Oral rifamycin SV compositions

Patent metadata

Field	Value
Publication number	US-11564883-B2
Application number	US-201816762760-A
Country	US
Kind code	B2
Filing date	Nov 7, 2018
Priority date	Nov 10, 2017
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

Oral pharmaceutical compositions containing rifamycin SV, or a pharmaceutically salt thereof, characterized in that they are formulated in a higher strength (about 600 mg/tablet) and in such a manner to obtain a modified profile of the rifamycin SV, or a pharmaceutically acceptable salt thereof, in the proximal portion of the intestine, i.e. in the small intestine (duodenum, jejunum and ileum). In one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment in a subject of small intestine bacterial overgrowth (SIBO) and/or irritable bowel syndrome (IBS) and/or in the treatment of cholera. In one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment in a subject of hepatic encephalopathy, hepatic cirrhosis, pouchitis and/or spontaneous bacterial perotinitis. In one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment in a subject of non-alcoholic fatty liver disease, non-alcoholic fatty liver or non-alcoholic steatohepatitis.

First claim

The invention claimed is:

1. An oral pharmaceutical composition in the form of a solid dosage form comprising 540-660 mg of rifamycin SV, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients,
wherein the oral pharmaceutical composition further comprises:
(a) one or more lipophilic compounds selected from the group consisting of (i) unsaturated or hydrogenated alcohol, (ii) fatty acid, salt, or ester thereof, (iii) fatty acid mono-, di- or triglyceride or polyethoxylated derivative thereof, (iv) wax, (v)ceramide, (vi) cholesterol derivative or mixture thereof, (b) one or more hydrophilic compounds, and (c) one or more amphiphilic compound; and a gastro-resistant coating comprising a polymer selected from the group consisting of methacrylic acid-methyl methacrylate copolymer 1:2, methacrylic acid methyl methacrylate 1:1 copolymer, and methylacrylic acid-ethylacrylate 1:1 copolymer, and

wherein the pharmaceutical composition is formulated for modified release,
wherein the solid dosage form comprises a core and the gastro-resistant coating covering the core,
wherein the pharmaceutical composition releases not less than about 50% of the amount of rifamycin SV, or a pharmaceutically acceptable salt thereof, comprising the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution apparatus II complying with USP <711> for 6 hours, wherein the dissolution apparatus comprises 900 mL of an aqueous buffer at pH 6.4 and at a temperature of 37±0.5° C., and wherein the aqueous solution is stirred at a rate of 100 rpm, and
wherein the oral pharmaceutical composition releases the rifamycin SV, or a pharmaceutically acceptable salt thereof, when the solid dosage form is placed in an aqueous medium having a pH in the range of about pH 5 to about pH 6.5.

2. The oral pharmaceutical composition according to claim 1 , wherein the oral pharmaceutical composition is formulated to release the rifamycin SV, or a pharmaceutically acceptable salt thereof, in the small intestine, or following passage of the solid dosage form into the pylorus passage in the proximal part of the intestine.

3. The oral pharmaceutical composition according to claim 1 , wherein the administration of one or more of the solid dosage forms to a subject exhibits a t max,0-24 of the rifamycin SV in the plasma of the subject of about 9.50 hours.

4. The oral pharmaceutical composition according to claim 1 , wherein the administration of three or more of the solid dosage forms to a subject exhibits a C max,0-24 of the rifamycin SV in the plasma of the subject of about 6.23±4.52 ng/mL.

5. The oral pharmaceutical composition according to claim 1 , wherein the administration of three or more of the solid dosage forms to a subject exhibits an AUC 0-24 of the rifamycin SV in the plasma of the subject of about 947.92±20.24 (ng)(h)/ml following administration of three oral pharmaceutical compositions to a human.

6. The oral pharmaceutical composition according to claim 1 , wherein it provides a urine elimination rate of the rifamycin SV in a subject to which the oral pharmaceutical composition is administered of not more than 1% of the total amount of rifamycin SV, or a pharmaceutically acceptable salt thereof, administered to the subject.

7. The oral pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition releases not more than 10% of the amount of rifamycin SV, or a pharmaceutically acceptable salt thereof, comprising the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution apparatus II complying with USP <711> for 2 hours, wherein the dissolution apparatus comprises 1000 mL of an aqueous solution comprising 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ether at pH 1 and at a temperature of 37±0.5° C., and wherein the aqueous solution is stirred at a rate of 50 rpm.

8. The oral pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition contains no more than about 2 wt % of rifamycin S.

9. The oral pharmaceutical composition according claim 1 , wherein the pharmaceutical composition contains no more than about 1 wt % of rifamycin B.

10. The oral pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition contains no more than 10,000 parts per million of ethanol.

11. The oral pharmaceutical composition according to claim 1 , wherein the solid dosage form contains less than 2 wt % of rifamycin S and less than 1 wt % of rifamycin B following storage of the solid dosage form at 25° C. and 60% relative humidity for 3 months.

12. The oral pharmaceutical composition according to claim 1 , wherein the solid dosage form is contained in a package, wherein the package comprises materials to protect the solid dosage form from heat and light.

13. The oral pharmaceutical composition according to claim 1 , wherein the solid dosage form is in the form of a tablet.

14. A method of treating a condition in a subject in need thereof, comprising administering to the subject an effective amount of the oral pharmaceutical composition according to claim 1 , wherein the condition is small intestine bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), IBS having predominant diarrhea (IBS-D), IBS having alternated predominant diarrhea or constipation (IBS-M), or cholera.

15. The method according to claim 14 , wherein the oral pharmaceutical composition is administered to the subject at a daily dose of 600 mg, 1200 mg or 1800 mg for a period from a few days up to several months.

16. A method of treating a subject suffering from IBS-D, comprising administering the oral pharmaceutical composition according to claim 1 , wherein the oral pharmaceutical composition is administered to the subject three times per day for 1 or more days, and wherein the subject experiences a relief of stool consistency compared with a baseline according to a 7-point Bristol stool form scale.

17. The oral pharmaceutical composition according to claim 1 , wherein the one or more hydrophilic compounds is selected from the group consisting of (i) cellulose derivative and their ester, or salt, (ii) alkylcelluloses, (iii) carboxyalkylcelluloses, (iv) polyvinyl alcohol, (v) carboxyvinyl derivative, (vi) polysaccharide, (v) natural or synthetic gum, (vi) alginic acid, and (vii) polyalcohol.

18. The oral pharmaceutical composition according to claim 1 , wherein the one or more amphiphilic compounds (i) polar lipid, (ii) ceramide, (iii) glycol alkyl ether, and (iv) natural or synthetic gum.

Assignees

• Cosmo Technologies Ltd

Inventors

• Moro Luigi
• Longo Luigi Maria

Classifications

• A61K9/0053 Primary

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K31/395

  having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins · CPC title

• A61K9/2846 Primary

  Poly(meth)acrylates · CPC title

• A61P1/12

  Antidiarrhoeals · CPC title

• A61P31/12

  Antivirals · CPC title