ITMI20000360A1 - ORAL GEL CONTAINING SULFURATED AMINO ACID COMPOUNDS - Google Patents
ORAL GEL CONTAINING SULFURATED AMINO ACID COMPOUNDS Download PDFInfo
- Publication number
- ITMI20000360A1 ITMI20000360A1 IT2000MI000360A ITMI20000360A ITMI20000360A1 IT MI20000360 A1 ITMI20000360 A1 IT MI20000360A1 IT 2000MI000360 A IT2000MI000360 A IT 2000MI000360A IT MI20000360 A ITMI20000360 A IT MI20000360A IT MI20000360 A1 ITMI20000360 A1 IT MI20000360A1
- Authority
- IT
- Italy
- Prior art keywords
- gel
- gel according
- agent
- sodium
- present
- Prior art date
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- 229940041672 oral gel Drugs 0.000 title claims description 6
- -1 AMINO ACID COMPOUNDS Chemical class 0.000 title description 3
- 239000000499 gel Substances 0.000 claims description 68
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 50
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 25
- 229960003180 glutathione Drugs 0.000 claims description 22
- 108010024636 Glutathione Proteins 0.000 claims description 19
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 18
- 235000010323 ascorbic acid Nutrition 0.000 claims description 15
- 239000011668 ascorbic acid Substances 0.000 claims description 15
- 229960005070 ascorbic acid Drugs 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 11
- 239000003765 sweetening agent Substances 0.000 claims description 11
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 235000003599 food sweetener Nutrition 0.000 claims description 10
- 239000003755 preservative agent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 235000006708 antioxidants Nutrition 0.000 claims description 9
- 230000003472 neutralizing effect Effects 0.000 claims description 9
- 229960003080 taurine Drugs 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000796 flavoring agent Substances 0.000 claims description 8
- 239000003349 gelling agent Substances 0.000 claims description 8
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 7
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 7
- 230000003078 antioxidant effect Effects 0.000 claims description 7
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 7
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 7
- 239000002502 liposome Substances 0.000 claims description 7
- 229930182817 methionine Natural products 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000008139 complexing agent Substances 0.000 claims description 6
- 235000013355 food flavoring agent Nutrition 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940087168 alpha tocopherol Drugs 0.000 claims description 5
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 5
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 5
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 5
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 5
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 235000010241 potassium sorbate Nutrition 0.000 claims description 5
- 239000004302 potassium sorbate Substances 0.000 claims description 5
- 229940069338 potassium sorbate Drugs 0.000 claims description 5
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 5
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 5
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 5
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 5
- 229960000984 tocofersolan Drugs 0.000 claims description 5
- 235000004835 α-tocopherol Nutrition 0.000 claims description 5
- 239000002076 α-tocopherol Substances 0.000 claims description 5
- 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 claims description 4
- 229920001817 Agar Polymers 0.000 claims description 4
- 241000416162 Astragalus gummifer Species 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 229920001615 Tragacanth Polymers 0.000 claims description 4
- 235000010489 acacia gum Nutrition 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008272 agar Substances 0.000 claims description 4
- 235000010419 agar Nutrition 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 235000019568 aromas Nutrition 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000010981 methylcellulose Nutrition 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 235000010487 tragacanth Nutrition 0.000 claims description 4
- 239000000196 tragacanth Substances 0.000 claims description 4
- 229940116362 tragacanth Drugs 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 244000215068 Acacia senegal Species 0.000 claims description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 3
- 241000207199 Citrus Species 0.000 claims description 3
- 229920000084 Gum arabic Polymers 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000000205 acacia gum Substances 0.000 claims description 3
- 238000007664 blowing Methods 0.000 claims description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 3
- 235000020971 citrus fruits Nutrition 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
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- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
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- 210000003800 pharynx Anatomy 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229960002718 selenomethionine Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 239000010891 toxic waste Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
Description
Descrizione dell’invenzione industriale dal titolo : Description of the industrial invention entitled:
Gel orale contenente composti aminoacidici solforati» Oral gel containing sulfur amino acid compounds "
CAMPO DELL'INVENZIONE FIELD OF THE INVENTION
Un gel orale contenente glutatione facoltativamente in associazione con metionina e/o taurina consente l'assorbimento transmucosale di questi principi attivi evitandone la degradazione a livello gastrico. An oral gel containing glutathione optionally in association with methionine and / or taurine allows the transmucosal absorption of these active ingredients avoiding their degradation in the stomach.
STATO DELL’ARTE STATE OF THE ART
Il glutatione (γ-L-glutamil-L-cisteinilglicina), la metionina (acido 2-amino-4-metiltiobutanoico) e la taurina (acido 2-aminoetansolfonico) sono composti aminoacidici solforati di notevole interesse farmacologico. Glutathione (γ-L-glutamyl-L-cysteinylglycine), methionine (2-amino-4-methylthiobutanoic acid) and taurine (2-aminoethanesulfonic acid) are sulfur amino acid compounds of considerable pharmacological interest.
Il glutatione è un antiossidante e come tale è utile in tutti in quegli stati in cui si instaura un aumento di radicali liberi, molecole altamente reattive che possono provocare danni aH'organismo. L'aumento di radicali liberi si può avere in condizioni patologiche, quali le infezioni da HIV, la cirrosi epatica, o anche in condizioni più comuni quali l’eccessiva assunzione di alcolici, il digiuno o l’affatica mento fisico. Glutathione is an antioxidant and as such it is useful in all those states in which an increase of free radicals is established, highly reactive molecules that can cause damage to the organism. The increase in free radicals can occur in pathological conditions, such as HIV infections, liver cirrhosis, or even in more common conditions such as excessive alcohol intake, fasting or physical fatigue.
Anche la taurina è un antiossidante, e inoltre aiuta l'assorbimento e l'eliminazione dei grassi, e può fungere da neurotrasmettitore in alcune zone del cervello e nella retina. Taurine is also an antioxidant, and also aids in the absorption and elimination of fat, and can act as a neurotransmitter in certain areas of the brain and in the retina.
La metionina è un precursore della cistina e della creatina, entrambi amminoacidi antiossidanti, aiuta a ridurre i livelli di colesterolo nel sangue, e favorisce la rimozione dal fegato dei rifiuti tossici e la rigenerazione del tessuto epatico e dei reni. Methionine is a precursor of cystine and creatine, both antioxidant amino acids, helps reduce blood cholesterol levels, and promotes the removal of toxic waste from the liver and the regeneration of liver tissue and kidneys.
Per quanto riguarda il glutatione, nonostante la sua sopra detta importanza, esso è commercialmente disponibile in forma orale solo come componente di integratori alimentari. Per quanto riguarda le specialità medicinali che lo contengono, esse sono presenti sul mercato in numero estremamente limitato, e solo in forma di iniettabili, questo a causa del fatto che tale molecole viene per la maggioranza inattivata ad opera di peptidasi a livello gastrico. Regarding glutathione, despite its aforementioned importance, it is commercially available in oral form only as a component of food supplements. As for the medicinal specialties that contain it, they are present on the market in an extremely limited number, and only in the form of injectables, due to the fact that these molecules are for the most part inactivated by peptidases in the stomach.
La taurina viene commercializzata sia come iniettabile che in forma orale, nello specifico in capsula di gelatina dura. Questa forma di somministrazione orale viene rifiutata da alcuni soggetti per i quali la digestione della capsula risulta difficile. Taurine is marketed in both injectable and oral form, specifically in hard gelatin capsule. This oral form of administration is rejected by some individuals for whom digestion of the capsule is difficult.
Il brevetto EP 0 339 508 (a nome Altergon) descrive una compressa da sciogliersi in bocca contenente acetil-cisteina in miscela con bicarbonato sodico o potassico, un dolcificante ed un aromatizzante. Il particolare il ruolo dei sali di bicarbonato consiste nel neutralizzare il pH della N-acetil-cisteina che essendo alquanto acido può causare fenomeni irritativi nella cavità orale. Patent EP 0 339 508 (in the name of Altergon) describes a tablet to be dissolved in the mouth containing acetyl-cysteine in a mixture with sodium or potassium bicarbonate, a sweetener and a flavoring. The particular role of bicarbonate salts consists in neutralizing the pH of N-acetyl-cysteine which, being somewhat acidic, can cause irritation in the oral cavity.
Il brevetto EP 0349 797 (a nome Klinge Pharma) descrive, tra l’altro, un medicamento orale in forma di soluzione o dispersione contenente N-acetil-cisteina stabilizzata per aggiunta di acido ascorbico o di un suo sale. Questo brevetto è criticato nella successiva domanda di brevetto WO 98/47534, a nome della stessa Klinge Pharma, in quanto l’uso del solo acido ascorbico sposta il pH verso valori acidi che accrescono il fenomeno ossidativo del principio attivo e ne rendono ancora più sgradevole il sapore già di per sé scarsamente palatabile. Questa domanda di brevetto descrive, tra l’altro, medicamenti per la somministrazione orale di composti cisteinilici o dicisteinilici, in particolare N-acetil-cisteina, e/o glutatione in combinazione con un farmaco antiinfiammatorio non steroideo, e caratterizzate da una miscela di stabilizzatori costituita da almeno tre componenti del tipo acido ascorbico, un suo sale o un suo estere, uno o più tocoferoli, uno o più carotenoidi, uno o più flavonoidi o loro derivati. Il quantitativo di acido ascorbico di questa miscela è decisamente più basso rispetto alle formulazioni deH’arte nota. Patent EP 0349 797 (in the name of Klinge Pharma) describes, among other things, an oral medicament in the form of a solution or dispersion containing N-acetyl-cysteine stabilized by the addition of ascorbic acid or one of its salt. This patent is criticized in the subsequent patent application WO 98/47534, in the name of Klinge Pharma itself, as the use of ascorbic acid alone shifts the pH towards acidic values which increase the oxidative phenomenon of the active ingredient and make it even more unpleasant. the flavor itself is scarcely palatable. This patent application describes, inter alia, medicaments for the oral administration of cysteinyl or dicysteinyl compounds, in particular N-acetyl-cysteine, and / or glutathione in combination with a non-steroidal anti-inflammatory drug, and characterized by a mixture of stabilizers consisting of at least three components of the ascorbic acid type, a salt or an ester thereof, one or more tocopherols, one or more carotenoids, one or more flavonoids or their derivatives. The amount of ascorbic acid in this mixture is much lower than in the formulations of the known art.
La domanda di brevetto EP 0 839 528 descrive composizioni solubili in bocca contenenti N-acetil-cisteina e ciclodestrina unitamente ad agenti dolcificanti, aromi ed eccipienti. Patent application EP 0 839 528 describes mouth-soluble compositions containing N-acetyl-cysteine and cyclodextrin together with sweetening agents, flavorings and excipients.
La domanda di brevetto WO 99/00106 Patent application WO 99/00106
rivendica composizioni orale per ridurre i danni indotti da radicali liberi provenienti da tabacco ed inquinamento ambientale, comprendenti una combinazione di glutatione ridotto, una sorgente di selenio scelta tra seleniometionina e seleniocisteina, acido ascorbico, α-tocoferolo ed un amminoacido contenente zolfo, al fine di ridurre detto danno nella cavità orale, nella faringe e nelle prime vie respiratorie. claims oral compositions to reduce the damage induced by free radicals from tobacco and environmental pollution, including a combination of reduced glutathione, a selenium source chosen from selenomethionine and seleniocysteine, ascorbic acid, α-tocopherol and a sulfur-containing amino acid, in order to reduce said damage in the oral cavity, pharynx and upper respiratory tract.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
E' stato ora sorprendentemente trovato un tipo di formulazione transmucosale per somministrare glutatione facoltativamente in associazione con metionina e/o taurina, che garantisce l’assorbimento di questi principi attivi. A type of transmucosal formulation has now been surprisingly found for administering glutathione optionally in association with methionine and / or taurine, which guarantees the absorption of these active ingredients.
Pertanto la presente invenzione si riferisce ad un gel orale contenente glutatione facoltativamente in associazione con metionina e/o taurina e, come eccipienti, antiossidanti, agenti neutralizzanti, conservanti, solventi, aromi naturali, agenti dolcificanti e gelificanti. Therefore the present invention refers to an oral gel containing glutathione optionally in association with methionine and / or taurine and, as excipients, antioxidants, neutralizing agents, preservatives, solvents, natural flavors, sweetening and gelling agents.
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
Oggetto della presente invenzione è un gel orale per la somministrazione transmucosale di glutatione facoltativamente in associazione con metionina e/o taurina contenente, come eccipienti, almeno un antiossidante scelto dal gruppo comprendente acido ascorbico ed i suoi sali ed esteri, idrossianisolo butilato (BHA), idrossitoluene butilato (BHT), monotioglicerolo, sodio metabisolfito, sodio tiosolfato, α-tocoferolo; almeno un agente neutralizzante, almeno un agente conservante, un solvente, agenti gelificanti; aromatizzanti e/o dolcificanti. Object of the present invention is an oral gel for transmucosal administration of glutathione optionally in association with methionine and / or taurine containing, as excipients, at least one antioxidant selected from the group comprising ascorbic acid and its salts and esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), monothioglycerol, sodium metabisulfite, sodium thiosulfate, α-tocopherol; at least one neutralizing agent, at least one preservative agent, one solvent, gelling agents; flavoring and / or sweeteners.
Ai fini della presente invenzione, per glutatione si intendono sia la forma ridotta (GSH) che quella ridotta etil estere. For the purposes of the present invention, by glutathione is meant both the reduced form (GSH) and the reduced ethyl ester.
Il gel della presente invenzione viene confezionato in buste mono-dose contenente da 0,5 a 10 g di prodotto, preferibilmente 2,5 g. The gel of the present invention is packaged in single-dose bags containing from 0.5 to 10 g of product, preferably 2.5 g.
Il gel oggetto della presente invenzione contiene da 1 a 300 mg, preferibilmente 50 mg di singolo principio attivo per singola dose. The gel object of the present invention contains from 1 to 300 mg, preferably 50 mg of a single active ingredient for a single dose.
Gli antiossidanti presenti nel gel dell’invenzione vengono usati nelle seguenti quantità che sono riferite a 100 g di gel The antioxidants present in the gel of the invention are used in the following quantities which refer to 100 g of gel
Acido ascorbico 0,01-1 g , preferibilmente 0,1 g Ascorbic acid 0.01-1 g, preferably 0.1 g
Ascorbile palmitato 0,1-10 g , preferibilmente 1 g Ascorbyl palmitate 0.1-10 g, preferably 1 g
BHA 0,05-5 g , preferibilmente 0,5 g BHA 0.05-5 g, preferably 0.5 g
BHT 0,05-5 g , preferibilmente 0,5 g Monotioglicerolo 0,05-5 g , preferibilmente 0,5 g Sodio metabisolfito 0,004-0,4 g , preferibilmente 0,04 g BHT 0.05-5 g, preferably 0.5 g Monothioglycerol 0.05-5 g, preferably 0.5 g Sodium metabisulfite 0.004-0.4 g, preferably 0.04 g
Sodio tiosolfato 0,004-0,4 g , preferibilmente 0,04 g Sodium thiosulfate 0.004-0.4 g, preferably 0.04 g
α -Tocoferolo 0,12-12 g , preferibilmente 1 ,2 g α -Tocopherol 0.12-12 g, preferably 1.2 g
Gli agenti neutralizzanti utili ai fini della presente invenzione sono idrossido di sodio o di potassio in soluzione acquosa in concentrazione tale da consentire di portare il pH a valori fisiologici o comunque tali da evitare l'instaurarsi di fenomeni ossidativi a carico del principio attivo. Preferibilmente il gel della presente invenzione contiene sodio idrossido in soluzione acquosa quanto basta a dare un pH di 5,5, tenendo conto che questa quantità ovviamente varia non solo in funzione del principio attivo presente nel gel, ma anche della natura e quantità degli altri eccipienti. I conservanti nel gel dell’invenzione sono scelti dal gruppo comprendente metil-p-idrossibenzoato, propil-p-idrossibenzoato, acido ascorbico, potassio sorbato. Essi vengono usati nelle seguenti quantità che sono riferite a 100 g di gel The neutralizing agents useful for the purposes of the present invention are sodium or potassium hydroxide in aqueous solution in a concentration such as to allow the pH to be brought to physiological values or in any case such as to avoid the establishment of oxidative phenomena on the active principle. Preferably the gel of the present invention contains sodium hydroxide in aqueous solution enough to give a pH of 5.5, taking into account that this quantity obviously varies not only as a function of the active principle present in the gel, but also of the nature and quantity of the other excipients. . The preservatives in the gel of the invention are selected from the group comprising methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, ascorbic acid, potassium sorbate. They are used in the following quantities which refer to 100 g of gel
Metil-p-idrossibenzoato 0,0025-2,5 g , preferibilmente 0,08 g Propil-p-idrossibenzoato 0,0025-2,5 g , preferibilmente 0,08 g Acido ascorbico 0,2-20 g , preferibilmente 2 g Potassio sorbato 0,2-20 g , preferibilmente 2 g Solventi utili ai fini della presente invenzione sono miscele idroalcoliche farmaceuticamente accettabili. Preferibilmente, il gel della presente invenzione contiene alcool etilico 95° in quantità di da 10 a 50 g su 100 g di gel, preferibilmente 32 g. Methyl-p-hydroxybenzoate 0.0025-2.5 g, preferably 0.08 g Propyl-p-hydroxybenzoate 0.0025-2.5 g, preferably 0.08 g Ascorbic acid 0.2-20 g, preferably 2 g Potassium sorbate 0.2-20 g, preferably 2 g Solvents useful for the purposes of the present invention are pharmaceutically acceptable hydroalcoholic mixtures. Preferably, the gel of the present invention contains 95 ° ethyl alcohol in an amount of from 10 to 50 g per 100 g of gel, preferably 32 g.
Aromi utili ai fini della presente invenzione sono tutti quelli comunemente usati in tecnica farmaceutica per migliorare/mascherare il sapore sgradevole dei composti solforato. Essi sono, ad esempio, aromi agrumati, menta, cioccolato, frutti di bosco, che possono essere usati sia singolarmente che in opportuna combinazione tra loro. Preferibilmente gli aromi usati sono quelli agrumati, ancor più preferibilmente il gel contiene acido citrico anidro. Aromas useful for the purposes of the present invention are all those commonly used in the pharmaceutical technique to improve / mask the unpleasant taste of sulfur compounds. They are, for example, citrus aromas, mint, chocolate, berries, which can be used both individually and in appropriate combination with each other. Preferably the aromas used are citrus ones, even more preferably the gel contains anhydrous citric acid.
Il gel della presente invenzione contiene anche agenti dolcificanti. Essi possono essere usati in contemporanea o in alternativa agli aromatizzanti, preferibilmente in contemporanea. Esempi di agenti dolcificanti sono aspartame, saccarosio, fruttosio, maltosio, glucosio, mannitolo, sorbitolo, xilitolo, maltitolo, saccarina, maltodestrina. The gel of the present invention also contains sweetening agents. They can be used simultaneously or as an alternative to flavorings, preferably simultaneously. Examples of sweetening agents are aspartame, sucrose, fructose, maltose, glucose, mannitol, sorbitol, xylitol, maltitol, saccharin, maltodextrin.
Gli agenti gelicanti utili ai fini della presente invenzione sono uno o più di quelli in grado di fornire tempi di gelificazione brevi. Ad esempio, i gelificanti della presente invenzione possono essere scelti tra quelli qui elencati nelle quantità indicate che sono riferite a 100 g di gel The gelling agents useful for the purposes of the present invention are one or more of those capable of providing short gelling times. For example, the gelling agents of the present invention can be selected from those listed here in the quantities indicated which refer to 100 g of gel.
sodio carbossimetilcellulosa 0,2-20 g , preferibilmente 2 g metilcellulosa 0,5-50 g , preferibilmente 5 g cellulosa microcristallina 0,2-20 g , preferibilmente 2 g gomma xantano 0,3-30 g , preferibilmente 3 g gomma adragante 0,16-16 g , preferibilmente 1 ,6 g agar 0,2-20 g , preferibilmente 2 g gomma guar 0,5-15 g , preferibilmente 1 ,48 g gomma arabica 0,2-20 g , preferibilmente 2 g sodium carboxymethylcellulose 0.2-20 g, preferably 2 g methylcellulose 0.5-50 g, preferably 5 g microcrystalline cellulose 0.2-20 g, preferably 2 g xanthan gum 0.3-30 g, preferably 3 g tragacanth 0 , 16-16 g, preferably 1.6 g agar 0.2-20 g, preferably 2 g guar gum 0.5-15 g, preferably 1.48 g gum arabic 0.2-20 g, preferably 2 g
sodio alginato 0,25-25 g , preferibilmente 2,5 g polivinilpirrolidone 0,2-20 g , preferibilmente 2 g carbossivinilpolimeri 0,2-20 g , preferibilmente 2 g sodium alginate 0.25-25 g, preferably 2.5 g polyvinylpyrrolidone 0.2-20 g, preferably 2 g carboxyvinylpolymers 0.2-20 g, preferably 2 g
Il gel della presente invenzione può contenere almeno un agente complessante. Gli agenti complessanti utili ai fini della presente invenzione sono quelli comunemente usati nel ramo, ad esempio acido etilendiaminotetraacetico (EDTA) ed i suoi sali. Essi sono contenuti nel gel in quantità di da 0,05 a 5 g per 100 g di gel, preferibilmente 0,5 g. The gel of the present invention can contain at least one complexing agent. The complexing agents useful for the purposes of the present invention are those commonly used in the art, for example ethylenediaminotetraacetic acid (EDTA) and its salts. They are contained in the gel in amounts of from 0.05 to 5 g per 100 g of gel, preferably 0.5 g.
Facoltativamente, il gel dell'invenzione contiene anche altri eccipienti farmaceuticamente accettabili. Tra questi si citano, ad esempio, liposomi e betacidodestrine, in particolare liposomi ottenuti per evaporazione in fase inversa (REV) e liposomi unilamellari grandi (LUV). Optionally, the gel of the invention also contains other pharmaceutically acceptable excipients. These include, for example, liposomes and beta-acid dextrins, in particular liposomes obtained by reverse phase evaporation (REV) and large unilamellar liposomes (LUV).
Il gel della presente invenzione viene prodotto secondo tecniche comuni nel ramo, tenendo presente che tutte le operazioni vanno condotte in ambiente privo di ossigeno. Ad esempio, insufflando continuativamente azoto, il principio attivo o la miscela di principi attivi viene sciolto in acqua unitamente all'agente aromatizzante. A questa soluzione è aggiunto l'agente antiossidante o la miscela di questi. Detta miscela ha un pH di circa 2,7, per cui vi si aggiunge una soluzione di agente neutralizzante fino a portare il pH a 5,5. Una volta raggiunto questo valore, sì insuffla azoto per 5 minuti, quindi si aggiunge il dolcificante o la miscela di questi, mentre a parte viene sciolto l’agente conservante o le miscele di questi nel solvente del gel. Sempre insufflando azoto, la soluzione contenente il/i conservante/i viene aggiunta alla miscela, seguita dal gelificante o dalla miscela di questi sotto vigorosa agitazione. Dopo circa 10 minuti si ottiene un gel di colore bianco. The gel of the present invention is produced according to techniques common in the art, bearing in mind that all operations must be carried out in an oxygen-free environment. For example, by continuously blowing nitrogen, the active principle or the mixture of active principles is dissolved in water together with the flavoring agent. To this solution is added the antioxidant agent or the mixture of these. Said mixture has a pH of about 2.7, whereby a solution of neutralizing agent is added to bring the pH to 5.5. Once this value is reached, it insufflates nitrogen for 5 minutes, then the sweetener or the mixture of these is added, while the preservative agent or mixtures of these are dissolved separately in the solvent of the gel. Still blowing in nitrogen, the solution containing the preservative / s is added to the mixture, followed by the gelling agent or the mixture of these under vigorous stirring. After about 10 minutes a white gel is obtained.
Di seguito vengono forniti esempi di composizioni di gel secondo la presente invenzione. Examples of gel compositions according to the present invention are given below.
ESEMPIO 1 EXAMPLE 1
Formulazione 1 Formulation 1
E' stata preparata una mono-dose da 2,5 g del gel dell’invenzione contenente i seguenti componenti: A 2.5 g mono-dose of the gel of the invention was prepared containing the following components:
ESEMPIO 2 EXAMPLE 2
Valutazione dei livelli ematici a seguito di somministrazione del gel contenente glutatione ridotto Evaluation of blood levels following administration of the gel containing reduced glutathione
E’ stato condotto un test per valutare le modificazioni del GSH a livello dei globuli rossi a seguito di somministrazione orale di glutatione ridotto. Il protocollo sperimentale si rifà a quanto descritto da Witschii A. et al., Eur. J. Gin. Pharmacol., 43:667-669, 1992. Questo lavoro riporta che è impossibile incrementare neH’uomo il glutatione circolante a seguito di somministrazione orale di un’unica dose di 3 g di glutatione. A test was conducted to evaluate changes in GSH in red blood cells following oral administration of reduced glutathione. The experimental protocol is based on what was described by Witschii A. et al., Eur. J. Gin. Pharmacol., 43: 667-669, 1992. This work reports that it is impossible to increase circulating glutathione in humans following oral administration of a single dose of 3 g of glutathione.
Sono stati arruolati 6 soggetti sani di età attorno ai 30 anni e di peso medio di 73,6 kg per una statura media di 175 cm. Le valutazioni sono state effettuate al mattino (con inizio alle ore 8:00) essendo i soggetti liberi di assumere la loro usuale colazione. A ciascuno dei soggetti è stato applicato un catetere venoso a livello della vena anticubitale del braccio e si sono eseguiti inizialmente due prelievi a distanza di 30 minuti per determinare i valori basali di GSH negli eritrociti. Six healthy subjects aged around 30 years and with an average weight of 73.6 kg for an average stature of 175 cm were enrolled. The assessments were carried out in the morning (starting at 8:00 am) as the subjects were free to take their usual breakfast. A venous catheter was applied to each of the subjects at the level of the anticubital vein of the arm and initially two samples were taken 30 minutes apart to determine the basal values of GSH in the erythrocytes.
I soggetti hanno successivamente assunto 3 g di glutatione ridotto formulato secondo l’esempio 1. A partire dal momento della somministrazione si sono eseguiti 7 prelievi venosi ad intervalli di 30 minuti (pertanto l'ultimo prelievo è avvenuto a 3,5 ore dalla somministrazione del principio attivo). Durante il programma sperimentale i soggetti non hanno assunto né cibi né bevande. The subjects subsequently took 3 g of reduced glutathione formulated according to example 1. Starting from the moment of administration, 7 venous samples were taken at 30-minute intervals (therefore the last sample took place 3.5 hours after the administration of the active principle). During the experimental program, the subjects took neither food nor drink.
Ogni determinazione, con corrispondente valore di controllo, del GSH è stata effettuata a livello cellulare dei globuli rossi. Il sangue (5 ml) è stato raccolto in provette eparinizzate e la determinazione del GSH nei globuli rossi è stata eseguita con il metodo di Beutler (Beutler E., Gelbart T., Clin. Chim. Acta, 1986, 158(1 ):115-123). Each determination, with corresponding control value, of GSH was carried out at the cellular level of red blood cells. Blood (5 ml) was collected in heparinized tubes and the determination of GSH in red blood cells was performed by the Beutler method (Beutler E., Gelbart T., Clin. Chim. Acta, 1986, 158 (1): 115-123).
Nessuno dei soggetti ha riferito effetti indesiderati. None of the subjects reported any undesirable effects.
Nella successiva tabella vengono riportati i valori medi della concentrazione di GSH rilevata all'interno del globulo rosso durante il periodo di valutazione. The following table shows the average values of the concentration of GSH detected within the red blood cell during the evaluation period.
I risultati dimostrano che la concentrazione del GSH all'interno del globulo rosso è statisticamente invariata a confronto con il valore basale fino a 2,5 ore dalla somministrazione del gel dell'invenzione. L'innalzamento dei valori alla 3<a >ora non risulta significativo, mentre dopo le 3,5 ore la concentrazione del glutatione a livello eritrocitario rappresenta un aumento statisticamente significativo (p<0,05). L'analisi statistica è stata effettuata mediante il test t di Student (a a 2 code). The results show that the concentration of GSH inside the red blood cell is statistically unchanged compared to the basal value up to 2.5 hours after administration of the gel of the invention. The increase in values at the 3 <a> hour is not significant, while after 3.5 hours the concentration of glutathione in the erythrocyte represents a statistically significant increase (p <0.05). Statistical analysis was performed using Student's t-test (a 2-tailed).
Claims (33)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI000360A IT1317856B1 (en) | 2000-02-25 | 2000-02-25 | ORAL GEL CONTAINING SULFURATED AMINO ACID COMPOUNDS. |
| AU46470/01A AU4647001A (en) | 2000-02-25 | 2001-02-23 | Oral gel containing sulfurated amino acid compounds |
| PCT/EP2001/002060 WO2001062267A2 (en) | 2000-02-25 | 2001-02-23 | Oral gel containing sulfurated amino acid compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI000360A IT1317856B1 (en) | 2000-02-25 | 2000-02-25 | ORAL GEL CONTAINING SULFURATED AMINO ACID COMPOUNDS. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI20000360A0 ITMI20000360A0 (en) | 2000-02-25 |
| ITMI20000360A1 true ITMI20000360A1 (en) | 2001-08-25 |
| IT1317856B1 IT1317856B1 (en) | 2003-07-15 |
Family
ID=11444201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT2000MI000360A IT1317856B1 (en) | 2000-02-25 | 2000-02-25 | ORAL GEL CONTAINING SULFURATED AMINO ACID COMPOUNDS. |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU4647001A (en) |
| IT (1) | IT1317856B1 (en) |
| WO (1) | WO2001062267A2 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995003063A1 (en) * | 1993-07-22 | 1995-02-02 | Esseti S.A.S. Laboratorio Chimico Farmaco Biologico Di A. Ievoli & C. | Oral pharmaceutical compositions comprising reduced glutathion |
| US5906811A (en) * | 1997-06-27 | 1999-05-25 | Thione International, Inc. | Intra-oral antioxidant preparations |
-
2000
- 2000-02-25 IT IT2000MI000360A patent/IT1317856B1/en active
-
2001
- 2001-02-23 AU AU46470/01A patent/AU4647001A/en not_active Abandoned
- 2001-02-23 WO PCT/EP2001/002060 patent/WO2001062267A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| IT1317856B1 (en) | 2003-07-15 |
| AU4647001A (en) | 2001-09-03 |
| WO2001062267A2 (en) | 2001-08-30 |
| ITMI20000360A0 (en) | 2000-02-25 |
| WO2001062267A3 (en) | 2001-12-20 |
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