US-12622914-B2 - Pharmaceutical rectal suppository compositions of 6-thioguanine, methods of treatment and/or methods of manufacturing

Abstract

Described is a rectal suppository. The rectal suppository comprises 6-thioguanine, at least one hard fat, and at least one surfactant. Further or alternatively, the rectal suppository comprises about 1 to 9 mg of 6-thioguanine. Further or alternatively, there is described a method of preventing, treating and/or managing inflammatory bowel disease in a subject. The method comprises administering a rectal suppository to the subject in need thereof. Further or alternatively, there is described a method of manufacturing a rectal suppository. The method comprises the steps of (a) heating a hard fat to become a liquid hard fat, (b) adding at least one surfactant to the liquid hard fat, (c) adding 6-thioguanine to the liquid hard fat, (d) forming the hard fat into a rectal suppository. Step (b) is optionally carried out before step (c) or after step (c).

Inventors

• Peter William Surman
• Zhen Shi
• Fergus Cameron Binnie
• Christopher Ritchie
• Yuefeng Long

Assignees

• DOUGLAS PHARMACEUTICALS LTD.

Dates

Publication Date

20260512

Application Date

20240823

Priority Date

20230824

Claims (17)

1. 1 . A rectal suppository comprising: about 1 to 30 mg of 6-thioguanine, about 80 to 99.9% w/w of at least one hard fat, wherein the hard fat comprises less than about 10 mole % of one or more unsaturated fatty acid(s) and has a hydroxyl value of less than 40 mg KOH/g, about 0.1 to 20% w/w of at least one surfactant, and about 0.25 to 1% w/w of a suspending agent, wherein one surfactant is polysorbate 80.
2. 2 . The suppository of claim 1 wherein the suppository comprises about 5 to 20 mg of 6-thioguanine.
3. 3 . The suppository of claim 1 wherein the suppository comprises about 90 to 99.5% w/w of the hard fat.
4. 4 . The suppository of claim 1 wherein the suppository comprises about 0.1 to 5% w/w of the surfactant.
5. 5 . The suppository of claim 1 wherein the surfactant additionally comprises from any one or more a polyoxyethylene derivative of natural or hydrogenated vegetable oil(s), a alkyl/dialykyl sulfate, sulfonate or sulfosuccinate salt, a polyoxyethylene fatty acid ester, a phospholipid, a transesterification product of natural vegetable oil triglyceride and polyalkylene polyol, a sorbitan fatty acid ester, a pentaerythritol fatty acid ester, a polyoxyethylene glycol alkyl ether and/or ester, a sucrose ester, an ethoxylated fatty alcohol, or a fatty acid salt.
6. 6 . The suppository of claim 1 wherein the suspending agent is selected from one or more of: silicon dioxide, a clay, aluminum monostearate and magnesium stearate.
7. 7 . The suppository of claim 1 wherein the suppository comprises an antioxidant.
8. 8 . The suppository of claim 1 wherein the suppository has a total weight of about 800 to about 3000 mg.
9. 9 . A method of treating inflammatory bowel disease in a subject, the method comprising administering a rectal suppository comprising: about 1 to 30 mg of 6-thioguanine, about 80 to 99.9% w/w of at least one hard fat, wherein the hard fat comprises less than about 10 mole % of one or more unsaturated fatty acid(s) and has a hydroxyl value of less than 40 mg KOH/g, about 0.1 to 20% w/w of at least one surfactant, and about 0.25 to 1% w/w of a suspending agent, to the subject in need thereof, wherein one surfactant is polysorbate 80.
10. 10 . The method of claim 9 wherein the inflammatory bowel disease effects the rectum.
11. 11 . The method of claim 9 wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease, effecting the rectum.
12. 12 . The method or use of claim 11 wherein the ulcerative colitis is ulcerative proctitis, proctosigmoiditis, and/or left-sided colitis.
13. 13 . The suppository of claim 1 wherein the 6-thioguanine in the suppository has a particle size distribution of D50 of less than about 100 μm.
14. 14 . The suppository of claim 1 wherein the surfactant has a melting point below 35° C.
15. 15 . The suppository of claim 1 wherein the suppository has a melting range of about 33 to 38° C.
16. 16 . The suppository of claim 1 wherein the suppository exhibits release of the 6-thioguanine in vitro in dissolution medium that corresponds to: (a) about 20 to about 100% of the 6-thioguanine at about 20 minutes from placement of the suppository in the dissolution medium, (b) not less than about 40% of the 6-thioguanine at about 60 minutes from placement of the suppository in the dissolution medium, wherein the dissolution medium is 0.05 M phosphate buffer with a pH 6.8±0.05, at 37.0° C.±0.5° C.
17. 17 . The suppository of claim 1 wherein the suppository exhibits release of the 6-thioguanine in vitro in dissolution medium that corresponds to: (a) about 60 to about 100% of the 6-thioguanine at about 20 minutes from placement of the suppository in the dissolution medium, (b) not less than about 80% of the 6-thioguanine at about 60 minutes from placement of the suppository in the dissolution medium, wherein the dissolution medium is 0.05 M phosphate buffer with a pH 6.8±0.05, at 37.0° C.±0.5° C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of AU2023902710, filed on Aug. 24, 2023, and AU2024901720, filed on Jun. 7, 2024, which are herein specifically incorporated by reference in their entireties. BACKGROUND 6-thioguanine (6-TG) is principally used to treat acute nonlymphocytic leukemias. The oral immediate release tablets sold under brand names Tabloid™ or Lanvis™ contain 40 mg of 6-thioguanine. Tabloid™ and Lanvis™ are not recommended for maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity. Patients being treated with 6-TG must be monitored for indications of liver toxicity. Further, patients with an inherited deficiency of thiopurine methyltransferase (TPMT) or Nudix hydrolase 15 (NUDT15) are at higher risk of toxicity and typically require 10% or less of the standard 6-thioguanine dosage. Oral 6-thioguanine is sold in the Netherlands under brand name Thiosix™ for treatment of inflammatory bowel disease (Crohn's disease or ulcerative colitis). The daily dose recommended on the label is 0.3 mg per kg of body weight with a maximum dose of 25 mg per day. Each Thiosix™ tablet is 10 mg or 20 mg and has a score line to enable the tablet to be divided into two doses. Tabloid™ and Lanvis™ are also used off label in other countries to treat inflammatory bowel disease but are not registered for this use. Crouwel F, Simsek M, van Doorn A S, Mulder C J J, Buiter H J C, Barclay M L, Florin T H, de Boer-N K. “Rectally Administrated Thioguanine for Distal Ulcerative Colitis: A Multicenter Case Series”, Inflammatory Bowel Diseases, Volume 29, Issue 6, June 2023, pages 1000-1004, describes use of 20 mg thioguanine enemas and rectal suppositories to treat proctitis and left-sided colitis. The rectal suppositories were prescribed on an individual basis under a special access scheme in Australia, which is available where no alternative drug formulation is licensed. The 20 mg rectal suppositories were made and dispensed by licensed compounding pharmacies using Good Manufacturing Practice thioguanine and excipients. The paper does not disclose the excipients used in the rectal suppositories. However, Timothy Florin (University of Queensland), one of the authors of the paper, has confirmed the sole ingredients of the rectal suppositories were 6-thioguanine and cocoa butter. The 6-thioguanine was sieved using 40 #sieve prior to combining with the melted cocoa butter. 40 #sieve is equivalent to 400 μm, so the thioguanine had a particle size no larger than 400 μm. Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art. SUMMARY In a first aspect there is provided a rectal suppository comprising: 6-thioguanine,at least one hard fat, andat least one surfactant. In one aspect there is provided a rectal suppository comprising about 1 to 9 mg of 6-thioguanine. In one aspect there is provided a rectal suppository comprising about 1 to 9 mg of 6-thioguanine and at least one hard fat. In one aspect there is provided a rectal suppository comprising about 1 to 9 mg of 6-thioguanine, at least one hard fat, and at least one surfactant. In at least one example, the suppository comprises about 1 to 30 mg of 6-thioguanine. In at least one example, the suppository comprises about 3 to 25 mg of 6-thioguanine. In at least one example, the suppository comprises about 5 to 20 mg of 6-thioguanine. In at least one example, the suppository comprises about 8 to 30 mg of 6-thioguanine. In at least one example, the suppository comprises about 8 to 25 mg of 6-thioguanine. In at least one example, the suppository comprises about 10 to 20 mg of 6-thioguanine. In at least one example, the suppository comprises about 15 to 30 mg of 6-thioguanine. In at least one example, the suppository comprises about 17 to 25 mg of 6-thioguanine. In at least one example, the suppository comprises about 20 mg of 6-thioguanine. In at least one example, the suppository comprises about 6 to 15 mg of 6-thioguanine. In at least one example, the suppository comprises about 8 to 12 mg of 6-thioguanine. In at least one example, the suppository comprises about 10 mg of 6-thioguanine. In at least one example, the suppository comprises about 1 to 9 mg of 6-thioguanine. In at least one example, the suppository comprises about 2 to 9 mg of 6-thioguanine. In at least one example, the suppository comprises about 3 to 9 mg of 6-thioguanine. In at least one example, the suppository comprises about 3 to 7 mg of 6-thioguanine. In at least one example, the suppository comprises about 4 to 6 mg of 6-thioguanine. In at least one example, the suppository comprises about 5 mg of 6-thioguanine. In at least one example, the suppository