WO2022250641A1 - Formulations prepared from allium sa tivuml. extract and their effect on osteoarthritis - Google Patents
Formulations prepared from allium sa tivuml. extract and their effect on osteoarthritis Download PDFInfo
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- WO2022250641A1 WO2022250641A1 PCT/TR2022/050495 TR2022050495W WO2022250641A1 WO 2022250641 A1 WO2022250641 A1 WO 2022250641A1 TR 2022050495 W TR2022050495 W TR 2022050495W WO 2022250641 A1 WO2022250641 A1 WO 2022250641A1
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- WIPO (PCT)
- Prior art keywords
- microemulsion
- methanol extract
- allium sativum
- formulation
- allicin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 59
- 238000009472 formulation Methods 0.000 title claims abstract description 58
- 239000000284 extract Substances 0.000 title description 9
- 230000002875 effect on osteoarthritis Effects 0.000 title description 3
- 241000234282 Allium Species 0.000 title description 2
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 69
- 240000002234 Allium sativum Species 0.000 claims abstract description 44
- 239000000401 methanolic extract Substances 0.000 claims abstract description 42
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 claims abstract description 19
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000010081 allicin Nutrition 0.000 claims abstract description 19
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 18
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000004094 surface-active agent Substances 0.000 claims description 18
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 11
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 10
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 9
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000013641 positive control Substances 0.000 description 9
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- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 5
- 102000003952 Caspase 3 Human genes 0.000 description 5
- 108090000397 Caspase 3 Proteins 0.000 description 5
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- 241000196324 Embryophyta Species 0.000 description 4
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- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 238000001727 in vivo Methods 0.000 description 3
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- 229920002125 Sokalan® Polymers 0.000 description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
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- 210000004417 patella Anatomy 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 241000121157 Achyranthes japonica Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000025674 Anterior Cruciate Ligament injury Diseases 0.000 description 1
- 101000573882 Coccidioides posadasii (strain C735) Neutral protease 2 homolog MEP3 Proteins 0.000 description 1
- 239000006000 Garlic extract Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 241001135917 Vitellaria paradoxa Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 1
- 210000001264 anterior cruciate ligament Anatomy 0.000 description 1
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- 229960001631 carbomer Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
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- 235000020706 garlic extract Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
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- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 210000000281 joint capsule Anatomy 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 210000003314 quadriceps muscle Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940057910 shea butter Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
Definitions
- the invention relates to microemulsion formulations designed with methanol extract containing at least 0.45% allicin, which is obtained from Allium sativum L. garlic, and the effects of said formulations on osteoarthritis.
- Osteoarthritis is a disease with a chronic course whose incidence increases with advanced age and causes damage especially to load-bearing joints. Many studies are currently being conducted to develop cartilage-protective agents that will slow down cartilage destruction and delay the application of total joint replacement, which is the last step in the treatment of primary osteoarthritis (OA), a disease characterized by progressive degeneration of articular cartilage. The development of agents that can restore the balance in this disease, in which the balance between production and destruction in cartilage tissue is disrupted, requires high cost and advanced technology.
- OA primary osteoarthritis
- the aim of the treatment of OA which develops due to different etiopathologic causes and is a progressive disease is to reduce pain, increase the range of motion of the joint and relieve functional impairment.
- this disease in which different conservative methods are used in the treatment, it is aimed to delay the need for surgical intervention and to slow down the cartilage destruction that starts from the early stages of osteoarthritis but does not give clinical findings.
- Turkey is one of the richest countries in the world in terms of plant diversity and plants are frequently used in traditional treatment.
- KR102044659 Another application numbered KR102044659 (Bl), discloses the use of fermented Achyranthes japonica Nakai plant extract for use in the treatment of osteoarthritis.
- microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin and have determined the effects of these formulations in the treatment of osteoarthritis.
- the present invention relates to microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin.
- the present invention relates to the microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin for use in the treatment of osteoarthritis or relief of symptoms thereof.
- FIG. 1 In this graph, the numbers of Caspase-3 positive cells in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) are shown in percentages (%).
- FIG. 2 In this graph, the numbers of Metalloproteinase-3 (MMP-3) positive cells in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) are shown in percentages (%).
- MMP-3 Metalloproteinase-3
- Figure 3 In this graph, statistical evaluation of safranine-o staining intensity in articular cartilage in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) is shown.
- FIG. 4 In this graph, evaluation of histopathologic changes in cartilage using the Mankin scoring system in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) is shown.
- the microemulsion formulation according to the invention is characterized by consisting of Allium sativum L. methanol extract containing at least 0.45% allicin and a microemulsion system comprising at least one oil phase - two or more surfactants - two or more co- surfactants at least one solvent.
- Allium sativum L. methanol extract containing at least 0.45% allicin comprised in the microemulsion formulation according to the invention is provided in an amount of 3% to 10%, preferably in an amount of 4% to 8%, particularly preferably in an amount of 5% by weight.
- the oil phase in the microemulsion system comprised in the microemulsion formulation according to the invention is provided in a ratio of 40-50%, preferably in a ratio of 42% to 48%, particularly preferably in a ratio of 44% by weight.
- the surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention are provided in total in a ratio of 40% to 50%, preferably in a ratio of 42% to 48%, particularly preferably in a ratio of 45% by weight.
- the co-surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention are provided in a ratio of 0.5% to 15%, preferably in a ratio of 1% to 10%.
- the solvent in the microemulsion system comprised in the microemulsion formulation according to the invention is provided in total in a ratio of 1% to 15%, preferably in a ratio of 1% to 10%.
- the oil phase in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from a group consisting of isopropyl myristate, shea butter, cocoa butter, lanolin, and vegetable oils. Isopropyl myristate (TPM) is preferably used as the oil phase.
- At least two surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from sodium stearate, poloxamers, sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60) and polysorbate 80 (Tween 80).
- Tween 60 and Span 80 are used as the surfactant.
- At least two co-surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from polyacrylic acid (carbomer), ethanol, propanol, isopropanol, butanol, propylene glycol, polyethylene glycol, sodium alginate, agar gel, gelatin, carrageenan.
- polyacrylic acid carboxymer
- propanol isopropanol
- butanol propylene glycol
- polyethylene glycol sodium alginate
- agar gel agar gel
- gelatin carrageenan
- PEG polyethylene glycol
- PEG polyethylene glycol
- ethanol particularly preferably PEG-400
- ethanol are used as co surfactant.
- the solvent in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from water, ethanol, propanol, isopropanol, butanol, propylene glycol, acetonitrile, ethyl ether, ethyl acetate.
- water is used as the solvent.
- a preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
- Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system consists of; isopropyl myristate, tween 60, span 80, PEG-400, water, and ethanol, and in that it comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
- Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
- Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
- Another object of the invention is the formulations according to the invention comprising Allium sativum L. methanol extract containing at least 0.45% allicin for use in the treatment of osteoarthritis or relief of symptoms thereof.
- A. sativum garlic in powder form is kept in 250 mL methanol for 1 hour. Then the solvent was separated and removed in a low-pressure dryer. At the end of the process, approximately 3 g A. sativum methanol extract was obtained.
- IPM isopropyl myristate
- Tween 60 and Span 80 surfactants
- PEG400 and ethanol (EtOH) as co-surfactants.
- the ratio of PEG400:EtOH is 1:8.
- the ratio of surfactant: co-surfactant used in the formulation can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 by weight (w/w).
- Example 3 Preparation of Microemulsion Formulation comprising Allium sativum L. Methanol Extract
- microemulsion formulation was prepared to comprise 5% by weight (w/w) Allium sativum L. methanol extract and microemulsion system.
- the patella was relocated, the joint was washed and the tissues were sutured.
- Result and Evaluation The experiments conducted show that the microemulsion formulation containing Allium sativum L. according to the invention has a lower number of Caspase-3 and MMP-3 positive cells compared to the osteoarthritis control sample ( Figure 1 and Figure 2). This indicates that the microemulsion formulation gives a positive result in the treatment or relief of symptoms of osteoarthritis. Also, in the in-vivo test conducted, it is shown that when compared to the positive control substance used in the market for the treatment of osteoarthritis and containing hyaluronic acid, the microemulsion formulation containing Allium sativum L.
- methanol extract shows the same effect as the positive control sample ( Figure 1 and Figure 2).
- the formulations comprising Allium sativum L. methanol extract reduce the number of Caspase-3 and MMP-3 positive cells almost to the number of Caspase-3 and MMP-3 positive cells in healthy tissue ( Figure 1 and Figure 2).
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Abstract
The invention relates to the microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient and the effects of said formulations on osteoarthritis.
Description
FORMULATIONS PREPARED FROM ALLIUM SA TIVUM L. EXTRACT AND THEIR EFFECT ON OSTEOARTHRITIS
Field of the Invention
The invention relates to microemulsion formulations designed with methanol extract containing at least 0.45% allicin, which is obtained from Allium sativum L. garlic, and the effects of said formulations on osteoarthritis.
State of the Art
Osteoarthritis is a disease with a chronic course whose incidence increases with advanced age and causes damage especially to load-bearing joints. Many studies are currently being conducted to develop cartilage-protective agents that will slow down cartilage destruction and delay the application of total joint replacement, which is the last step in the treatment of primary osteoarthritis (OA), a disease characterized by progressive degeneration of articular cartilage. The development of agents that can restore the balance in this disease, in which the balance between production and destruction in cartilage tissue is disrupted, requires high cost and advanced technology.
The aim of the treatment of OA which develops due to different etiopathologic causes and is a progressive disease is to reduce pain, increase the range of motion of the joint and relieve functional impairment. In this disease, in which different conservative methods are used in the treatment, it is aimed to delay the need for surgical intervention and to slow down the cartilage destruction that starts from the early stages of osteoarthritis but does not give clinical findings. The fact that plant-based medicines are frequently used in many fields today directs studies towards natural products that are a source of biodiversity. Turkey is one of the richest countries in the world in terms of plant diversity and plants are frequently used in traditional treatment.
For example, application numbered US2020215143 (Al) discloses the use of cherry extract
and cherry seed oil in the treatment of osteoarthritis symptoms.
Another application numbered KR102044659 (Bl), discloses the use of fermented Achyranthes japonica Nakai plant extract for use in the treatment of osteoarthritis.
However, the fact that studies on extracts obtained from natural components are usually conducted on the extracts collected from nature or non-standardized extracts significantly weakens the reproducibility of the resulting product.
Given the state of the art, there is a need for drug-quality pharmaceutical formulations that are reliable, derived from pharmacopeia-quality plant sources and standardized.
The inventors conducted studies in this respect have developed microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin and have determined the effects of these formulations in the treatment of osteoarthritis.
Summary of the Invention
In one aspect, the present invention relates to microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin.
In another aspect, the present invention relates to the microemulsion formulations comprising Allium sativum L. methanol extract containing at least 0.45% allicin for use in the treatment of osteoarthritis or relief of symptoms thereof.
Description of the Figures
Figure 1: In this graph, the numbers of Caspase-3 positive cells in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) are shown in percentages (%).
Figure 2: In this graph, the numbers of Metalloproteinase-3 (MMP-3) positive cells in the
cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) are shown in percentages (%).
Figure 3: In this graph, statistical evaluation of safranine-o staining intensity in articular cartilage in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) is shown.
Figure 4: In this graph, evaluation of histopathologic changes in cartilage using the Mankin scoring system in the cases of healthy control (101), osteoarthritic control (102), positive control (103) administration and Allium sativum L. Methanol extract microemulsion formulation administration (104) is shown.
The descriptions of the abbreviations in the figures are as follows;
A: Amount of caspase-3 positive cells (%)
B: Amount of MMP-3 positive cells (%)
C: Intensity of Safranine-0 Staining
D: Mankin Scoring
101: Healthy control
102: Osteoarthritic control
103: Positive control
104: Allium sativum L. methanol extract
Detailed Description of the Invention
In a preferred embodiment of the invention, the microemulsion formulation according to the invention is characterized by consisting of Allium sativum L. methanol extract containing at least 0.45% allicin and a microemulsion system comprising at least one oil phase - two or more surfactants
- two or more co- surfactants at least one solvent.
Allium sativum L. methanol extract containing at least 0.45% allicin comprised in the microemulsion formulation according to the invention is provided in an amount of 3% to 10%, preferably in an amount of 4% to 8%, particularly preferably in an amount of 5% by weight.
The oil phase in the microemulsion system comprised in the microemulsion formulation according to the invention is provided in a ratio of 40-50%, preferably in a ratio of 42% to 48%, particularly preferably in a ratio of 44% by weight.
The surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention are provided in total in a ratio of 40% to 50%, preferably in a ratio of 42% to 48%, particularly preferably in a ratio of 45% by weight.
The co-surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention are provided in a ratio of 0.5% to 15%, preferably in a ratio of 1% to 10%.
The solvent in the microemulsion system comprised in the microemulsion formulation according to the invention is provided in total in a ratio of 1% to 15%, preferably in a ratio of 1% to 10%. The oil phase in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from a group consisting of isopropyl myristate, shea butter, cocoa butter, lanolin, and vegetable oils. Isopropyl myristate (TPM) is preferably used as the oil phase. At least two surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from sodium stearate, poloxamers, sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), polysorbate 20 (Tween 20), polysorbate 40 (Tween 40),
polysorbate 60 (Tween 60) and polysorbate 80 (Tween 80). In a preferred embodiment of the invention, Tween 60 and Span 80 are used as the surfactant.
At least two co-surfactants in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from polyacrylic acid (carbomer), ethanol, propanol, isopropanol, butanol, propylene glycol, polyethylene glycol, sodium alginate, agar gel, gelatin, carrageenan. In a preferred embodiment of the invention, polyethylene glycol (PEG), particularly preferably PEG-400, and ethanol are used as co surfactant.
The solvent in the microemulsion system comprised in the microemulsion formulation according to the invention can be selected from water, ethanol, propanol, isopropanol, butanol, propylene glycol, acetonitrile, ethyl ether, ethyl acetate. In a preferred embodiment of the invention, water is used as the solvent.
Accordingly, a preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
40-50% at least one oil phase 40-50% two or more surfactants 0.5-15% two or more co-surfactants 1-15% solvent and in that Allium sativum L. methanol extract contains at least 0.45% allicin.
Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system consists of; isopropyl myristate, tween 60, span 80, PEG-400, water, and ethanol, and in that it
comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
40-50% isopropyl myristate 40-50% tween 60 and span 80
- 0.5-15% PEG-400 and Ethanol
1-15% water, and in that it comprises 3%- 10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
Another preferred embodiment of the invention is directed to a microemulsion formulation comprising Allium sativum L. methanol extract, said formulation comprises a microemulsion system and Allium sativum L. methanol extract, and it is characterized in that the microemulsion system comprises;
- 40-50% isopropyl myristate
- 5-10% tween 60 and 30-40% span 80
- 0.5-2% PEG-400 and 5-10% ethanol
- 1-15% water, and in that it comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient.
Another object of the invention is the formulations according to the invention comprising Allium sativum L. methanol extract containing at least 0.45% allicin for use in the treatment of osteoarthritis or relief of symptoms thereof.
In this study, garlic extract formulated as a microemulsion formulation was studied in vitro and in vivo in animals for its effect on osteoarthritis. In this regard, the extract which was placed in both a natural agent and a carrier system showed good results both macroscopically and histologically against osteoarthritis.
EXAMPLES:
Example 1: Preparation of Allium sativum L. Methanol Extract
50 grams of A. sativum garlic in powder form is kept in 250 mL methanol for 1 hour. Then the solvent was separated and removed in a low-pressure dryer. At the end of the process, approximately 3 g A. sativum methanol extract was obtained.
Example 2: Preparation of Microemulsion System
In the microemulsion system, isopropyl myristate (IPM) was used as an oil, Tween 60 and Span 80 as surfactants and PEG400 and ethanol (EtOH) as co-surfactants. The ratio of PEG400:EtOH is 1:8. The ratio of surfactant: co-surfactant used in the formulation can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 by weight (w/w).
Example 3: Preparation of Microemulsion Formulation comprising Allium sativum L. Methanol Extract
The microemulsion formulation was prepared to comprise 5% by weight (w/w) Allium sativum L. methanol extract and microemulsion system.
Example 4: In Vivo Experiments
Method: Animals were anesthetized by injecting them ketamine (80 mg/kg, i.p.) - xylazine (10 mg/kg, i.p.). Osteoarthritis was induced with anterior cruciate ligament injury through an approach of lateral parapatellar skin incision on the right knees of animals and medial meniscectomy injury. In the surgical technique; after skin incision of the right knee, the joint capsule was reached by crossing the vastus lateralis muscle, the patella laterale was luxated, and the femoral condyle and tibial plateau were exposed. Firstly, the anterior cruciate ligament was amputated and then a medial meniscectomy was performed. The patella was relocated, the joint was washed and the tissues were sutured.
Result and Evaluation: The experiments conducted show that the microemulsion formulation containing Allium sativum L. according to the invention has a lower number of Caspase-3 and MMP-3 positive cells compared to the osteoarthritis control sample (Figure 1 and Figure 2). This indicates that the microemulsion formulation gives a positive result in the treatment or relief of symptoms of osteoarthritis. Also, in the in-vivo test conducted, it is shown that when compared to the positive control substance used in the market for the treatment of osteoarthritis and containing hyaluronic acid, the microemulsion formulation containing Allium sativum L. methanol extract shows the same effect as the positive control sample (Figure 1 and Figure 2). The formulations comprising Allium sativum L. methanol extract reduce the number of Caspase-3 and MMP-3 positive cells almost to the number of Caspase-3 and MMP-3 positive cells in healthy tissue (Figure 1 and Figure 2).
Also, in the histochemical studies conducted with safranine-o, it is shown that the microemulsion comprising the inventive extract gives better results than the market product used as a positive control (Figure 3). After the administration of the microemulsion comprising the inventive extract, it is shown that the degeneration on the articular cartilage surface of the specimens decreased and the number of chondrocytes increased. Similarly, when the histopathological changes between the samples were evaluated using the Mankin scoring system, it is shown that the microemulsion formulation according to the invention is significantly different and shows better efficacy compared to the market product used as a positive control (Figure 4).
Claims
1. Microemulsion formulations comprising Allium sativum L. methanol extract comprising at least 0.45% allicin.
2. A microemulsion formulation according to claim 1, wherein it comprises Allium sativum L. methanol extract comprising at least 0.45% allicin, and a microemulsion system comprising;
• at least one oil phase
• two or more surfactants
• two or more co- surfactants
• at least one solvent.
3. A microemulsion formulation according to claim 1 or 2, wherein Allium sativum L. methanol extract comprising at least 0.45% allicin is 3% to 10% by weight.
4. A microemulsion formulation according to any one of claims 1-3, wherein said formulation consists of the microemulsion system and Allium sativum L. methanol extract, and the microemulsion system comprises;
• 40-50% at least one oil phase
• 40-50% two or more surfactants
• 0.5-15% two or more co-surfactants
• 1-15% solvent.
5. A microemulsion formulation according to any one of claims 1-4, wherein said formulation consists of the microemulsion system and Allium sativum L. methanol extract, and the microemulsion system consists of isopropyl myristate, tween 60, span 80, PEG-400, water and ethanol and comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
6. A microemulsion formulation according to any one of claims 1-5, wherein said formulation consists of the microemulsion system and Allium sativum L. methanol
extract, and the microemulsion system comprises;
• 40-50% isopropyl myristate
• 40-50% tween 60 and span 80
• 0.5-15% PEG-400 and Ethanol
• 1-15% water, and it comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
7. A microemulsion formulation according to any one of claims 5 and 6, wherein said formulation consists of the microemulsion system and Allium sativum L. methanol extract, and the microemulsion system comprises;
• 40-50% isopropyl myristate
• 5-10% tween 60 and 30-40% span 80
• 0.5-2% PEG-400 and 5-10% ethanol
• 1-15% water, and
• it comprises 3-10% Allium sativum L. methanol extract containing at least 0.45% allicin as the active ingredient in the formulation.
8. The microemulsion formulations according to any one of claims 1-7, comprising
Allium sativum L. methanol extract containing at least 0.45% allicin for use in the treatment of osteoarthritis or relief of symptoms thereof.
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| Application Number | Priority Date | Filing Date | Title |
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| TR2021008852 | 2021-05-28 | ||
| TRTR2021/008852 | 2021-05-28 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11346712A (en) * | 1998-06-11 | 1999-12-21 | Takehiko Kugo | Sperm enhancing food and its production |
| CN1267090C (en) * | 2004-09-09 | 2006-08-02 | 华中科技大学 | Garlicin injection emulsion and its preparing method |
-
2022
- 2022-05-27 WO PCT/TR2022/050495 patent/WO2022250641A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11346712A (en) * | 1998-06-11 | 1999-12-21 | Takehiko Kugo | Sperm enhancing food and its production |
| CN1267090C (en) * | 2004-09-09 | 2006-08-02 | 华中科技大学 | Garlicin injection emulsion and its preparing method |
Non-Patent Citations (2)
| Title |
|---|
| QIAN Y-Q ET AL: "Downregulating PI3K/Akt/NF-[kappa]B signaling with allicin for ameliorating the progression of osteoarthritis: in vitro and vivo studies", FOOD AND FUNCTION, vol. 9, no. 9, 1 September 2018 (2018-09-01), pages 4865 - 4875, XP002807498 * |
| WILLIAMS FRANCES MK ET AL: "Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action", BMC MUSCULOSKELETAL DISORDERS, BIOMED CENTRAL, LONDON, GB, vol. 11, no. 1, 8 December 2010 (2010-12-08), pages 280, XP021087728, ISSN: 1471-2474, DOI: 10.1186/1471-2474-11-280 * |
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