MXPA97000515A - Controlled release of steroids from azu coatings - Google Patents

Abstract

The present invention relates to: a compressed medicinal tablet comprising a core of the tablet and a sugar coating, the sugar coating contains a dose of a hormonal steroid and an amount of microcrystalline cellulose which controls the rate of steroid release

Description

CONTROLLED RELEASE OF STEROIDS FROM SUGAR COATINGS BACKGROUND OF THE INVENTION In the last three decades, a substantial effort has been made to identify methods for controlling the rate of drug release from pharmaceutical tablets. Excipients have been incorporated into the nuclei of the tablets to control their dissolution, and hence the absorption, of drugs. Tablets and spheroids have been coated with polymers to provide a slow drug release, controlled by diffusion, or a site-specific release. Tablets and dosage forms of encapsulated spheroids containing multiple dro-gas have also been prepared, either in admixture or as separate layers of tablet or spheroids. Drugs are provided to perform multiple functions, or to provide synergy. Such tablets are especially useful in those circumstances where conventional therapy dictates the use of more than one drug having different but compatible activities. For example, diuretic agents are often administered with antihypertensive agents, and progestational agents in conjunction with estrogens. BRIEF DESCRIPTION OF THE INVENTION In accordance with this invention, there is provided a pharmaceutical blank comprising an internal compressed core and an outer sugar coating, wherein the compressed core optionally does not contain a pharmacologically active agent, or one or more non-spheroidal, pharmacologically active agents that are conventionally administered in conjunction with a hormonal steroid, the improvement is characterized in that it comprises the incorporation of a hormonal steroid and an amount that controls the release rate of the hormonal steroid, micro-crystalline cellulose in the sugar coating. The compressed core of the tablet may be free of any medicament, or may contain a pharmaceutical agent other than a steroid, ie, compatible with the steroid and any other therapeutic agent in the sugar coating. Thus, the sugar-coated tablets of this invention may contain one or more pharmacologically active agents, wherein the improvement over prior sugar-coated tablets comprises the incorporation of an amount of microcrystalline cellulose which controls the rate of release of the sugar. of the hormonal steroid in conjunction with a hormonal steroid in the sugar coating. The sugar coated tablet can be finished with color coatings, and polished as is common in coated tablets. The content of the core of the tablet is very independent of the sugar coating in the sense that the sugar coating and the hormonal steroid contained therein dissolve before the disintegration of the compressed core of the tablet and the dissolution of any component of drug present in the nucleus. The excipient components employed in the core tablet formulation may include pharmaceutically acceptable, water-soluble and / or water-insoluble substances, such as lactose, calcium phosphate, starch, calcium carbonate, dextrose, sorbitol, mannitol, cellulose microcrystalline, sucrose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, alginates, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, croscarmellose sodium, sodium starch glycollate, magnesium stearate, stearic acid, polyethylene glycol, sodium lauryl sulfate, silica of smoke, talc and si-milares. The sugar coating containing the hormonal steroid also contains an amount of microcrystalline cellulose that controls the release rate of the steroid, and, in certain circumstances, polyvinylpyrrolidone, to au-xylate in the application of the sugar coating. The core of the tablet is produced by compression of a mixture, which has preferably been granulated, of the pharmaceutically acceptable excipients, and, if desired, a therapeutic agent compatible with the steroid to be incorporated with the amount of microcrystalline cellulose that controls the release rate in the sugar coating. The core of the tablet may have an unplasticized or plasticized seal coating, designed to modify the release characteristics of the drug of any drug (s) contained within the core, or to protect them against moisture and / or oxygen. Non-medicated nuclei are those that are conventionally used as placebo tablets in pharmacological studies. DETAILED DESCRIPTION OF THE INVENTION This invention provides an improved compressed tablet in which, in addition to a conventional internal tablet core, which optionally contains no drugs, or contains one or more drugs that are pharmacologically compatible with a steroid in the outer coating of sugar , a sugar coating is present, comprising a hormonal steroid in an amount of about 0.1 to about 20 weight percent of the sugar coating; microcrystalline cellulose in an amount from about 0.1 to about 3 percent by weight of the sugar coating; polyvinyl pyrrolidone from about 0 to about 5 percent by weight of the sugar coating; and sugar. On a unit dose basis, the tablet contains from about 0.01 to about 50 milligrams, preferably from about 0.015 to about 40 milligrams, and more preferably from about 0.02 to 30 milligrams, of total hormone steroid loading in the layer of loaded sugar coating. If desired, a base layer of inert sugar filling can be applied over a sealing layer, prior to the steroid-loaded sugar coating layer. The re-dressing of sugar from the inert sub-layer containing the filler can be made with sucrose containing from about 7.5 to about 15 percent micro-crystalline cellulose. The external sugar coating may contain a coloring agent, such as titanium dioxide, or a primary, secondary or combined dye, as is customary in the tabletting art. If desired, the coloring agent can be applied as a separate coating layer on the outer layer of sugar. A final polish can be used to additionally finish and complete the tablet. The sugar used in the production of the sugar coatings referred to by this specification is a sugar product, such as sucrose, derived from sources such as beet or cane, or starch, converted sources of saccharides or polysaccharides, which are considered suitable for the purposes of coating tablets. The sugar currently preferred is sucrose. It has been found that the release of a hormonal steroid from the sugar coating can be controlled by limiting the amount of microcrystalline cellulose to from about 0.1 to about 3 percent by weight of the sugar coating. This use of a small amount of microcrystalline cellulose in the sugar coating is different from the use of this excipient as a compression aid, or to assist in the disintegration of a tablet core. In the latter case, the concentration of microcrystalline cellulose may rise to as much as 15 to 30 weight percent. Examples of suitable hormone steroids for incorporation into the sugar coating formulations of this invention include, for example, one or more of the following steroids: medroxyprogesterone acetate, levonorgestrel, gestodene, medrogestone, estradiol, estriol, ethinyl estradiol, mestranol, estrone, dienestrol, hexestrol, diethylstilbestrol, progesterone, desogestrel, norgestimate, hydroxyprogesterone, norethindrone, norethindone acetate, norgestrel, megestrol acetate, methyltestosterone, ethyl-estrenol, methandienone, oxandrolone, trimegestone, diono-gest, and the like. Additionally, tissue selective progesterone and / or progesterone antagonists, which may or may not have the typical steroidal functionality, may be formulated in this technology. These include, but are not limited to: RU-486, onapristone, ZK-137316, 0RG-31730, and HRP-2000. When desired, steroid steroids and progestogenic steroids may be used in combination in the sugar coatings.

To illustrate the control of the in vitro dissolution rate of steroids in the absence and in the presence of microcrystalline cellulose, the following illustrative examples are presented, without limitation: EXAMPLE 1 A sugar coating, consisting of the following solids, was applied on a tablet core, using either a non-perforated or a perforated coating vessel. Sucrose, NF 87% Polyvinylpyrrolidone 3% Medroxyprogesterone acetate, USP 10% The rate of dosilution of the steroid was determined according to C711 > from USP XX, page 959 (1980), using apparatus 2, operating at 50 rpm, dissolving in 0.54% sodium lauryl sulfate in water at 37 ° C in six repeated experiments (Method A). CV represents the coefficient of variation between these experiments, expressed as a percentage. Time (min) Percent of Released Steroid (CV) 5 93 (5.2) 10 94 (5.3) 30 95 (5.3) 60 95 (5.4) 120 95 (5.4) EXAMPLE 2 Coated tablets were dissolved in the same manner, with the same coating of sugar from above, in 0.13% sodium lauryl sulfate in 0.1 N HCl at 37 ° C, using Apparatus 1 USP at 100 rpm, in six experiments (method B). The results of this study were: Time (min) Percentage of Released Steroid (CV%) 83 (6.0) 10 85 (5.8) 30 85 (6.2) 60 85 (6.1) 120 85 (6.2) EXAMPLE 3 Additional tablets, coated in the same way, with the same sugar composition, were attached to a separate procedure. -Content of continuous flow dissolution test, in 0.12% sodium lauryl sulfate in 0.1 N HCl at 37 ° C, using a SOTAX Dissotest Apparatus at a flow rate of 5.7 ml / minute (Method C). The results of three separate runs were as follows: Time (min.) Percent of Released Steroid (CV%) 30 90.9 (2.9) 60 94.2 (3.0) 90 95.3 (2.9) 120 96.0 (3.0) 210 97.4 (3.0) 300 98.9 (3.6) Of these studies, n vitro is Of course, the medroxyprogesterone acetate, used here as a typical hormonal steroid, is released from the sugar coating extremely quickly. EXAMPLE 4 For comparison purposes, and to illustrate the unexpected properties of the sugar coatings of this invention, a sugar coating was applied on a tablet core, which consisted of the following solids: Sucrose, NF 86.5% Microcrystalline Cellulose 0.5% PVP 3.0% Medroxyprogesterone Acetate, USP 10.0% Using the sugar-coated tablets containing the microcrystalline cellulose, and following Method A, the following dissolution data were obtained from three runs: jL_n vitro: Time (min) Percent of Released Steroid (CV%) 19.5 (49.5) 10 29.9 (32.8) 30 50.0 (23.0) 60 61.6 (19.5) 120 74.2 (19.2) EXAMPLE 5 With sugar coated tablets, containing additional microcrystalline cellulose, prepared in the same manner as above, following Method B in six runs, the following data were obtained: Time (min) Percentage of Released Steroid (CV%) 5 2.3 (34.4) 10 8.2 (27.0) 30 17.9 (16.1) 60 26.5 (13.6) 120 32.7 (16.6 EXAMPLE 6 And, following Method C, with the tablets containing microcrystalline cellulose in the sugar coating, in three runs, the following data were obtained: Time (min.) Percent of Released Steroid (CV%) 30 2.8 (34.4) 60 4.1 (24.8) 90 5.1 (22.3) 120 6.4 (22.3) 210 11.0 (19.4) 300 14.3 (11.0) From these data, it is apparent that a small amount of microcrystalline cells in the sugar coating (in this case 0.5% by weight of the sugar coating solids) has markedly retarded the release rate of the hormonal steroid. EXAMPLE 7 Sugar coated tablets were prepared, in which the sugar coating contained 0.0%, 0.5% or 2% microcrystalline cellulose, in combination with 3.0% polyvinylpyrrolidone, 10.0% medroxyprogesterone acetate and sucrose. These tablets were given to four beagle dogs under fasting conditions, and blood steroid levels were determined at 0, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, and 24 hours. The resulting data were plotted, the area under the curve (AUC) was calculated for a period of twenty-four hours, and the time in which the maximum plasma concentration occurred was determined to be as follows: Cellulose Mi-ABC (0-24 hr) Crocrystalline Cmax% ngxhr / ml tmax (hr) (ng / ml) 0.0 345 0.6 37.8 0.5 294 1.0 36.9 2.0 294 1.1 24.6 From these data on live dogs, it is obvious that it occurs a marked change in the bioavailability of a hormoal steroid when the concentration of microcrystalline cellulose in the sugar coating increases from 0.0 to one containing 0.5 to 2.0% microcrystalline cellulose. Thus, the release rate of the hormonal steroid incorporated in a sugar coating can be controlled by the incorporation of very small amounts of microcrystalline cellulose into the sugar coating. EXAMPLE 8 Sugar coated tablets were prepared, in which the sugar coating contained 0.25, 0.5% or 0.8% microcrystalline cellulose in combination with 0.5% polyvinylpyrrolidone, 5.0% raedroxyprogesterone acetate and sucrose. These tablets were subjected to an in vitro dissolution test, using the USP Disintegration Apparatus (USP XX, < 201, page 958) (1980) with 0.54% sodium lauryl sulfate solution medium at 37 ° C. The following test data was obtained: Percentage of Dissolved Medroxyprogesterone Acetate (CV%) Cellulose Time Cellulose Cellulose (min) Microcrist. Microcrist. Microcrist. 0.25% to 0.5% to 0.8% 15 97.8 (5.2) 72.6 (9.5) 32.4 (15.2) 30 98.8 (5.3) 89.9 (6.3) 62.8 (8.2) 45 99.3 (5.2) 95.2 (5.6) 76.6 (6.9) 60 99.1 (5.2) 98.3 (5.7) 84.4 (6.6) 90 99.9 (5.3) 100.9 (6.0) 94.4 (6.9) 120 100.3 (5.6) 102.4 (5.3) 98.0 (7.1) These dosage forms were also evaluated in a human bioavailability study . Dosage forms were administered in a cross-over design to twelve healthy female subjects. Blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4.5, 6, 8, and 12 hours, and the plate was tested for medroxyprogesterone acetate. The following data were obtained: Microcrystalline cellulose ABC (0-12 hr) tmax (hr) Cmax (ng / ml # 0.25% 26.0 ± 14.3 2.9 ± 1.3 4.24 ± 3.0 0. 5% 25.8 ± 10.5 3.2 ± 1.2 3.88 ± 1.87 0. 8% 13.2 ± 4.0 3.9 ± 1.6 1.99 ± 0.73 # Mean values ± 1 standard deviation From the data of vitro dissolution and human bioavailability in vivo, it is clear that the characteristics of drug release and bioavailability of the hormonal steroid are controlled by the concentration of microcrystalline cellulose in the sugar coating. EXAMPLE 9 A sugar coating, containing 5 mg of medrogestrone in a sucrose matrix, with 0.4% microcrystalline cellulose and 0.5% polyvinyl pyrrolidone, was applied to a sealed and sugar-coated tablet core. The in vitro dissolution profile of this dosage form was compared to that of a rapidly disintegrating compressed tablet, containing 5 mg of medrogestrone, using the dissolution test described in < 7l of USP XX, page 959 (1980), using Apparatus 2, operating at 50 rpm, with 900 ml of sodium lauryl sulfate at 0.54% at 37 ° C. The following data were obtained: Average Percentage of Medrogestone Released ( CV) Conventional Tablet Sugar Coated Tablet Disintegrating Time Containing Medrogestone (minutes) Rapidly in the Revestim. of Sugar 15 95 (2.0) 6 (11.2) 30 95 (2.9) 11 (6.9) 45 97 (1.6) 15 (6.4) 60 97 (1.9) 18 (6.6) 120 98 (1.9) 25 (6.2) The dramatic effect The reduced dissolution of medrogestone when the hormone is incorporated into the sugar coating containing 0.4% microcrystalline cellulose is clearly demonstrated. A preferred embodiment of this invention is a compressed tablet in which the core of the tablet contains a unit dose of an estrogenic compound, or a mixture thereof, in an amount from about 0.1 to about 5.0 milligrams, or more preferably from about 0.3 to about 2.5 milligrams, in combination with excipients, compression aids and standard fillers. More desirably, the conjugated estrogens found in the core of the tablet comprise the naturally occurring conjugated estrogen product known as Premapn. On a sugar coating on the compressed tablet an additional coating of sugar is applied, containing about 1 to about of 50 milligrams, and preferably from about 1.5 to about 30 milligrams, of medroxyprogesterone acetate, a colored coating, and finally, a polish coating. In other applications, it is preferable to employ a non-medicated core with a sugar coating containing a steroid, such as trimegestone, and more preferably, a sugar coating containing a mixture of steroids, such as trimegestone and a conjugated estrogen.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (7)

1. CLAIMS 1. In a pharmaceutical tablet comprising an internal compressed core and an outer sugar coating, wherein the compressed core optionally does not contain a pharmacologically active agent, or comprises one or more non-spheroidal pharmacologically active agents, which are conventionally administered in conjunction with a hormonal steroid, the improvement is characterized in that it comprises the incorporation of a hormonal steroid and an amount of microcrystalline cellulose that controls the release rate of the hormonal steroid in the sugar coating.
2. 2. In a pharmaceutical tablet comprising a compressed, non-medicated core and a sugar coating, the improvement is characterized in that it comprises incorporating a hormonal steroid and an amount of microcrystalline cellulose which controls the release rate of the hormonal steroid in the coating of sugar.
3. 3. A pharmaceutical tablet according to claim 1, characterized in that the sugar present in the composition of the coating is sucrose.
4. 4. A pharmaceutical tablet according to claim 1, characterized in that the hormonal steroid present in the sugar coating is medroxyprogesterone acetate, levonorgestrel, gestodene, medrogestone, estradiol, estriol, ethinylestradiol, mestranol, estrone, dienestrol, hexestrol, diethylstilbestrol, progesterone, desogestrel, norgestimate, hydroxyprogesterone, norethindrone, norethindone acetate, norgestrel, megestrol acetate, methyl-testosterone, ethylestrerenol, eti iestrenol, methandienone, oxandrolone, trimegestone or dienogest.
5. 5. A pharmaceutical tablet according to claim 1, characterized in that the hormonal steroid present in the sugar coating is RU-486, onapristo-ne, ZK-137316, 0RG-31730 or HRP-2000.
6. 6. A pharmaceutical tablet according to claim 1, characterized in that the sugar coating comprises sucrose, from about 0.1% to about 3% microcrystalline cellulose, by weight, polyvinylpyrrolidone in an amount from 0 to about 5% by weight. weight, and a hormonal steroid in an amount from 0.1 to about 20% by weight.
7. 7. A pharmaceutical tablet according to claim 1, characterized in that the sugar coating contains an estrogenic steroid and a progestogenic steroid.