WO2020160619A1 - A glycation reducing composition and method of use thereof - Google Patents

A glycation reducing composition and method of use thereof Download PDF

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Publication number
WO2020160619A1
WO2020160619A1 PCT/AU2020/050094 AU2020050094W WO2020160619A1 WO 2020160619 A1 WO2020160619 A1 WO 2020160619A1 AU 2020050094 W AU2020050094 W AU 2020050094W WO 2020160619 A1 WO2020160619 A1 WO 2020160619A1
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Prior art keywords
composition
vitamin
formulated
amount
present
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PCT/AU2020/050094
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French (fr)
Inventor
Raymond Denis PALMER
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Helium 3 Biotech Pty Ltd
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Priority claimed from AU2019900346A external-priority patent/AU2019900346A0/en
Application filed by Helium 3 Biotech Pty Ltd filed Critical Helium 3 Biotech Pty Ltd
Publication of WO2020160619A1 publication Critical patent/WO2020160619A1/en

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    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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Definitions

  • the present disclosure relates to a glycation reducing composition and a method of use thereof.
  • advanced glycation endproducts include reactive products that lead to cell damage, which is thought to be associated with age-related dysfunction of tissues and/or organs. Additionally, advanced glycation endproducts are also potentially associated with the development of morbidities within the ageing populations world-wide.
  • compositions that will reduce the concentration of advanced glycation endproducts in a cell when administered in a therapeutically effective dose to a subject in need thereof and a method of using such a composition.
  • Advanced glycation endproducts accumulate in multicellular organisms, such as humans, with the passage of time. Accumulation of advanced glycation endproducts is associated with deleterious effects that are typically termed“ageing”. These deleterious effects, including a deterioration of cell function, lead to an increase of ageing-related pathologies and inevitably accelerate mortality. A reduction in the concentration of advanced glycation endproducts may delay onset of ageing-related negative effects on the health of an individual and contribute to economic benefits insofar as the costs associated with an increase in the ageing populations world-wide may be diminished.
  • the present disclosure in one aspect sets forth a composition including a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E, the composition formulated to reduce the concentration of an advanced glycation endproduct in a cell of a subject.
  • the present disclosure in another aspect sets forth a method of reducing the concentration of an advanced glycation endproduct in a cell of a subject, the method including administering to a subject in need thereof a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
  • the present disclosure is directed to a composition that reduces the concentration of advanced glycation endproducts in one or more cell of a multicellular organism, such as humans, that may arise with the passage of time.
  • the present disclosure also relates to a method of use of the composition.
  • the term“advanced glycation endproducts” should be understood for the purposes herein to define that those compounds that are formed when a protein or a lipid combine with a carbohydrate in one or more cell of an organism.
  • composition formulated to reduce the concentration of an advanced glycation endproduct in a cell of a subject.
  • the composition including a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
  • a therapeutically effective dose refers to an amount of a composition administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E is present in an amount of 20 - 150 mg.
  • b-alanine is present in an amount of 40 mg.
  • aminoguanidine is present in an amount of 10 mg.
  • carcinine is present in an amount of 50 mg.
  • carnosine is present in an amount of 50 mg.
  • pyridoxamine is present in an amount of 50 mg.
  • quercetin is present in an amount of 50 mg.
  • vitamin E is present in an amount of 40 mg.
  • the vitamin E is a-tocopherol. In another preferred embodiment, the vitamin E is b-tocopherol. In another preferred embodiment, the vitamin E is g-tocopherol. In another preferred embodiment, the vitamin E is d-tocopherol. In another preferred embodiment, the vitamin E is a- tocotrienol. In another preferred embodiment, the vitamin E is b- tocotrienol. In another preferred embodiment, the vitamin E is y- tocotrienol. In another preferred embodiment, the vitamin E is d- tocotrienol.
  • composition herein disclosed may be delivered to a subject in need thereof by any one of several routes.
  • the composition may be delivered via buccal, infusion (e.g., a bolus infusion), inhalation, intracranial injection, enteral, intradermal, intramuscular, intranasal, intraocular, intraperitoneally, intravenously, orally, rectal, rectal, subcutaneously, sublingual, topically, transdermal, vaginal, or any combination thereof.
  • the composition may be formulated for enteral administration.
  • composition herein disclosed may be formulated for delayed release (also termed sustained or slow release, timed release, delayed release, or controlled release).
  • delayed release also termed sustained or slow release, timed release, delayed release, or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site in a delayed release manner.
  • Delayed-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling barrier.
  • a particularly preferred embodiment of the composition may be formulated in an enteric coating layer.
  • the enteric coating layer may include one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates.
  • the composition disclosed herein may be formulated with a buffering agent to protect the compound from low pH of the gastric environment and/or an enteric coating.
  • composition when administer orally, buccally, or sublingually, may be formulated with a flavouring agent, e.g., in a liquid, solid or semi-solid formulation.
  • a flavouring agent e.g., in a liquid, solid or semi-solid formulation.
  • Preferred embodiments may include one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment.
  • Preferred embodiments will include at least one excipient that is biocompatible and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the excipient facilitates absorption. In yet a further particularly preferred embodiment, the excipient enhances solubility.
  • the composition may be a tablet formulation.
  • the composition may be a powder formulation.
  • the powder formulation may be in a capsule.
  • the composition may be a liquid formulation.
  • the composition may be formulated for parenteral administration.
  • the composition may be formulated for subcutaneous administration.
  • the composition may be formulated for intramuscular administration.
  • the composition may be formulated for intravenous administration.
  • the composition may be formulated for intradermal administration.
  • the composition may be formulated for transdermal administration.
  • composition disclosed herein will be administered for a sufficient amount of time to selectively purge senescent cells from one or more tissue in a subject, wherein the purging of such cells does not lead to a cancer.
  • purging of senescent cells may ameliorate at least one symptom associated with a number of pathologies.
  • Such pathologies may include age-related loss of pulmonary function, Alzheimer's disease, angina, aortic aneurysm, arrhythmia, arteriosclerosis, asthma, atherosclerosis, atopic dermatitis, brain aneurysm, bronchiectasis, cardiac diastolic dysfunction, a cancer, cardiac fibrosis, cardiac stress resistance, cardiomyopathy, carotid artery disease, cataracts, chronic obstructive pulmonary disease, chronic renal failure, congestive heart failure, coronary artery disease, coronary thrombosis, cutaneous lupus, cutaneous lymphomas, cystic fibrosis, dementia, diabetes, diabetic ulcer, diseases and disorders related to photosensitivity or photoaging, dysesthesia, eczema, eczematous eruptions, emphysema, endocarditis, eosinophilic dermatosis, fibrohistocytic proliferations of skin, frailty, glaucoma,
  • a method of reducing the concentration of an advanced glycation endproduct in a cell of a subject including administering to a subject in need thereof a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
  • the method may include a treatment course no longer than (a) one month, or (b) no longer than two months, or (c) no longer than three months.
  • each treatment course is no longer than (a) five days, (b) seven days, (c) ten days, (d) fourteen days, or (e) twenty-one days.
  • the composition is administered every second day or every third day of each treatment course.
  • the composition is administered once daily during each treatment course.
  • the composition is administered twice daily during each treatment course. Suitable interval periods between treatments will be known to a person skilled in the art.
  • the subject may be a multicellular animal.
  • the multicellular animal is a human.

Abstract

As animals, including humans, age, a number of complex reactions including Amadori reactions, Maillard reactions, and Schiff-base reactions lead to an increase in the concentration of advanced glycation endproducts in the cells. Such advanced glycation endproducts include reactive products that lead to cell damage, which is thought to be associated with age-related dysfunction of tissues and/or organs. Additionally, advanced glycation endproducts are also potentially associated with the development of morbidities within the ageing populations world-wide. Given the afore- mentioned dysfunction and morbidities within the ageing populations around the world, a need exists for a composition that will reduce the concentration of advanced glycation endproducts in a cell when administered in a therapeutically effective dose to a subject in need thereof and a method of using such a composition. The present disclosure relates to a glycation reducing composition and a method of use thereof.

Description

A GLYCATION REDUCING COMPOSITION AND METHOD OF USE THEREOF
Field of Invention
The present disclosure relates to a glycation reducing composition and a method of use thereof.
Background of Invention
As animals, including humans, age, a number of complex reactions including Amadori reactions, Maillard reactions, and Schiff-base reactions lead to an increase in the concentration of advanced glycation endproducts in the cells. Such advanced glycation endproducts include reactive products that lead to cell damage, which is thought to be associated with age-related dysfunction of tissues and/or organs. Additionally, advanced glycation endproducts are also potentially associated with the development of morbidities within the ageing populations world-wide.
Given the afore-mentioned dysfunction and morbidities within the ageing populations around the world, a need exists for a composition that will reduce the concentration of advanced glycation endproducts in a cell when administered in a therapeutically effective dose to a subject in need thereof and a method of using such a composition.
Summary
Advanced glycation endproducts accumulate in multicellular organisms, such as humans, with the passage of time. Accumulation of advanced glycation endproducts is associated with deleterious effects that are typically termed“ageing”. These deleterious effects, including a deterioration of cell function, lead to an increase of ageing-related pathologies and inevitably accelerate mortality. A reduction in the concentration of advanced glycation endproducts may delay onset of ageing-related negative effects on the health of an individual and contribute to economic benefits insofar as the costs associated with an increase in the ageing populations world-wide may be diminished.
The present disclosure in one aspect sets forth a composition including a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E, the composition formulated to reduce the concentration of an advanced glycation endproduct in a cell of a subject.
The present disclosure in another aspect sets forth a method of reducing the concentration of an advanced glycation endproduct in a cell of a subject, the method including administering to a subject in need thereof a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
The reference to any prior art in this specification is not and should not be taken as an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia or in any other country.
It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed, unless otherwise stated. In the present specification and claims, the word“comprising” and its derivatives including“comprises” and“comprise” include each of the stated integers but does not exclude the inclusion of one or more integers. The claims as filed with this application are hereby incorporated by reference in the description.
Detailed Description
The present disclosure is directed to a composition that reduces the concentration of advanced glycation endproducts in one or more cell of a multicellular organism, such as humans, that may arise with the passage of time. The present disclosure also relates to a method of use of the composition. The term“advanced glycation endproducts” should be understood for the purposes herein to define that those compounds that are formed when a protein or a lipid combine with a carbohydrate in one or more cell of an organism.
In a preferred embodiment, there is provided a composition formulated to reduce the concentration of an advanced glycation endproduct in a cell of a subject. The composition including a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
Without wishing to be bound by theory, a therapeutically effective dose refers to an amount of a composition administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
It will be appreciated that the amount of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E will depend on a preferred route of administration, the rate and expected duration of release of the composition, and the nature of the condition, disease or disorder to be treated or prevented. In a preferred embodiment, each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E is present in an amount of 20 - 150 mg. In a further preferred embodiment, b-alanine is present in an amount of 40 mg. In yet a further preferred embodiment, aminoguanidine is present in an amount of 10 mg. In yet a further preferred embodiment, carcinine is present in an amount of 50 mg. In yet a further preferred embodiment, carnosine is present in an amount of 50 mg. In yet a further preferred embodiment, pyridoxamine is present in an amount of 50 mg. In yet a further preferred embodiment, quercetin is present in an amount of 50 mg. In yet a further preferred embodiment, vitamin E is present in an amount of 40 mg.
In another preferred embodiment, the vitamin E is a-tocopherol. In another preferred embodiment, the vitamin E is b-tocopherol. In another preferred embodiment, the vitamin E is g-tocopherol. In another preferred embodiment, the vitamin E is d-tocopherol. In another preferred embodiment, the vitamin E is a- tocotrienol. In another preferred embodiment, the vitamin E is b- tocotrienol. In another preferred embodiment, the vitamin E is y- tocotrienol. In another preferred embodiment, the vitamin E is d- tocotrienol.
A person skilled in the art will appreciate that the composition herein disclosed may be delivered to a subject in need thereof by any one of several routes. By way of non-limiting example, the composition may be delivered via buccal, infusion (e.g., a bolus infusion), inhalation, intracranial injection, enteral, intradermal, intramuscular, intranasal, intraocular, intraperitoneally, intravenously, orally, rectal, rectal, subcutaneously, sublingual, topically, transdermal, vaginal, or any combination thereof. Preferably, the composition may be formulated for enteral administration.
It will be appreciated that the composition herein disclosed may be formulated for delayed release (also termed sustained or slow release, timed release, delayed release, or controlled release). Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site in a delayed release manner. Delayed-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling barrier.
A particularly preferred embodiment of the composition may be formulated in an enteric coating layer. In a preferred embodiment, the enteric coating layer may include one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates. A skilled person will appreciate that the composition disclosed herein may be formulated with a buffering agent to protect the compound from low pH of the gastric environment and/or an enteric coating. Furthermore, the composition may, when administer orally, buccally, or sublingually, may be formulated with a flavouring agent, e.g., in a liquid, solid or semi-solid formulation. Preferred embodiments may include one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment. Preferred embodiments will include at least one excipient that is biocompatible and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
In a particularly preferred embodiment, the excipient facilitates absorption. In yet a further particularly preferred embodiment, the excipient enhances solubility.
In a further preferred embodiment, the composition may be a tablet formulation.
In a further preferred embodiment, the composition may be a powder formulation. In a particularly preferred embodiment, the powder formulation may be in a capsule.
In a further preferred embodiment, the composition may be a liquid formulation. Preferably, the composition may be formulated for parenteral administration. In a particularly preferred embodiment, the composition may be formulated for subcutaneous administration. In a further particularly preferred embodiment, the composition may be formulated for intramuscular administration. In a further particularly preferred embodiment, the composition may be formulated for intravenous administration. In a further particularly preferred embodiment, the composition may be formulated for intradermal administration. In a further particularly preferred embodiment, the composition may be formulated for transdermal administration.
A skilled person will appreciate that the composition disclosed herein will be administered for a sufficient amount of time to selectively purge senescent cells from one or more tissue in a subject, wherein the purging of such cells does not lead to a cancer. A skilled person will also appreciated that such purging of senescent cells may ameliorate at least one symptom associated with a number of pathologies. Such pathologies may include age-related loss of pulmonary function, Alzheimer's disease, angina, aortic aneurysm, arrhythmia, arteriosclerosis, asthma, atherosclerosis, atopic dermatitis, brain aneurysm, bronchiectasis, cardiac diastolic dysfunction, a cancer, cardiac fibrosis, cardiac stress resistance, cardiomyopathy, carotid artery disease, cataracts, chronic obstructive pulmonary disease, chronic renal failure, congestive heart failure, coronary artery disease, coronary thrombosis, cutaneous lupus, cutaneous lymphomas, cystic fibrosis, dementia, diabetes, diabetic ulcer, diseases and disorders related to photosensitivity or photoaging, dysesthesia, eczema, eczematous eruptions, emphysema, endocarditis, eosinophilic dermatosis, fibrohistocytic proliferations of skin, frailty, glaucoma, hearing loss, herniated intervertebral disc, Huntington's disease, hypercholesterolemia, hyperlipidemia, hyperpigmentation, hypertension, hypertension, immunobullous dermatosis, impaired angiogenesis, impaired endothelium-dependent vasodilation, inflammatory bowel disease, vitamin D metabolic abnormalities, kyphosis, liver fibrosis, macular degeneration, metabolic syndrome, mild cognitive impairment, mitral valve prolapse, motor neuron dysfunction, muscle fatigue, myocardial infarction, nevi, rashes, obesity, oral mucositis, oral submucosa fibrosis, osteoarthritis, osteoarthritis, osteoporosis, osteoporosis, pathologies associated with the cardiovascular system through endothelium-derived NO production, pancreatic fibrosis, Parkinson's disease, pathologies associated with cellular calcium homeostasis, pathologies associated with perturbed TRPV5, i.e., transient receptor potential cation channel subfamily v member 5, pathologies of the skin, pemphigoid, pemphigus, peripheral vascular disease, presbyopia, pruritis, psoriasis, pulmonary fibrosis, pulmonary fibrosis, reactive neutrophilic dermatosis, renal disease, renal failure, rhytides, sarcopenia, skin conditions, skin wound healing, stroke, urticaria, and vision loss.
In another embodiment, there is provided a method of reducing the concentration of an advanced glycation endproduct in a cell of a subject. The method including administering to a subject in need thereof a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
In preferred embodiments of the method disclosed herein, the method may include a treatment course no longer than (a) one month, or (b) no longer than two months, or (c) no longer than three months. In further preferred embodiments, each treatment course is no longer than (a) five days, (b) seven days, (c) ten days, (d) fourteen days, or (e) twenty-one days. In further preferred embodiments, the composition is administered every second day or every third day of each treatment course. In another specific embodiment, the composition is administered once daily during each treatment course. In another preferred embodiment, the composition is administered twice daily during each treatment course. Suitable interval periods between treatments will be known to a person skilled in the art.
In a preferred embodiment, the subject may be a multicellular animal. Preferably, the multicellular animal is a human.
The features described with respect to one embodiment may be applied to other embodiments, or combined with, or interchanged with, the features of other embodiments without departing from the scope of the present invention.
Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

What is claimed is:
1 . A composition comprising a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E, the composition formulated to reduce the concentration of an advanced glycation endproduct in a cell of a subject.
2. The composition of claim 1 , wherein each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E is present in an amount of 20 - 150 mg.
3. The composition of either claim 1 or claim 2, wherein b-alanine is present in an amount of 40 mg.
4. The composition of either claim 1 or claim 2, wherein aminoguanidine is present in an amount of 10 mg.
5. The composition of either claim 1 or claim 2, wherein carcinine is present in an amount of 50 mg.
6. The composition of either claim 1 or claim 2, wherein carnosine is present in an amount of 50 mg.
7. The composition of either claim 1 or claim 2, wherein pyridoxamine is present in an amount of 50 mg.
8. The composition of either claim 1 or claim 2, wherein quercetin is present in an amount of 50 mg.
9. The composition of either claim 1 or claim 2, wherein vitamin E is present in an amount of 40 mg.
10. The composition of any one of claims 1 to 9, wherein the vitamin E is a- tocopherol.
1 1 . The composition of any one of claims 1 to 9, wherein the vitamin E is b- tocopherol.
12. The composition of any one of claims 1 to 9, wherein the vitamin E is y- tocopherol.
13. The composition of any one of claims 1 to 9, wherein the vitamin E is d- tocopherol.
14. The composition of any one of claims 1 to 9, wherein the vitamin E is a- tocotrienol.
15. The composition of any one of claims 1 to 9, wherein the vitamin E is b- tocotrienol.
16. The composition of any one of claims 1 to 9, wherein the vitamin E is y- tocotrienol.
17. The composition of any one of claims 1 to 9, wherein the vitamin E is d- tocotrienol.
18. The composition of any one of claims 1 to 17, formulated for enteral administration.
19. The composition of claim 18, formulated for delayed release.
20. The composition of claim 19, formulated in an enteric coating layer.
21 . The composition of claim 20, wherein the enteric coating layer includes one or more of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and water-based polymer solutions or dispersions of acrylates.
22. The composition of any one of claims 1 to 21 , further comprising one or more pharmaceutically acceptable dispersant, excipient, pH-buffering compound, and pigment.
23. The composition of claim 22, wherein the excipient facilitates absorption.
24. The composition of claim 22, wherein the excipient enhances solubility.
25. The composition of any one of claims 1 to 24, wherein the composition is a tablet formulation.
26. The composition of any one of claims 1 to 25, wherein the composition is a powder formulation.
27. The composition of claim 25, wherein the powder formulation is in a capsule.
28. The composition of any one of claims 1 to 24, wherein the composition is a liquid formulation.
29. The composition of any one of claims 1 to 24 and 28, formulated for parenteral administration.
30. The composition of claim 29, formulated for subcutaneous administration.
31 . The composition of claim 29, formulated for intramuscular administration.
32. The composition of claim 29, formulated for intravenous administration.
33. The composition of claim 29, formulated for intradermal administration.
34. The composition of claim 29, formulated for transdermal administration.
35. A method of reducing the concentration of an advanced glycation endproduct in a cell of a subject, the method comprising administering to a subject in need thereof a therapeutically effective dose of each of b-alanine, aminoguanidine, carcinine, carnosine, pyridoxamine, quercetin, and vitamin E.
36. The method of claim 35, wherein the subject is a human.
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