Preformulation for tabletting natural mixtures of conjugated estrogens
A pharmaceutical preformulation in the form of a solid, free-flowing dry extract of a natural mixture of conjugated equine estrogens, which is particularly suitable use in for solid galenic forms, e.g. tabletting. The conjugated estrogens are available for further galenic processing in a form which assures the chemical stability of the hormones and permits advantageous processing into solid galenic forms, for example a tablet. The invention furthermore relates to a method for producing these preformulations in the form of a dry extract.
1. A pharmaceutical preformulation in the form of a tabletable, solid, free-flowing, dry extract;
(a) wherein said solid extract contains a uniform amount of a mixture of natural conjugated equine estrogens per amount of support material, defined relative to the main hormone constituents;
(b) wherein the uniform active-substance content is applied by spraying an aqueous solution consisting essentially of an extract of said mixture of natural conjugated equine estrogens from pregnant mares' urine onto a powdered or granular pharmaceutical support material consisting essentially of material selected from the group consisting of microcrystalline celluloses and mixtures of microcrystalline cellulose with lactose, and thereafter drying,
(c) wherein said preformulation has the active-substance content including free estrogens and other solids calculated as dry matter relative to the amount of the pharmaceutical support material in the preformulation lying in the range from 0.25 to 0.70 gram of dry matter per gram of support material;
(d) wherein said preformulation has the active-substance content calculated as the ratio of said mixture of natural equine conjugated estrogens relative to the amount of the pharmaceutical support material lying in the range from 35 to 100 mg of conjugated estrogens per gram of support material;
(e) wherein said preformulation contains conjugated estrogens in the following proportions:
52.5 to 61.5% estrone;
22.5 to 30.5% equilin;
13.5 to 19.5% 17-α-dihydroequilin;
2.5 to 9.5% estradiol, and
0.5 to 4.0% 17-β-dihydroequilin;
(f) wherein in said preformulation the proportion of free hormones relative to the total hormone content in the active substance is less than 5% by weight; and
(g) wherein the preformulation has a particle-size distribution corresponding to the following sieve analysis:
100% by weight of the particles pass through a sieve mesh size of 500 μm;
at least 98% by weight of the particles pass through a sieve mesh size of 250 μm;
about 65 to 99.5% by weight of the particles pass through a sieve mesh size of 160 μm;
about 35 to 87% by weight of the particles pass through a sieve mesh size of 125 μm; and
fines of less than 23% by weight passing through a sieve mesh size of 63 μm.
2. A preformulation according to claim 1 , wherein said preformulation has the active substance content lying in the range from 0.28 to 0.64 gram of dry matter per gram of support material.
3. A preformulation according to claim 1 , wherein said preformulation has the active substance content calculated as the ratio of said mixture of natural equine conjugated estrogens relative to the amount of the pharmaceutical support material lying in the range from 43 to 90 mg of conjugated estrogens per gram of support material.
4. A preformulation according to claim 1 , wherein said preformulation has a residual moisture content of at most 3.0% by weight, relative to the entire preformulation as 100% by weight.
5. A preformulation according to claim 4 , wherein said preformulation has a residual moisture content of at most 1.0% by weight, relative to the entire preformulation as 100% by weight.
6. A preformulation according to claim 1 , wherein the active-substance content, calculated as total hormone content, lies in the range from about 35 to 100 mg per gram of the pharmaceutical support material.
7. A preformulation according to claim 6 , wherein the active-substance content, calculated as total hormone content, lies in the range from about 43 to 90 mg per gram of the pharmaceutical support material.
8. A preformulation according to claim 1 , wherein the proportion of free hormones relative to the total hormone content in the active substance is less than 2% by weight.
9. A preformulation according to claim 1 , wherein the pharmaceutical support material is a microcrystalline cellulose or a mixture of microcrystalline celluloses.
10. A preformulation according to claim 1 , wherein the pharmaceutical support material is a mixture of microcrystalline cellulose and lactose.
11. A preformulation according to claim 10 , wherein the weight ratio of microcrystalline cellulose to lactose lies in the range of 8:2 to 6:4.
12. A preformulation according to claim 11 , wherein the weight ratio of microcrystalline cellulose to lactose lies in the range of about 7.5:2.5 to 6.5:3.5.
13. A preformulation according to claim 12 , wherein the weight ratio of microcrystalline cellulose to lactose is about 7:3.
14. A preformulation according to claim 1 , wherein the mean bulk volume of the preformulation lies in the range from 1.8 to 3.0 ml/g.
15. A preformulation according to claim 1 , wherein the mean bulk density of the preformulation lies in the range from 0.3 to 0.6 grams/ml.
16. A preformulation according to claim 1 , wherein the preformulation has a particle-size distribution corresponding to the following sieve analysis:
about 0.15% to at most 2% by weight of the particles larger than a mesh size of 250 μm;
about 3 to 31% by weight of the particles larger than a mesh size of 160 μm;
about 8 to 36% by weight of the particles larger than a mesh size of 125 μm; and
fines of the particles of about 3 to at most 23% by weight passing through a sieve mesh size of 63 μm.
17. A preformulation according to claim 1 , wherein the preformulation has a mean particle size lying in the range from 50 to 250 μm.
18. A preformulation according to claim 17 , wherein the preformulation has a mean particle size lying in the range from 75 to 150 μm.