarily serves the purpose of separating the tablet ingredients and water, which is a major constituent of the coating formulation used thereafter. A secondary function is to strengthen the tablet core.
It has now been found that coated dosage units of the above type can be made in a more economical way, while still preventing the transfer of the steroid out of the composition.
For, surprisingly, the aforementioned seal coat when used as an end-layer, i.e., as a surface layer coating the dosage unit, suitably serves this purpose.
Hence, the invention is a dosage unit of the above type, with the surface layer being a sealing coat as normally used in a sugar coating process, hereinafter referred to as “seal coat”, in brief. Thus, the invention resides in a novel pharmaceutical end-product which has, as its outer surface, a layer that has only been known as an intermediate layer rather than as an end-layer.
It was found that a seal coat almost completely prevents the steroid of the above type from being transferred out of the dosage unit.
In another respect, the invention resides in more economical process of preparing a coated dosage unit comprising making a dosage unit containing a composition comprising a steroid having two hydrogen atoms at position
3
of the steroid skeleton and subjecting the dosage unit to coating steps comprising the application of a seal coat. For, such a process being known, the invention is that any further coating steps after the application of the seal coat are refrained from. Thus, the invention resides in a process of a known type, wherein, surprisingly, a step considered in the art to be crucial, can be refrained from.
In yet another respect, the invention resides in the unexpected new use of a seal coat known in itself Thus, the seal coat, applied on a dosage unit containing a composition comprising a steroid having two hydrogen atoms at position 3 of the steroid skeleton, is used for the purpose of preventing transfer of the steroid out of the composition.
The tendency of the apolar active compound to transfer out of the composition is of particular concern when the tablet cores or granules comprise very low dosages of said apolar active compounds. This is the case in tablets and granules comprising the progestagen desogestrel, allylestrenol, ethylestrenol, or lynestrenol. Tablets having desogestrel as active ingredient comprise usually 25-150 aeg, and typically 25, 50, 75, 100, or 150 aeg of desogestrel. Tablets having allylestrenol as active ingredient comprise usually 10-75 mg, and typically 25 mg of allylestrenol, and tablets having ethylestrenol or lynestrenol as active ingredient comprise usually 0.5-10 mg, and typically 2.0 or 2.5 mg of ethylestrenol or lynestrenol. For desogestrel, allylestrenol, ethylestrenol, or lynestrenol, which are used as active ingredient in contraceptive or HRT (hormone replacement therapy) drugs, this is not acceptable in view of their safety and reliability. A loss of for example 10% of the active substance within the shelf-life has therefore a dramatic effect on the amount of active ingredient in the tablet, and could lead to a tablet having less than the treshold amount of active ingredient to exert full activity. It is now found that sugar-coating can be used for other purposes than preventing moisture to enter the tablet or granule; it also can be used to prevent the transfer of a steroid having two hydrogen atoms at position 3 of the steroid skeleton, such as desogestrel, allylestrenol, ethylestrenol, or lynestrenol from the tablet or granule to the environment. The sugar-coated dosage unit apart from the steroid having two hydrogen atoms at position 3 of the steroid skeleton, such as desogestrel, allylestrenol, ethylestrenol, or lynestrenol can further comprise an estrogen.
Examples of estrogens include ethinyl estradiol, &bgr;-estradiol, mestranol (17-à-ethinyl estradiol 3-methylether), estrone, estradiol, estradiol valerate and other estradiol esters, and other compounds with estrogenic activity. Ethinyl estradiol and &bgr;-estradiol are the preferred estrogen.
As used herein, “transfer” includes any process in which the steroid having two hydrogen atoms at position
3
of the steroid skeleton prematurely leaves the dosage unit.
The term “dosage unit” generally refers to physically discrete units suitable as unitary dosages for humans or animals, each containing a predetermined quantity of active material (e.g. estrogen and/or desogestrel) calculated to produce the desired effect. Examples of such dosage units are tablets, granulates, powders, and pills.
Methods and compositions for making various dosage units excipients and granules are known to those skilled in the art. For example, methods and compositions for making tablets and pills are described in Remington's (18th edition, A. R. Gennaro Ed., Mack Publishing Co. Easton, Pa., 1990), at pages 1633 through 1665.
The concentration of steroid or steroids included in the tableting mixture, and eventually the dosage unit, will of course depend on the particular steroid's potency, its intended use, and the eventual mass of the dosage unit. The amount of a steroid or steroids used in a dosage unit will be well-known to those skilled in the art.
A tablet core or granule according to the invention comprise typically a diluent and optionally a binder. Preferably the tablet core or granulate will also include a disintegrating agent.
Diluents or “filler excipients” are agents added to dosage units to increase the granules' and resulting dosage units' bulk. The preferred diluent for use in this regard is lactose. Other diluents include mannitol, sorbitol, cellulose, xylitol, dextrose, fructose, calcium phosphate, NaCaPO4, sucrose, and mixtures thereof. The diluent will typically make up from 70 to 95% by weight of the resulting steroid loaded granules.
Binders are agents used to impart cohesive properties to the granules, resulting in more physically stable dosage units, and include hydroxypropylcellulose, amylopectin, starch, povidone (polyvinylpyrrolidone), hydroxypropylmethylcellulose, gelatin, and starch based binders. The preferred binder for use with the invention is amylopectin. The binder will typically make up from 0.5 to 5% by weight of the resulting steroid loaded tablet cores or granules.
Disintegrating agent or “disintegrators” are substances or mixtures of substances added to a tablet to facilitate its breakup or disintegration after administration. Typically such agents are modified or unmodified starches, clays, cross-linked PVP, modified or un-modified celluloses, gums or algins. The
Akzo Nobel NV
Joynes Robert M.
Page Thurman K.
Turner Allen
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