Orodispersible tablet containing Estetrol

• US 10,894,014 B2
• Filed: 06/17/2016
• Issued: 01/19/2021
• Est. Priority Date: 06/18/2015
• Status: Active Grant

• Current Assignee: Estetra S.A. (Abbvie Incorporated)
• Original Assignee: Estetra SPRL
• Inventors: Jaspart, Severine Francine Isabelle, Platteeuw, Johannes Jan, Van Den Heuvel, Denny Johan Marijn
• Primary Examiner(s): Chang, Kyung S
• Application Number:
  US15/737,233
• Publication Number:
  US 20180185271A1
• Time in Patent Office: 1,677 Days
• Field of Search: None
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit containing at least 100 μg of an estetrol component selected from estetrol, estetrol esters and combinations thereof; wherein the solid dosage unit can be obtained by a process that comprises: providing a loading liquid comprising organic solvent; estetrol component and optionally one or more other pharmaceutically acceptable ingredients; mixing 1 part by weight of the loading liquid with 0.5-20 parts by weight of carrier particles to produce wet particles; removing organic solvent from the wet particles to produce loaded particles; optionally mixing the loaded particles with one or more tabletting excipients; and forming the loaded particles or the mixture of the loaded particles and the one or more tabletting excipients into a solid dosage unit. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

Claims

1. A process of making an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg and containing at least 300 μ

g of an estetrol component selected from one or more of estetrol and estetrol esters, comprising;

providing carrier particles having a volume weighted average particle size of 10 μ

m to 400 μ

m;

providing a loading liquid comprising an organic solvent in an amount of at least 50 wt. % selected from one or more of methanol, ethanol, isopropanol, and acetone;

the estetrol component in an amount of 1-50 wt. %, and one or more other pharmaceutically acceptable ingredients in an amount of 0-49 wt. %;

mixing 1 part by weight of the loading liquid with 0.5-20 parts by weight of the carrier particles to produce wet particles;

removing the organic solvent from the wet particles to produce loaded particles;

optionally, mixing the loaded particles with one or more tabletting excipients to produce a mixture; and

forming the loaded particles or the mixture into a solid dosage unit having a weight between 30 and 1,000 mg and containing at least 300 μ

g of the estetrol component.

2. The process according to claim 1, wherein the carrier particles contain a water-soluble carbohydrate in an amount of at least 30 wt. %, selected from one or more of monosaccharides, disaccharides, trisaccharides, and C₄-C₁₂ sugar alcohols.

3. The process according to claim 2, wherein the carrier particles contain the water-soluble carbohydrate in an amount of at least 50 wt. %.

4. The process according to claim 2, wherein the water-soluble carbohydrate is selected from one or more of maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, and mannitol.

5. The process according to claim 1, wherein the carrier particles contain mannitol in an amount of at least 20 wt. %.

6. The process according to claim 1, wherein the carrier particles contain lactose in an amount of at least 10 wt. %.

7. The process according to claim 1, wherein more than 90 wt. % of the estetrol component in the loading liquid is dissolved when the loading liquid is mixed with the carrier particles.

8. The process according to claim 1, wherein the estetrol component is present in the loading liquid in an amount of 2-40 wt. %.

9. The process according to claim 1, wherein the loading liquid contains a binder in an amount of 0.5-40 wt. % selected from one or more of cellulose derivatives and polyethylene glycol.

10. The process according to claim 9, wherein the binder is ethylcellulose.

11. The process according to claim 1, wherein the wet particles are produced by combining the loading liquid and the carrier particles in a high shear granulator, a low shear granulator, or a fluidized bed granulator.

12. The process according to claim 1, wherein the organic solvent is removed from the wet particles in a fluidized bed granulator.

13. The process according to claim 1, wherein the loading liquid contains at least 60 wt. % ethanol.

14. The process according to claim 1, wherein the wet particles are prepared by mixing the loading liquid with the carrier particles in a weight ratio that is in the range of 1:

0.8 to 1;

12.

15. The process according to claim 1, wherein the loaded particles have a volume mean diameter in a range of from 100 to 4,000 μ

m.

16. The process according to claim 1, wherein the tabletting excipients contain a disintegrating agent in an amount of 0-20% by weight of the dosage unit, selected from one or more of modified starches, crosslinked polyvinylpyrrolidone, and crosslinked carmellose.

17. The process according to claim 1, wherein the one or more tabletting excipients comprise at least 30% by weight of the dosage unit of one or more selected from lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, and polyvinyl pyrrolidone.

18. The process according to claim 1, wherein the dosage unit is formed by direct compression or compression molding.

19. The process according to claim 1, wherein the dosage unit has a weight between 40 and 500 mg.

20. The process according to claim 1, wherein the dosage unit contains 0.3-100 mg of the estetrol component.

21. The process according to claim 1, wherein the estetrol component is estetrol.