STABILIZED SOLUBILITY-ENHANCED FORMULATIONS FOR ORAL DELIVERY

• US 20100247632A1
• Filed: 03/24/2010
• Published: 09/30/2010
• Est. Priority Date: 03/24/2009
• Status: Active Grant

• Current Assignee: Haimen Pharma Inc.
• Original Assignee: ADDS Pharmaceuticals, LLC
• Inventors: DONG, Liang C., Co, Katrina Andrea U., Pollock-Dove, Crystal, Li, Shu
• Granted Patent: US 9,005,608 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A23L 33/10 using additives addition of substantially indigestible substances A23L33/21
• CPC Class Codes: A23L 33/105 Plant extracts, their artificial duplicates or their derivatives
• CPC Class Codes: A23L 33/15 Vitamins
• CPC Class Codes: A23L 33/155 Vitamins A or D
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

Methods and compositions are described whereby poorly water-soluble beneficial agents such as vitamins and co-factors are formulated into self-emulsifying formulas (SEF) and optionally sorbing the SEF into pores of porous solid particulates, or preparing supersaturated solutions (SSS) and sorbing the SSS into pores of porous solid particulates. These formulations are useful as dosage forms with oral availability.

Claims

1. An oral dosage form comprising at least one poorly water-soluble beneficial agent, and a carrier which is:

a) a self-emulsifying formulation (SEF) comprising a non-ionic water-miscible surfactant, a water-immiscible lipid-soluble component, and, optionally, a fatty acid mono- or di-glyceride;

or

b) an SEF as set forth in a) sorbed onto porous particulates;

or

c) a super-saturated solution (SSS) comprising an alcohol and a polymeric stabilizer sorbed onto porous particulates.

2. The dosage form of claim 1, wherein the beneficial agent comprises CoQ₁₀, Vitamin A, Vitamin D, Vitamin E, Vitamin K, lycopene, lutein, resveratrol, Ginseng extract or mixtures thereof.

3. The dosage form of claim 2, wherein the beneficial agent comprises CoQ₁₀.

4. The dosage form of claim 3, wherein said CoQ₁₀ is present in the SEF or SSS at a concentration of at least 10 mg/ml or of more than 100 mg/ml.

5. The dosage form of claim 1, wherein the water-soluble, non-ionic surfactant comprises Vitamin E TPGS, Cremophor™

EL, Tween 80 and/or Solutol®

HS-15, and the lipid-soluble component comprises omega-3 fatty acids, omega-3 fatty acid ethyl esters, acetated monoglyceride, medium chain mono-, diglyceride, glyceryl caprate, glyceryl caprylate, propylene glycol caprylate, tocopherol or mixtures thereof.

6. The dosage form of claim 1, wherein the polymeric stabilizer of the SSS is selected from the group consisting of Pluronic®

F127, low-molecular weight polyvinylpyrrolidone (PVP K12), poly(vinyl acetate polymer-co-vinylpyrrolidone) (VA

     64) and hydroxypropylmethyl cellulose (HPMC E3 and K3).

7. The dosage form of claim 1, wherein said porous solid particulates are of calcium hydrogen phosphate and/or aluminometallosilicate and/or silicon dioxide.

8. The dosage form of claim 7, wherein the said porous solid particulates are crystalline and possess pore sizes less than 0.1 μ

m;

a specific surface area of >

30 m²/g, and sorb at least 0.5 ml/g of the SSS or SEF while maintaining flowability.

9. The dosage form of claim 1 which is contained in a two-piece hard or soft capsule.

10. The dosage form of claim 1, wherein the carrier is as defined in b) or c) and wherein said dosage form is a tablet that further includes at least a disintegrant, a binding agent and a lubricant.

11. The dosage form of claim 10 which is a bilayer tablet.

12. A process for preparing the dosage form of claim 1 which comprises

i) preparing a super-saturated solution (SSS) of said beneficial agent at an elevated temperature,

ii) sorbing the SSS into porous particulates, and

iii) cooling the particulates.

13. The process of claim 12 which further includes encapsulating the particulates prepared in step iii) into a two-piece hard capsule, or

which further includes blending and granulating the porous particulates prepared in step iii) with water-soluble vitamins or minerals or other pharmaceutical excipients to obtain granules and compressing the granules into a tablet.

14. A process for preparing the dosage form of claim 1 which comprises

i) dissolving said beneficial agent into a self-emulsifying formulation (SEF) at an elevated first temperature,

ii) cooling the SEF of i) or

iii) sorbing the SEF of i) into porous particulates, and cooling the particulates.

15. The process of claim 14 which further includes encapsulating the cooled SEF prepared in step ii) or the particulates prepared in step iii) into a two-piece hard capsule, or

which further includes blending and granulating the porous particulates prepared in step iii) with water-soluble vitamins or minerals or other pharmaceutical excipients to obtain granules and compressing the granules into a tablet.

16. A drink concentrate comprising a SEF of at least one poorly water-soluble beneficial agent which agent is CoQ₁₀, Vitamin A, Vitamin D, Vitamin E, or Vitamin K or mixtures thereof.