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WO2021138561A1 - Nouvelles compositions de tétrahydrocurcumine, procédés de fabrication associés et procédés d'utilisation associés - Google Patents

Nouvelles compositions de tétrahydrocurcumine, procédés de fabrication associés et procédés d'utilisation associés Download PDF

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Publication number
WO2021138561A1
WO2021138561A1 PCT/US2020/067670 US2020067670W WO2021138561A1 WO 2021138561 A1 WO2021138561 A1 WO 2021138561A1 US 2020067670 W US2020067670 W US 2020067670W WO 2021138561 A1 WO2021138561 A1 WO 2021138561A1
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WO
WIPO (PCT)
Prior art keywords
thcu
pharmaceutical formulation
composition
foregoing
peg
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2020/067670
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English (en)
Inventor
Donald Jeffrey Keyser
Alvaro F. Guillem
Richard A. ZAGER
Bhupinder Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Renibus Therapeutics Inc
Original Assignee
Renibus Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Renibus Therapeutics Inc filed Critical Renibus Therapeutics Inc
Publication of WO2021138561A1 publication Critical patent/WO2021138561A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to novel tetrahydrocurcumin (THCu) compositions, novel methods of manufacturing, and methods of using these compositions for therapeutic applications.
  • THCu tetrahydrocurcumin
  • THCu is a major metabolite of the curcuminoid, curcumin and can be used for its anti-fibrotic and anti-oxidant activities.
  • THCu is a strong anti-oxidative molecule, and can be obtained by the hydrogenation of curcumin.
  • THCu can be used as an anti-oxidant in oxidative stress diseases.
  • THCu is relatively safe at high dosages (80 mgs/kg body weight)
  • one of the major disadvantages of THCu is its low solubility, in which it has poor solubility in water at acidic and at physiological pH. Another disadvantage is its ability to hydrolyze rapidly in basic solutions.
  • U.S. Pat. 9,375,408 issued June 28, 2016, to Dr. Bhupinder Singh describes the production of THCu through hydrogenation of curcumin.
  • the '408 patent discloses that THCu is poorly absorbed and is rapidly metabolized.
  • the '408 patent discloses the deuteration of THCu. Deuteration at one or two alcohol sites of THCu can delay glucuronidation, thus improving the half-life of THCu.
  • the present invention involves a pharmaceutical formulation comprising tetrahydrocurcumin (THCu) and lacking detectable amounts of HHC.
  • the invention involves a pharmaceutical formulation comprising a second component having a relative retention time between that of THCu and HHC.
  • the THCu composition includes only one component with a retention time that is greater than that of THCu.
  • the present invention involves pharmaceutical formulations comprising the above THCu composition combined with a liposome carrier composition.
  • the liposome carrier comprises a first lipid, wherein the first lipid is polyenylphosphatidylcholine.
  • the composition comprises at least 5% of the polyenylphosphatidylcholine by weight and no more than 95% of the polyenylphosphatidylcholine by weight.
  • the formulation may further comprise an antioxidant selected from Vitamin E, Vitamin C or alpha lipoic acid.
  • the composition in another aspect may comprise at least 5% of antioxidant by weight and no more than 95% of the antioxidant by weight.
  • the composition may comprise an excipient, wherein the excipient is a sugar, lactose, sucrose, mannitol, sorbitol, cellulose preparations of maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • the composition may alternatively or, in addition, further comprise a lipophilic solvent, a fatty oil, or an organic oil.
  • the invention also relates to a method of treating or preventing a disorder, wherein the method comprises administering the pharmaceutical formulation of any of the foregoing claims to a patient in need thereof.
  • the disorder is selected from kidney disease, chronic kidney disease, and polycystic kidney disease.
  • Fig. 1 shows a synthetic pathway for THCu according to an aspect of the invention.
  • Fig. 2 shows geometric mean plasma concentrations of THCu and d6-THCu after oral administration of a single 100 mg dose of each test article to male rats - linear left panel) and semi-logarithmic (right panel) axes.
  • Fig. 3 is a table including data showing individual animal plasma concentrations.
  • Fig. 4 is a table including descriptive statistics for plasma concentrations.
  • Fig. 5 is a table including individual animal pharmacokinetic parameters.
  • Fig. 6 is a table including descriptive statistics for pharmacokinetic parameters.
  • Fig. 7 includes graphs showing individual animal THCu and THCu- d6 plasma concentrations versus time on a linear scale.
  • Fig. 8 includes graphs showing individual animal THCu and THCu- d6 plasma concentrations versus time on a linear scale.
  • Fig. 9 includes graphs showing individual animal THCu and THCu- d6 plasma concentrations versus time on a semi-logarithmic scale.
  • Fig. 10 includes graphs showing individual animal THCu and THCu-d6 plasma concentrations versus time on a semi-logarithmic scale.
  • Curcumin can be hydrogenated resulting in a composition comprising THCu, which has the following structure:
  • THCu THCu
  • Ferulic acid (1) is abundantly available from plants and is a very cheap source of raw material. Reduction of ferulic acid followed by protection of the phenol with benzoate results in 3 in high yields. From the acid chloride of 3 we can make the 8-ketoester 5, which on further alkylation with another molecule of the acid chloride results in 6. More experiments are needed to optimize the conversion of acid chloride to 6. Krapcho deethoxycarbonylation followed by the hydrolysis of benzoate results in THCu according to the scheme shown in Fig 1.
  • Triethyl amine (10.5 mL, 75.0 mmol) was added to a suspension of potassium salt of ethyl malonate (5.1 g, 30.0 mmol) in acetonitrile (100 mL) and cooled to 0 °C.
  • anhydrous magnesium chloride (4.28 g, 45.0 mmol) was added and the mixture was continued to stir for another 1 h.
  • Compound 4 (9.42 g,
  • Example 1 The resulting composition from Example 1 was analyzed by gas chromatography, and compared to (A) a commercially available THCu prepared by hydrogenation of curcumin, (B) an in-house THCu product prepared by hydrogenation of curcumin, (C) hexahydrocurcumen (HHC), (D) a small scale synthesis of THCu according to the process of Example 1, and (E) a large scale synthesis of THCu according synthetic pathway described in Example 1.
  • A a commercially available THCu prepared by hydrogenation of curcumin
  • B an in-house THCu product prepared by hydrogenation of curcumin
  • HHC hexahydrocurcumen
  • D small scale synthesis of THCu according to the process of Example 1
  • E a large scale synthesis of THCu according synthetic pathway described in Example 1.
  • composition comprising predominantly THCu and lacking detectable amounts of the over-hydrogenated impurity HHC.
  • Example 3 The composition of Example 1 is combined with liposomes to make a THCu pharmaceutical formulation.
  • the liposome is polyenylphosphatidylcholine.
  • the composition includes between 5% and 95% polyenylphosphatidylcholine.
  • Example 3 The composition of Example 3 is administered to a patient suffering from a disorder selected from kidney disease, chronic kidney disease, and polycystic kidney disease.
  • the invention includes making a d6- Tetrahydrocurumin of the following formula:
  • the d6-THCu was formulated at a concentration of 10% w/w in the amounts and ratios provided below:
  • the THCu weight was adjusted based on purity of APL Per CoA, purity is 98.6%.
  • Phosal 75 ® SA is a phosphatidylcholine source for nutritional supplements, which includes lecithin in alcohol, safflower oil, glyceryl stearate, coconut oil, and ascorbyl palmitate that is sold by American Lecithin Company.
  • Captex® 300 is also known as Medium Chain Triglycerides (MCT), and is sold by Abitec.
  • the Captex composition includes 6.0% max of 6:0 Caproic Acid, 55.5- 85.0% 8:0 Caprylic Acid, 15.0-40.0% 10:0 Capric Acid and 4.0% max 12:0 lauric acid.
  • Labrasol® ALF Caprylocaproyl Polyoxyl-8 glycerides
  • Labrasol® ALF is a nonionic water- dispersible surfactant for lipid-based formulation to solubilize and increase oral bioavailability of poorly water-soluble APIs which is marketed by Gattefosse.
  • Labrasol® ALF consists of a small fraction of mono-, di- and triglycerides and mainly PEG-8 (MW 400) mono- and diesters of caprylic (Cs) and capric (C10) acids
  • Labrasol® ALF self-emulsifies in aqueous media forming a fine dispersion, i.e., microemulsion (SMEDDS).
  • SMEDDS microemulsion
  • compositions were prepared according to the following process. Set up the 5L jacketed reaction vessel and Julabo circulation heater. Begin heating the Julabo to 90°C. Dispense Phosal 75 SA, Captex 300, and Labrasol ALF (Items 2, 3, and 4) into appropriately sized containers. Add the Phosal 75 SA, Captex 300, and Labrasol ALF to the 5L reaction vessel. Mix contents until visually homogenous and product reaches a temperature of 85°C ⁇ 5°C. Add Tetrahydrocurcumin to vessel containing Phosal 75 SA, Captex 300, and Labrasol ALF while stirring. Mix until completely dissolved and visually homogenous. Reduce the Julabo temperature and allow the solution to cool to 30°C ⁇ 5°C while continuing to stir. Package product by adding 50mL to appropriate 60mL bottles. Continue until product is exhausted.
  • the d6-THCu version of the compound provides a desirable release profile compared to non-deuterated THCu.
  • Compositions were prepared using THCu as well as d6-THCu and their pk profiles were compared ash shown in FIG. 2.
  • Individual animal plasma concentrations are shown in the table found in Fig. 3.
  • Descriptive statistics for plasma concentrations are shown in the table found in Fig. 4.
  • Individual animal pharmacokinetic parameters are shown in the table found in Fig. 5.
  • Descriptive statistics for pharmacokinetic parameters are shown in the table found in Fig. 6.
  • Figs. 7 and 8 include graphs showing individual animal THCu and THCu-d6 plasma concentrations versus time on a linear scale.
  • Figs. 9 and 10 include graphs showing individual animal THCu and THCu-d6 plasma concentrations versus time on a semi-logarithmic scale.
  • the invention involves a liquid THCu composition.
  • the THCu active of this composition may be deuterated, or non-deuterated.
  • THCu was combined with PEG 300 (25 mg/ml).
  • THCu was combined with a PEG solubilizing agent, resulting in a liquid form of THCu.
  • the solubilizing agent was PEG 300 at a concentration of 25 mg/ml.
  • the liquid composition was added to HK-2 cells in three dosages. After 3h, HO-1 mRNA was measured. The PEG without THCu served as a control. The liquid composition exhibited a dose-dependent increase from 0.76 baseline to 1.8 at 10 ⁇ g/ml. The data demonstrate that the THCu composition described herein activates the Nrf2 pathway.
  • liquid THCu compositions described above would be suitable for an injectable composition.
  • This composition has particular advantages for acutely ill patients for whom oral administration of TH Cu is inconvenient or impossible.
  • the liquid THCu composition may be particularly useful for treating acute myocardial infarction, stroke, and traumatic brain injury.
  • the liquid composition may be administered via the parenteral route for one or more of these indications.
  • the liquid composition may be administered subcutaneously or intravenously.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne de nouvelles compositions de tétrahydrocurcumine (THCu), de nouveaux procédés de fabrication et des procédés d'utilisation de ces compositions pour des applications thérapeutiques. La ou les nouvelles voies synthétiques résultent en des compositions de THCu qui ne contiennent généralement pas d'hexahydrocurcumine (HHC) et comprennent un profil d'impuretés amélioré avec des espèces supplémentaires réduites qui sont généralement présentes dans des compositions de curcumine hydrogénée.
PCT/US2020/067670 2019-12-31 2020-12-31 Nouvelles compositions de tétrahydrocurcumine, procédés de fabrication associés et procédés d'utilisation associés Ceased WO2021138561A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962955577P 2019-12-31 2019-12-31
US62/955,577 2019-12-31

Publications (1)

Publication Number Publication Date
WO2021138561A1 true WO2021138561A1 (fr) 2021-07-08

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160058713A1 (en) * 2014-09-02 2016-03-03 Bhupinder Singh Methods of making a deuterated or a non-deuterated molecule and pharmaceutical formulations for treatment
IN201711042347A (fr) * 2017-11-26 2017-12-08
US20200281871A1 (en) * 2019-03-06 2020-09-10 Renibus Therapeutics, Inc. Novel tetrahydrocurcumin compositions, methods of making, and methods of using the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160058713A1 (en) * 2014-09-02 2016-03-03 Bhupinder Singh Methods of making a deuterated or a non-deuterated molecule and pharmaceutical formulations for treatment
IN201711042347A (fr) * 2017-11-26 2017-12-08
US20200281871A1 (en) * 2019-03-06 2020-09-10 Renibus Therapeutics, Inc. Novel tetrahydrocurcumin compositions, methods of making, and methods of using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAN ET AL.: "Biotransformation of Curcumin Through Reduction and Glucuronidation in Mice", DRUG METABOLISM AND DISPOSITION, vol. 27, 1 April 1999 (1999-04-01), pages 486 - 494, XP001041393 *
RAVIKUMAR ET AL.: "A Toxicological Evaluation of a Standardized Hydrogenated Extract of Curcumin (CuroWhitTM", JOURNAL OF TOXICOLOGY, vol. 2018, 23 January 2018 (2018-01-23), pages 1 - 16, XP055499302, DOI: 10.1155/2018/5243617 *

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