Pharmaceutical multiple-units formulation

• US 4,606,909 A
• Filed: 06/20/1984
• Issued: 08/19/1986
• Est. Priority Date: 11/20/1981
• Status: Expired due to Fees

• Current Assignee: Benzon Pharma
• Original Assignee: A/S Alfred Benzon
• Inventors: Bechgaard, Helle, Houmoller, Peter
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US06/622,393
• Time in Patent Office: 790 Days
• Field of Search: 424/19-22, 424/32, 424/33, 424/35
• US Class Current: 424/469
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

A pharmaceutical oral controlled release multiple-units formulation in which individual units comprise cross-sectionally substantially homogeneous cores containing particles of a sparingly soluble active substance, the cores being coated with a coating which is substantially resistant to gastric conditions, but which is erodable under the conditions prevailing in the small intestine, in particular an enteric coating which is substantially insoluble at a pH below 7 such as Eudragit® S (an anionic polymerizate of methacrylic acid and methacrylic acid methyl ester), is prepared by a process comprising comminuting an active substance together with a substance which is readily soluble in intestinal fluids such as an anionic detergent to obtain particles containing the active substance in intimate admixture with the readily soluble substance, combining the resulting particles into cross-sectionally substantially homogeneous cores together with components which accelerate the disintegration of the cores and intestinal fluids such as talc and saccharose, coating the individual cores with an erodable coating, and combining a multiplicity of the coated cores into a capsule or tablet formulation.

Such a coating may also be used when the active substance is a substance which exerts an irritating effect on the gastric mucosa and/or is unstable in an acidic environment.

Claims

1. A pharmaceutical oral controlled release multiple-units formulation, comprising a multiplicity of individual units;

(a) each unit comprising a cross-sectionally substantially homogeneous core coated, in an amount of from 2-25% of the total weight of the core, with an enteric coating which is substantially insoluble at a pH below 7 but soluble in the small intestine, the enteric coating comprising a material selected from the group consisting of acrylic polymers, shellac, cellulose acetate esters, polyvinyl acetate esters, hydroxypropylmethyl cellulose esters, alkyleneglycolether esters, N-butylacrylate-maleic anhydride copolymers, isobutylacrylate-maleic anhydride copolymers and ethylacrylate-maleic anhydride copolymers; and

(b) each core being constituted of a multiplicity of particles having average sizes of about 1-10 μ

m, each of which particles contains;

(i) a sparingly soluble active substance selected from the group consisting of indomethacin, spironolactone, ibuprofen, furosemide, sulfadiazine, sulfamerazine, progesterone, reserpine, pyrvinium embonate, mofebutazone, hydrochlorothiazide, tetracycline, tolbutamide, acetaminophen, testosterone, valporic acid, estradiol, acetazolamide, erythromycin, iron salts, hydralazine, carbamazepine, quinidine, and cardiac glycosides, in an amount of from 10-90% by weight of the particle; and

(ii) a readily soluble, dispersion-enhancing substance, in an amount of up to 10% by weight of the active substance, for increasing exposure of the active substance to intestinal fluids, the dispersion-enhancing substance being an anionic surfactant selected from the group consisting of sodium salts of fatty alcohol sulfates, sulfosuccinates, partial fatty acid esters of sorbitans, and partial fatty acid esters of polyhydroxyethylene sorbitans and polyhydroxyethylene fatty alcohol ethers;

the active substance and the dispersion-enhancing substance being co-comminuted with one another to form said particles, and the particles being admixed with a disintegration-enhancing substance comprising (1) a material which is readily soluble in intestinal fluids and is selected from the group consisting of saccharose, glucose, mannitol, sorbitol and lactose, (2) an insoluble material selected from the group consisting of talc, aluminum silicate, zinc oxide, titanium dioxide, colloidal silica and magnesium trisilicate, and (3) mixtures thereof, in an amount of at least 20% by weight of the particles.

2. The formulation of claim 1, in which the enteric coating comprises an acrylic polymer.

3. The formulation of claim 2, in which the enteric coating comprises a copolymer of methacrylic acid and a methacrylic acid methyl ester.

4. The formation of claim 1, in which the active substance is indomethacin.

5. The formulation of claim 1, in which the dispersion enhancing substance is sodium lauryl sulfate.

6. The formulation of claim 1, in which the disintegration-enhancing substance is an insoluble material selected from the group consisting of talc, aluminum silicate, zinc oxide, titanium dioxide, colloidal silica and magnesium trisilicate.

7. The formulation of claim 1, in which the disintegration enhancing-substance comprises a material which is readily soluble in intestinal fluids and is selected from the group consisting of saccharose, glucose, mannitol, sorbitol and lactose.

8. The formulation of claim 1, in which the disintegration-enhancing substance is a mixture of talc and saccharose.

9. The formulation of claim 1, in the form of a capsule containing the multiplicity of individual units.

10. The formulation of claim 9, in which the enteric coating comprises an acrylic polymer.

11. The formulation of claim 10, in which the enteric coating comprises a copolymer of methacrylic acid and a methacrylic acid methyl ester.

12. The formulation of claim 9, in which the active substance is indomethacin.

13. The formulation of claim 1, wherein the active substance is indomethacin, the dispersion-enhancing substance is sodium lauryl sulfate, the disintegration-enhancing substance is a mixture of talc and saccharose, and the enteric coating is a copolymer of methacrylic acid and methacrylic acid methyl ester.

14. The formulation of claim 9, in which the dispersion-enhancing substance is sodium lauryl sulfate.

15. The formulation of claim 9, wherein the active substance is indomethacin, the dispersion-enhancing substance is sodium lauryl sulfate, the disintegration-enhancing substance is a mixture of talc and saccharose, and the enteric coating is a copolymer of methacrylic acid and methacrylic acid methyl ester.

16. The formulation of claim 9, in which the disintegration-enhancing substance is an insoluble material selected from the group consisting of talc, aluminum silicate, zinc oxide, titanium dioxide, colloidal silica and magnesium trisilicate.

17. The formulation of claim 9, in which the disintegration enhancing-substance comprises a material which is readily soluble in intestinal fluids and is selected from the group consisting of saccharose, glucose, mannitol, sorbitol and lactose.

18. The formulation of claim 9, in which the disintegration-enhancing substance is a mixture of talc and saccharose.