KR-20260068101-A - Synthetic triterpene composition, method of preparation, and use thereof

Abstract

A synthetic triterpene composition, such as squalene, and a method for producing the composition by a novel chemical synthesis route are claimed. The squalene produced by the synthesis method described in the formulation of the present invention is of high purity and suitable for use in manufacturing vaccine adjuvants, antioxidant formulations, and drug delivery agents.

Inventors

• 데오르카르, 난드쿠마르
• 바훌레카르, 라만
• 소렌센, 에릭, 제이.
• 아흐텐하겐, 마르셀
• 실도르프, 토마스

Assignees

• 아반토 퍼포먼스 머티리얼즈, 엘엘씨
• 더 트러스티스 오브 프린스턴 유니버시티

Dates

Publication Date

20260513

Application Date

20240808

Priority Date

20230907

Claims (13)

1. A high-purity squalene composition comprising squalene having a purity of at least 98% by weight and less than 1 ppm of heavy metals.
2. (1) trans , trans -farnesol React with reagent to produce bis-farnesylamine Forming; and (2) Bis-farnesylamine React with -where R1 is benzyl, and R2, R3, and R4 are independently C 1-10 alkyl -, squalene A method for producing squalene, comprising forming
3. In paragraph 2, R2, R3, and R4 are methyl, method.
4. In paragraph 2, The reagents in steps (1) and (2) are p-toluene sulfonamide, cyanomethylenetributylphosphorane (CMBP), and sodium naphthalene, method.
5. In paragraph 2, In step (1), trans and trans -farnesol react with the reagent to form an intermediate A method forming, wherein X is a tosylate and the intermediate reacts with sodium naphthalene to form bis-farnesylamine, may be trityl and reacts with any acid, or may be nosyl and reacts with thioglycolic acid and a base to form bis-farnesylamine.
6. In paragraph 4, In step (1), trans , trans -farnesol reacts with p-toluenesulfonamide and (tributylphosphoranilidene)acetonitrile solution or cyanomethylenetributylphosphoran (CMBP) to produce bis-farnesyl-tosylamine A method of forming bis-farnesyl-tosylamine, and then bis-farnesyl-tosylamine reacting with sodium naphthalene to form bis-farnesylamine.
7. In paragraph 2, Synthesis is a method that occurs in the absence of a transition metal catalyst.
8. A composition comprising substantially pure squalene produced using the method of claim 2, wherein the substantially pure squalene comprises more than 98% by weight of squalene.
9. A method for preparing a vaccine formulation comprising adding substantially pure squalene of claim 8 to an oil-in-water emulsion to form a vaccine formulation.
10. A method for preparing a drug delivery formulation, comprising adding substantially pure squalene of claim 8 to an oil-in-water emulsion to form a drug delivery formulation.
11. A method for manufacturing a cosmetic formulation comprising adding substantially pure squalene of claim 8 to the cosmetic formulation.
12. A method for improving the anti-inflammatory and antioxidant properties of a lipid nanoparticle (LNP) formulation, comprising adding substantially pure squalene of claim 8 to the lipid nanoparticle formulation.
13. In paragraph 2, Method in which the reagent in step (1) is 2-nitrobenzenesulfonamide.

Description

Synthetic triterpene composition, method of preparation, and use thereof Cross-reference regarding related applications This application claims priority to U.S. Provisional Application No. 63/537,012 filed September 7, 2023 and U.S. Provisional Application No. 63/653,454 filed May 30, 2024, the contents of which are incorporated herein by reference in their entirety. The present invention generally relates to synthetic triterpene compositions, such as squalene, and a method for producing compositions by a novel chemical synthesis route. Squalene produced by the synthetic method described in the formulations of the present invention is suitable for use in manufacturing vaccine adjuvants, antioxidant formulations, and drug delivery agents. Squalene is a naturally occurring polyunsaturated hydrocarbon lipid with the molecular formula C30H50 and the chemical name 2,6,10,15,19,23-hexamethyltetracosa - 2,6,10,14,18,22-hexaene, and belongs to the triterpenes (compounds containing three terpene units). As mentioned above, squalene is mostly sourced from animals (sharks) or plants, which are considered unsustainable sources. Squalene and some of its derivatives function as precursors for various triterpene compounds. Squalene has been used primarily in the pharmaceutical industry as part of formulations (as an excipient) for designing drug delivery systems, and in the cosmetics industry. In vaccine formulations, squalene has been used as an adjuvant. In preclinical and clinical settings, squalene-based emulsions have been demonstrated to help improve immune responses to various diseases. The anti-inflammatory effects of squalene have been demonstrated in a zebrafish model. Reactive oxygen species (ROS) and free radicals are known to cause damage to proteins, lipids, and DNA. Several studies have been reported in the literature to demonstrate the antioxidant properties of squalene. The antioxidant activity of squalene was evaluated in vitro by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The activity was found to be dose-dependent, with the highest radical scavenging activity observed at a 1% squalene concentration. Therefore, squalene can also be used to enhance the anti-inflammatory and antioxidant capabilities of lipid nanoparticle (LNP) formulations. Technical processes for isolating squalene from various sources are well documented in the literature. However, processes for isolating squalene from plant or animal sources are lengthy and economically inefficient, and may not always yield squalene of the appropriate purity required, particularly for medicinal applications. It is reasonable to say that due to the increasing demand for squalene in the future, natural or biosynthetic sources of squalene will fall far short of supply. Therefore, there is a need for the development of new synthetic routes that yield high-purity squalene as well as being sustainable. The present invention addresses this problem by providing a novel and entirely synthetic route for producing squalene. U.S. Patent Application No. 16/972,291 by Fisher et al. uses farnesene, which is typically obtained as a mixture of alkene geometric isomers that can be reflected as impurities in squalene. The present invention relates to producing homogeneous squalene free of unwanted geometric and positional isomers using pure farnesol as a starting material. Pure farnesol is superior to mixtures of 'farnesene' as a starting material for the synthesis of squalene. This helps overcome the disadvantages of any mixture of alkene isomers in the starting material. In addition, the route from pure farnesol requires a relatively small number of steps. The present invention comprises a high-purity composition of synthetic squalene. The high-purity composition refers to squalene that is a transparent, colorless or pale yellow oily liquid with a purity greater than 97% and free of isomers. Typically, squalene is obtained from animal (shark liver) and plant (olive oil) sources. However, these sources are considered unsuitable when squalene is intended for medicinal use, because (1) the separation, extraction, and fractional crystallization processes used to produce squalene are cumbersome; (2) they do not yield the high-purity squalene required for medicinal use; and (3) there is a risk of pathogens and allergens. Therefore, it is important and desirable to have a viable alternative synthetic route for high-purity squalene intended particularly for medicinal use. In the present invention, a novel chemical synthesis process for producing this high-purity composition is disclosed. In certain embodiments, the present invention provides a novel method for synthesizing high-purity squalene by chemical reaction. In certain embodiments, the key starting material is bis-farnesylamine. Certain embodiments of this method further involve converting trans-transfarnesol to bis-farnesylamine. Other embodiments of this synthesis route further involve converting bis-farnesylamin