Hard capsule dosage form and uses therof

Abstract

The present invention relates to hard capsule dosage forms and uses thereof. The hard capsule dosage form comprises a hard-shell capsule, the hard-shell capsule contains a solid or semi-solid composition, the solid or semi-solid composition comprises a 25-hydroxyvitamin D compound, and the hard-shell capsule comprises cellulose ether and a gelling agent; and wherein the hard shell capsule is a capsule in the range of No. 3 to No. 5.

Description

Abstract The present invention relates to hard capsule dosage forms and uses thereof. The hard capsule dosage form comprises a hard-shell capsule, the hard-shell capsule contains a solid or semi-solid composition, the solid or semi-solidomposition comprises a 25-hydroxyvitamin D compound, and the hard-shell capsule comprises cellulose ether and a gelling agent; and wherein the hard shell capsule is a capsule in the range of No. 3 to No. 5.

Claims

1. A hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound, the hard shell capsule comprising a cellulose ether and a gelling agent; and wherein the hard shell capsule is a capsule in the size range of 3 to 5.

2. A hard capsule dosage form comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound and a stabilizer, wherein the hard shell capsule is a gelled hard shell capsule comprising a cellulose ether and a gelling agent; and wherein the hard capsule dosage form is a controlled release dosage form and the controlled release dosage form releases ≤30% of the 25-hydroxyvitamin D in the formulation within the first two hours of a two-stage dissolution test at pH 1.

2.

3. A hard capsule dosage form, comprising a hard shell capsule, wherein the hard shell capsule contains a solid or semisolid composition, wherein the solid or semisolid composition comprises a 25-hydroxyvitamin D compound and a stabilizer, and the hard shell capsule comprises hydroxypropyl methylcellulose and a gelling agent.

4. A hard capsule dosage form, comprising a hard shell capsule containing a solid or semisolid composition comprising a 25-hydroxyvitamin D compound and a stabilizer, wherein the hard shell capsule comprises hydroxypropyl methylcellulose and gellan gum.

5. The hard capsule dosage form according to any one of claims 1 to 4, wherein the 25-hydroxyvitamin D comprises or consists of calcifediol.

6. The hard capsule dosage form according to any one of claims 1 to 4, wherein the composition comprising the 25-hydroxyvitamin D comprises a mixture of the following components, wherein all amounts are specified by weight based on the total weight of the composition contained in the hard shell capsule: Calcifediol: approximately 0.01% to 0.03% or 0.0194%; Paraffins: about 25% to 30% or 27.95%; Mineral oil: approximately 30% to 35% or 32.26%; Hypromellose K100: approximately 7% to 13% or 9.98%; Mono- and diglycerides: approximately 14.5% to 20.5% or 17.5%; Lauroyl polyoxylglycerides: approximately 7% to 13% or 9.73%; Dehydrated ethanol, approximately 2% to 4% or 2.54%; and BHT: about 0.05% to 0.05% or 0.02%.

7. The hard capsule dosage form according to any one of claims 1 to 4, wherein the hard shell capsule comprises a mixture of the following components, wherein all amounts are specified by weight based on the total dry weight of the hard shell capsule: Gellan gum: about 1% to 10% or 5%; Titanium dioxide: about 0.01% to 4% or 2%; and Hydroxypropyl methylcellulose: qsp100.

8. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is present in an amount ranging from 0.1% to 10% by weight of the hard shell capsule.

9. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of natural seaweed, natural seed gum, natural plant exudate, natural fruit extract, biosynthetic gum and biosynthetic processed starch.

10. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of alginate, agar gum, guar gum, locust bean gum (carob), carrageenan, tara gum, gum arabic, gum ghatti, Khaya grandifolia gum, gum tragacanth, gum karaya, pectin, arabic (arabinan), xanthan gum, starch, konjac mannan, galactomannan, haran, gellan, exopolysaccharide, xanthan gum, acetylated gum, gellan gum, welan gum, rhamnose gum, furcellaran, succinoglycan, scleroglucan, schizophyllan, tamarind gum, curdlan gum, pullulan, and dextran.

11. The hard capsule dosage form according to any one of claims 1 to 3, wherein the gelling agent is one or more selected from the group consisting of gellan gum, carrageenan, pectin, and pullulan.

12. The hard capsule dosage form according to claim 1 or 2, wherein the cellulose ether is present in the hard shell capsule in an amount ranging from about 90% to 99.98% by weight of the hard shell capsule.

13. The hard capsule dosage form according to claim 1, wherein the hard shell capsule is a size 4 capsule.

14. The hard capsule dosage form of claim 2, wherein the solid or semisolid composition comprising the 25-hydroxyvitamin D comprises from about 2 weight percent to about 18 weight percent of the stabilizer, based on the total weight of the composition contained in the hard shell capsule.

15. The hard capsule dosage form according to any one of claims 2 to 4, wherein the stabilizer comprises a cellulosic stabilizer.

16. The hard capsule dosage form of claim 15, wherein the cellulose stabilizer comprises carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyanionic cellulose, and combinations thereof.

17. The hard capsule dosage form of claim 2, wherein the dosage form releases no more than about 7% of the 25-hydroxyvitamin D in the formulation within two hours in an acidic medium.

18. The hard capsule dosage form of claim 17, wherein the release in acidic medium is measured in a pH 1.2 medium at 37°C for two hours followed by dissolution measurement in a pH 6.8 buffered medium, and the dosage form releases up to 40% of the 25-hydroxyvitamin D in the formulation at the 4 hour time point.

19. The hard capsule dosage form of claim 18, wherein the dosage form releases at least 60% of the 25-hydroxyvitamin D in the formulation at a 6 hour time point.

20. The hard capsule dosage form of claim 19, wherein the dosage form releases at least 80% of the 25-hydroxyvitamin D in the formulation at an 8 hour time point.

21. The hard capsule dosage form of claim 17, wherein the release in acidic medium is measured in a pH 1.2 medium at 37°C for two hours followed by dissolution measurement in a pH 6.8 buffered medium, and wherein the dosage form releases up to 30% of the 25-hydroxyvitamin D in the formulation at the 2 hour time point, ≥50% and ≤75% of the 25-hydroxyvitamin D in the formulation at the 6 hour time point, and ≥80% of the 25-hydroxyvitamin D in the formulation at the 12 hour time point.

22. Use of a hard capsule dosage form according to any one of claims 1 to 4 in the manufacture of a dosage form for providing increased recovery and / or reduced degradation of 25-hydroxyvitamin D or calcifediol in the dosage form after exposure of the dosage form to acidic conditions, the dosage form comprising 25-hydroxyvitamin D or calcifediol, the use comprising disposing a formulation comprising 25-hydroxyvitamin D or calcifediol in a hard shell capsule to form the dosage form.

23. Use of a hard capsule dosage form according to any one of claims 1 to 4 as a medicament for delivering 25-hydroxyvitamin D or calcifediol to a subject in need thereof.

24. The use of claim 23, wherein the hard capsule formulation is delivered as repeated dosing to provide a baseline-adjusted steady-state Cmax of serum 25-hydroxyvitamin D or calcifediol in the range of about 25 ng / ml to about 98 ng / ml, optionally using a 30 μg dose of 25-hydroxyvitamin D or calcifediol.

25. The use of claim 23, wherein the hard capsule formulation is delivered as repeat dosing to provide a baseline-adjusted steady-state Cmax of serum 25-hydroxyvitamin D or calcifediol within the range of about 12.5 ng / ml to about 104.9 ng / ml of 25-hydroxyvitamin D or calcifediol, optionally using a 60 μg daily dose of 25-hydroxyvitamin D or calcifediol.

Images